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Cancer is a collective name for many different diseases caused by a common mechanism: uncontrolled cell division. Despite the redundancy and overlapping levels of cell-cycle control, errors occur. One of the critical processes monitored by the cell-cycle checkpoint surveillance mechanism is the proper replication of DNA during the S phase. Even when all of the cell-cycle controls are fully functional, a small percentage of replication errors (mutations) will be passed on to the daughter cells. If one of these changes to the DNA nucleotide sequence occurs within a gene, a gene mutation results. All cancers begin when a gene mutation gives rise to a faulty protein that participates in the process of cell reproduction. The change in the cell that results from the malformed protein may be minor. Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small, uncorrected errors are passed from parent cell to daughter cells and accumulate as each generation of cells produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumor can result.
The genes that code for the positive cell-cycle regulators are called proto-oncogenes. Proto-oncogenes are normal genes that, when mutated, become oncogenes—genes that cause a cell to become cancerous. Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In most instances, the alteration of the DNA sequence will result in a less functional (or non-functional) protein. The result is detrimental to the cell and will likely prevent the cell from completing the cell cycle; however, the organism is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk, a protein involved in cell-cycle regulation, to be activated before it should be could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undertake further cell divisions, the mutation would not be propagated and no harm comes to the organism. However, if the atypical daughter cells are able to divide further, the subsequent generation of cells will likely accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.
The Cdk example is only one of many genes that are considered proto-oncogenes. In addition to the cell-cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell-cycle checkpoints. Once a proto-oncogene has been altered such that there is an increase in the rate of the cell cycle, it is then called an oncogene.
Tumor Suppressor Genes
Like proto-oncogenes, many of the negative cell-cycle regulatory proteins were discovered in cells that had become cancerous. Tumor suppressor genes are genes that code for the negative regulator proteins, the type of regulator that—when activated—can prevent the cell from undergoing uncontrolled division. The collective function of the best-understood tumor suppressor gene proteins, retinoblastoma protein (RB1), p53, and p21, is to put up a roadblock to cell-cycle progress until certain events are completed. A cell that carries a mutated form of a negative regulator might not be able to halt the cell cycle if there is a problem.
Mutated p53 genes have been identified in more than half of all human tumor cells. This discovery is not surprising in light of the multiple roles that the p53 protein plays at the G1 checkpoint. The p53 protein activates other genes whose products halt the cell cycle (allowing time for DNA repair), activates genes whose products participate in DNA repair, or activates genes that initiate cell death when DNA damage cannot be repaired. A damaged p53 gene can result in the cell behaving as if there are no mutations (Figure 6.3.1). This allows cells to divide, propagating the mutation in daughter cells and allowing the accumulation of new mutations. In addition, the damaged version of p53 found in cancer cells cannot trigger cell death.
CONCEPT IN ACTION
Go to this website to watch an animation of how cancer results from errors in the cell cycle.
Cancer is the result of unchecked cell division caused by a breakdown of the mechanisms regulating the cell cycle. The loss of control begins with a change in the DNA sequence of a gene that codes for one of the regulatory molecules. Faulty instructions lead to a protein that does not function as it should. Any disruption of the monitoring system can allow other mistakes to be passed on to the daughter cells. Each successive cell division will give rise to daughter cells with even more accumulated damage. Eventually, all checkpoints become nonfunctional, and rapidly reproducing cells crowd out normal cells, resulting in tumorous growth.
- a mutated version of a proto-oncogene, which allows for uncontrolled progression of the cell cycle, or uncontrolled cell reproduction
- a normal gene that controls cell division by regulating the cell cycle that becomes an oncogene if it is mutated
- tumor suppressor gene
- a gene that codes for regulator proteins that prevent the cell from undergoing uncontrolled division
The Cell Cycle and Cancer - Essay Example
The cell cycle and cancer Cell cycle is the process by which cells divide or replicate leading to maturity of cells and organs and renewal of worn out cells. This paper seeks to discuss the cell cycle and cancer cell to identify the phase at which, in case of lost control, cancer cells grow. The paper also identifies difference between cancer cell cycle and normal cell cycle.The cell cycle is organized into distinct phases in which specific activities occurs towards cell division or replication.
The first phase, called the G0, is an inert phase that follows a previous cell cycle. G1 phase, where synthesis of “RNA, protein, and organelle” takes place is the second phase that precedes the S phase (Dudek, 2006, p. 123). At the S phase, DNA molecules synthesizes before “ATP synthesis” at the G2 phase (Dudek, 2006, p. 123). The last phase of the cell cycle is the M phase. It is the stage at which cells divide and consists of a number of stages, “prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis” (Dudek, 2006, p. 123). A change in regulation in the cell cycle, leading to cancer, is therefore most likely to occur at the M phase of the cell cycle.
This is because cancer cells results from uncontrollable cell division, yet cell division at the M phase (Hacker, Messer and Benchmann, 2009).There exist a number of differences between normal cell cycle and cancer cell cycle. Normal cell cycle is for example regulated by cell environmental factors while cancer cell cycle is independent. Unlike cancer cell cycle, normal cell cycle is limited to available space. The normal cells also die, unlike cancer cells (Annenberg Foundation, n.d.). ReferencesAnnenberg Foundation. (n.d.). Rediscovering Biology: Molecular to Global Perspectives, a 13-part Multi-media Course for In-service High School Biology Teachers, Annenberg/CPB Guide.
Los Angeles, CA: Annenberg Foundation Dudek, R. (2006). High-Yield™ Cell and Molecular Biology. Baltimore, MD: Lippincott Williams & WilkinsHacker, M., Messer, W. and Benchmann, K. (2009). Pharmacology: Principles and Practice. Burlington, MA: Academic Press
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- Essay on the Introduction to Cancer Cell Proliferation
- Essay on the Features of Cancer Cell Proliferation
- Essay on Growth Factors and the Cancer Cell Cycle
- Essay on Traits Affecting Cancer Cell Proliferation
- Essay on the Role of DNA in Cancer Cell Proliferation
- Essay on Immune System and Cancer Cell Proliferation
- Essay on Molecular Changes in Cancer Cell Proliferation
1. Essay on the Introduction to Cancer Cell Proliferation:
Cancer cells exhibit a number of unusual properties that distinguish them from normal cells. One key property is the ability of cancer cells to proliferate in an uncontrolled fashion, thereby leading to a progressive accumulation of dividing cells without regard to the needs of the body as a whole.
In reality, uncontrolled proliferation is not a single discrete property but rather a collection of traits that together allow cancer cells to escape from the usual restraints on cell prolifera­tion. The net result is that cancer cells circumvent the mechanisms designed to ensure that cells divide only when (and where) new cells are needed.
The normal mechanisms for controlling cell proliferation and see how they behave in cancer cells. Through such a discussion it will become apparent that cancer cells exhibit a distinctive collection of abnormal proper­ties, and while no single property is necessarily seen in every cancer cell, as a group these traits contribute to the “profile” of a typical cancer cell.
Although cancer can result from abnormal proliferation and development of tumours, the key issue is, whether the tumour is benign or malignant. The malignant tumour is capable of invading normal tissues, spreading in the body via circulatory or lymphatic systems and establishing secondary tumours (metastasis).
Most cancers fall into one of three main groups: carcinomas which arise from epithelial cells sarcomas are solid tumours of connective tissues such as muscle, bone, cartilage and fibrous tissue leukemia’s and lymphomas arise from blood forming cells and from cells of the immune systems, respectively. Further classification of tumours is based on tissue of origin and type of cell involved in malignancy.
A key feature of tumours is their development from single cells that begin to proliferate abnormally, hence clones of cells are present in tumours. The development of malignancy in cell clones is a multistep process accompanied by a series of changes in the cells. In general, cancer is considered as a multistep process involving mutation and selection of cells with progressively increasing capacity for proliferation, invasion and metastasis.
The first step, tumour initiation involves genetic alteration leading to abnormal proliferation of a single cell. Tumour progression continues as additional changes take place in tumour cell population. Metastasis occurs when tumour cells invade other organs and establish secondary sites of malignancy.
Substances that can cause cancer are called carcinogens, and include many agents such as radiation, chemicals, viruses and many more. Radiation and chemicals can initiate cancer by damaging DNA and inducing mutations in key target genes.
Some carcinogens contribute to cancer development by stimulating cell proliferation, rather than by inducing mutations. Such compounds are designated tumour promoters because by inducing increased cell division they produce a proliferative cell population during early stages of tumour development.
Classic examples are the phorbol esters that stimulate cell proliferation by activating protein kinase C. Hormones, particularly estrogens, are important as tumour promoters in the development of some human cancers. For example, the uterine epithelium responds to excess estrogen and increases the likelihood of development of endometrial cancer. Some viruses also induce cancer in experimental animals and humans, such as liver cancer and cervical carcinoma in humans.
Cancer cells display features that distinguish them from their normal counterparts. Cancer cells have abnormalities in the mechanisms that regulate normal cell proliferation, differentiation and survival. In culture, cancer cells can be distinguished from normal cells in displaying density- dependent inhibition of cell proliferation. Normal cells continue to divide until they reach a finite cell density.
They then stop dividing and become quiescent, arrested in the G0 stage of the cell cycle. The proliferation of cancer cells is independent of density-dependent inhibition. Such cells do not respond to signals that cause normal cells to cease proliferation.
Instead, tumour cells continue to grow to high cell densities in culture, this behaviour corresponds with their uncontrolled proliferation in vivo. The proliferation of many normal cells is controlled in part, by polypeptide growth factors. Cancer cells have reduced requirement for extracellular growth factors.
Both in vitro and in vivo, growth factor requirements of cancer cells are reduced contributing to unregulated proliferation of tumour cells. In some cases cancer cells produce growth factors that stimulate their own proliferation. Such an abnormal production of a growth factor leads to continuous stimulation of cell division, called autocrine growth stimulation, and makes cancer cells less dependent on growth factors from normal sources.
2. Essay on the Features of Cancer Cell Proliferation:
The concept of uncontrolled proliferation is unique to multicellular organisms. In most single-celled organisms, such as bacteria or yeast, the presence of sufficient nutri­ents in the surrounding environment is the main factor that determines whether cells will grow and divide.
The situation is reversed in multicellular organisms cells are usually surrounded by nutrient-rich extracellular fluids, but the organism as a whole would be quickly destroyed if each cell were to continually grow and divide just because it had access to adequate nutrients. Cancer is a potentially lethal reminder of what happens when cell proliferation continues unabated without being coordinated with the needs of the organism as a whole.
i. Cancer Cells Produce Tumors when Injected into Laboratory Animals:
It is the loss of normal growth control that causes cancer cells to produce a continually growing mass of tissue—in other words, a tumor—but uncontrolled growth does not mean that tumor cells always divide more rapidly than normal cells. Tumors can grow slowly, quickly, or some­where in between. The distinctive feature of tumor growth is not the speed of cell division but its uncontrolled nature.
In contrast to the proliferation of normal cells, where cell division and cell differentiation are kept in proper balance, this finely tuned arrangement is disrupted in tumors and cell division is uncoupled from cell differentiation, thereby leading to a progressive increase in the number of dividing cells.
To determine experimentally whether a particular cell behaves in this way, the cell must be injected into an appropriate host organism to see if a tumor will develop. Experiments involving animal cells are fairly straightfor­ward because the cells can simply be injected into animals of the same genetic type.
The situation with human cells is more complicated. Injecting human cancer cells into other humans for testing purposes would be unethical, and using standard laboratory animals is not reliable: An animal’s immune system is likely to reject human cells because they are of foreign origin.
One way around this obstacle is to inject human cells into mutant strains of mice whose immune systems are unable to attack and destroy foreign cells. When human cancer cells are injected into such immunologically deficient animals, the cells will usually grow into tumors without being rejected.
ii. Cancer Cells Exhibit Decreased Density-Dependent Inhibition of Growth:
Although studying cancer cells in intact organisms is useful for investigating some of the properties of malignant tumors, issues related to the control of cell proliferation are often easier to investigate in cells grown under artificial laboratory conditions. In such cell culture studies, cancer cells are isolated from a tumor and placed in a defined growth medium containing nutrients, salts, and other molecules required for cell growth.
The main reason for studying cells in culture is that this method allows the cells to be observed under carefully controlled conditions where their behavior can be assessed without the complicating effects of secondary factors present in an intact organism.
When most types of normal cells are placed in a culture vessel (test tube, bottle, flask, or dish) and then covered with an appropriate growth medium, they divide until the surface of the container is covered by a single layer of cells. When this monolayer stage is reached, cell movements and cell division both tend to stop.
In the early 1950s, Michael Abercrombie and Joan Heaysman intro­duced the term “contact inhibition” to refer to the decrease in cell motility that occurs when cells make contact with one another in culture. The same term has also been used to refer to the inhibition of cell division that takes place when culture conditions become crowded.
Because of the confusion that can result from the double meaning of this term, the phrase density-dependent inhibition of growth is now routinely used when referring to the inhibition of cell division that occurs in crowded cultures.
In contrast to normal cells, cancer cells do not stop dividing when they reach the monolayer stage. Instead, they continue to divide and gradually pile up on top of one another, forming multilayered aggregates (Figure 1). In other words, cancer cells are less susceptible to density- dependent inhibition of growth than are their normal counterparts.
The relationship between the tendency of cancer cells to grow to high population densities in culture and their ability to form tumors has been investigated using cancer cells that differ in their susceptibility to density- dependent inhibition of growth.
Cells that are very sensitive to density-dependent inhibition can be produced by growing cells under un-crowded conditions every time the population density increases and crowding is imminent, the cells are simply diluted and transferred to a new culture flask.
Cells obtained in this way will not grow to high popu­lation densities in culture. Alternatively, cell populations that are insensitive to density-dependent inhibition of growth can be produced by consistently growing cells in overcrowded conditions. Such cell populations become less susceptible to density-dependent inhibition of growth, reaching much higher population densities before cell divi­sion stops.
When these different cell populations are tested for their ability to produce tumors in mice, tumor-forming ability is found to be directly related to the loss of density- dependent growth control in other words, cells capable of growing to the highest population densities in culture are most effective at forming tumors in animals (Figure 2).
iii. Cancer Cell Proliferation is Anchorage-Independent:
Another way in which the proliferation of cancer cells differs from that of normal cells involves the requirement for anchorage. Most normal cells will not proliferate if they are put in a liquid growth medium and shaken or stirred to keep them in suspension, nor will they prolif­erate if they are placed in a semisolid medium such as soft agar. When they are provided with an appropriate solid surface to which they can adhere, however, the cells will attach to the surface, spread out, and begin to proliferate (Figure 3).
The growth of normal cells is therefore said to be anchorage-dependent. In contrast, most cancer cells grow well not just when they are anchored to a solid surface, but also when they are suspended in a liquid or semisolid medium. The growth of cancer cells is therefore said to be anchorage-independent.
In intact organisms, the requirement that cells be anchored before they can reproduce is met by binding cells to the extracellular matrix, an insoluble meshwork of protein and polysaccharide fibers that fills the spaces between neighboring cells. Cells attach themselves to the extracellular matrix through cell surface proteins called integrins, which bind to molecules present in the matrix.
Apoptotic cell death triggered by lack of contact with the extracellular matrix is called anoikis (from the Greek word for “homelessness”). Anoikis is an important safeguard for maintaining tissue integrity because it prevents normal cells from floating away and setting up housekeeping in another tissue.
The lack of anchorage simply causes cells to commit suicide along the way. Cancer cells are not subject to this normal safeguard because they are anchorage-independent and so can spread to distant sites without self-destructing.
Considerable evidence suggests that anchorage- independent growth exhibited by cells grown in culture is related to their ability to form tumors. One set of studies involved cells with many of the traits of cancer cells, including decreased density-dependent inhibition of growth, low requirements for external growth factors, and anchorage-independent growth.
Single cells were isolated from the original population and allowed to proliferate separately, thereby creating a series of clones, which are individual cell populations each derived from the proliferation of a single cell.
Careful analysis of the clones revealed that some of them had lost one or more of the initial properties. When the ability of these clones to produce tumors in animals was compared, anchorage- independent growth was the only property consistently retained by all the clones that could produce tumors. In other words, the ability to form tumors appeared to require cells whose growth in culture is anchorage-independent.
This connection between anchorage-independent growth and tumor formation is not without its exceptions, however. Some cells exposed to cancer-causing chemicals have been found to exhibit anchorage-independent growth in culture but do not form tumors when injected into animals.
In addition, studies involving a long-term culture of mouse cells, which were anchorage-dependent and unable to form tumors in animals, showed that the cells could acquire the capacity to form tumors if they were attached to glass beads prior to being implanted in mice. Such observations indicate that despite its general association with the ability to form tumors, anchorage- independent growth in culture is not an absolute prerequisite for tumor formation.
iv. Mechanisms for Replenishing Telomeres make Cancer Cells Immortal:
One of the most striking differences between normal cells and cancer cells involves their reproductive lifespans. When normal cells are grown in culture, they usually divide for only a limited number of times. For example, human fibroblasts—a cell type whose behavior has been extensively studied—divide about 50 to 60 times when placed in culture and then stop dividing, undergo a variety of degenerative changes, and may even die (Figure 4).
Cancer cells exhibit no such limit and continue dividing indefinitely, behaving as if they were immortal. A striking example is provided by HeLa cells, which were obtained from a malignant tumor of the uterus arising in a woman named Henrietta Lacks (hence the name “HeLa” cells).
After removing the tumor in a cancer operation performed in 1951, doctors placed some of its cells in culture. The cultured cells began to grow and divide and have continued to do so for more than 50 years, dividing more than 18,000 times with no signs of stopping.
Why are cancer cells capable of reproducing indefi­nitely in culture, whereas most normal human cells divide no more than 50 or 60 times? The answer is related to the mechanism by which cells replicate their DNA. Each time a cell divides, its chromosomal DNA molecules must be duplicated so that a complete set of genetic instructions can be distributed to each of the two cells produced by cell division.
However, the biochemical mechanism responsible for DNA replication has an inherent limitation- The enzymes that replicate DNA are unable to copy the very end of a linear DNA molecule, perhaps the final 50 to 100 nucleotides or so.
As a result, each time a DNA molecule is replicated it is in danger of losing a small amount of DNA at each of its two ends. If this trend were to continue indefinitely, DNA molecules would become shorter and shorter until there was nothing left, and we would not be here today!
To solve this so-called end-replication problem, cells place a special type of DNA sequence at the two ends, or telomeres, of each chromosomal DNA molecule. The special DNA consists of multiple copies of a short base sequence repeated over and over again. For example, in humans the six-base sequence TTAGGG is repeated about 2500 times in a row at the ends of each chromosomal DNA molecule at birth.
These telomere sequences are pro­tected by telomere capping proteins, and the DNA also loops back upon itself to protect the end of the chromo­some even further (Figure 5). Unlike genes, whose DNA base sequences code for useful products, telomeric DNA does not code for anything but simply consists of the same six-base sequence repeated again and again.
Placing such noncoding telomere DNA at the ends of each chromo­some ensures that a cell will not lose any important genetic information when DNA molecules are shortened slightly during replication.
Since telomeres get shorter with each cell division, they provide a counting device for tracking how many times a cell has divided. If a cell divides too many times, the telomeres become extremely short and are in danger of disappearing entirely. When this happens, the telo­meric DNA becomes too short to bind telomeric capping proteins or generate a loop, exposing a bare end of double-stranded DNA.
Such unprotected DNA ends are very unstable and often fuse with each other, creating joined chromosomes that tend to become fragmented and separate improperly at the time of cell division.
In normal cells, such a hazardous outcome is prevented by a mechanism in which the unprotected DNA at the end of a chromosome triggers a pathway that halts cell division or triggers cell death. This pathway helps protect organisms from any inappropriate, excessive proliferation of adult cells.
But what happens with cells that must divide for pro­longed periods of time, such as the germ cells that give rise to sperm and eggs or the bone marrow cells that continu­ally produce new blood cells? Such cells prevent excessive telomere shortening by producing an enzyme called telomerase, which adds new copies of the telomeric repeat sequence to the ends of existing DNA molecules.
The telomerase-catalyzed addition of new telomere repeat sequences prevents the gradual decline in telomere length that would otherwise occur at both ends of a chromosome during DNA replication. The presence of telomerase therefore allows cells to divide indefinitely without telomere shortening.
How do the preceding considerations apply to cancer cells? If cancer cells behaved like most normal cells, which do not produce telomerase, repeated cell divisions would cause the telomeres to become unusu­ally short and the cells would eventually be destroyed. Most cancer cells circumvent this problem by activating the gene that produces telomerase, thereby causing new copies of the telomeric repeat sequence to be continually added to the ends of their DNA molecules.
A few cancer cells activate an alternative mechanism for maintaining telomere sequences that involves the exchange of sequence information between chromo­somes. By one mechanism or the other, cancer cells maintain telomere length above a critical threshold and can therefore divide indefinitely.
3. Essay on Growth Factors and the Cancer Cell Cycle:
We have now seen that cancer cells differ from most normal cells in that they grow to high population densities in culture, exhibit anchorage-independent proliferation, and divide indefinitely because they possess mechanisms for maintaining telomere length.
These traits play an important permissive role in allowing cancer cells to continue dividing, but they do not actually cause cells to divide. The driving force for ongoing proliferation can be traced to abnormalities in the signalling systems that control cell division, the topic to which we now turn.
i. Cancer Cells Exhibit a Decreased Dependence on External Growth Factors:
The cells of multicellular animals do not normally divide unless they are stimulated to do so by an appropriate signalling protein known as a growth factor. For example, if cells are isolated from an organism and placed in a culture medium containing nutrients and vitamins, they will not proliferate unless an appropriate growth factor is also provided.
Growth media are therefore commonly supplemented with blood serum, which contains several growth factors that stimulate cell proliferation. One is platelet-derived growth factor (PDGF), a protein pro­duced by blood platelets that stimulates the proliferation of connective tissue cells and smooth muscle cells. Another growth factor in blood serum, called epidermal growth factor (EGF), is also widely distributed in tissues.
Some growth factors, such as EGF, stimulate the growth of a wide variety of cell types, whereas others act more selec­tively on particular target cells. Growth factors play important roles in stimulating tissue growth during embryonic and early childhood development, and during wound repair and cell replacement in adults.
For example, release of the growth factor PDGF from blood platelets at wound sites is instrumental in stimulating the growth of tissue required for wound healing.
Growth factors exert their effects by binding to receptor proteins located in the plasma membrane that forms the outer boundary of all cells. Different cell types have different plasma membrane receptors and hence differ in the growth factors to which they respond (Figure 6).
The binding of a growth factor to its corre­sponding receptor triggers a multistep cascade in which a series of signal transduction proteins relay the signal throughout the cell, triggering molecular changes that stimulate (or occasionally inhibit) cell growth and divi­sion.
Cells will not normally divide unless they are stimulated by an appropriate growth factor, but this restraint is circumvented in cancer cells by various mech­anisms that create a constant signal to divide, even in the absence of growth factors.
Some cancer cells achieve this autonomy by pro­ducing their own growth factors, thereby causing cell proliferation to be stimulated without the need for growth factors produced by other cells. Similarly, other cancer cells possess abnormal receptors that are perma­nently activated, causing cell division to occur whether growth factors are present or not.
Cancer cells may also produce excessive quantities or hyperactive versions of other proteins involved in relaying signals from cell surface receptors to the cell division machinery in the cell’s interior. The net effect of the preceding types of alterations is to cause the pathways that signal cell proliferation to become hyperactive or even autonomous, functioning in the absence of growth factors.
ii. The Cell Cycle is Composed of G1, S, G2, and M Phases:
To understand how pathways activated by growth factors ultimately cause a cell to divide, it is first necessary to review the events associated with cell division. In cells that are dividing, the nuclear DNA molecules must be duplicated and then distributed in a way that ensures that the two new cells each receive a complete set of genetic instructions. In preparing for and accomplishing these tasks, cells pass through a series of discrete stages called G1 phase, S phase, G2 phase, and M phase.
The four phases are collectively referred to as the cell cycle (Figure 7).
G1—the first phase to occur after a cell has just divided—vanes the most in length. A typical G1 phase lasts about 8 to 10 hours in human cells, but rapidly dividing cells may spend only a few minutes or hours in Gl. Conversely, cells that divide very slowly may become arrested in G1 and spend weeks, months, or even years in the offshoot of G1 called the G0 phase (G zero). After completing G1, the cell enters S phase, a period of roughly 6 to 8 hours when the chromosomal DNA molecules are replicated.
Next comes G2 phase, where 3 to 4 hours are spent making final preparations for cell division. The cell then enters M phase, which takes about an hour to physically divide the original cell into two new cells. The main events of M phase include division of the nucleus, or mitosis, followed by division of the cytoplasm, or cytokinesis. The two newly formed cells then enter again into G1 phase and begin preparations for another round of cell division.
Taken together, the G1, S, and G2 phases are collec­tively referred to as interphase. Besides providing the time needed for a cell to make copies of its DNA molecules, interphase is also a period of cell growth. Interphase occu­pies about 95% of a typical cell cycle whereas the actual process of cell division (M phase) only takes about 5%.
Overall, the time occupied by the various stages of the cycle allows a typical human cell to divide as often as once every 18 to 24 hours. However, the various cell types that make up the body differ greatly in cycle time, ranging from cells that divide very rapidly and continuously to differentiated cells that do not divide at all.
The variability observed in rates of cell division means that mechanisms must exist for regulating progression through the cell cycle. A key control point has been identified during late G1, where the cell cycle is usually halted in cells that stop dividing. For example, the division of cultured cells can be slowed down or stopped by allowing the cells to run out of either nutri­ents or growth factors, or by adding inhibitors of vital processes such as protein synthesis.
In such cases, the cell cycle is halted in late GI at a point referred to as the restriction point. Under normal conditions, the ability to pass through the restriction point is governed mainly by the presence of growth factors.
Cells that successfully move through the restriction point are committed to S phase and the remainder of the cell cycle, whereas those that do not pass the restriction point enter into GO and reside there for variable periods of time, awaiting a signal that will allow them to re-enter G1 and pass through the restriction point.
iii. Progression through the Cell Cycle is Driven by Cyclin-Dependent Kinases:
At the molecular level, passage through the restriction point and other key points in the cell cycle is controlled by proteins known as cyclin-dependent kinases (Cdks). Cdks are protein kinases, a term referring to a class of enzymes that regulate the activity of targeted protein mol­ecules by catalyzing their phosphorylation (attachment of phosphate groups to the targeted proteins).
During protein phosphorylation reactions, the phosphate group is donated to the targeted protein by the high-energy com­pound ATP (adenosine triphosphate), which is converted to ADP (adenosine diphosphate) during the reaction. Cells contain dozens of different protein kinases, each designed to regulate the activity of a specific group of proteins by catalyzing their phosphorylation.
As the name implies, a cyclin-dependent kinase (Cdk) only exhibits protein kinase activity when it is bound to another type of protein called a cyclin. Progression through the cell cycle is controlled by several Cdks that bind to different cyclins, thereby creating a variety of Cdk- cyclin complexes.
Cyclins involved in regulating the progression from G1 to S phase are called G1 cyclins, and the Cdk molecules to which they bind are known as G1 Cdks. Likewise, cyclins involved in regulating passage from G2 into M phase are called mitotic cyclins, and the Cdk molecules to which they bind are known as mitotic Cdks. Cdk-cyclin complexes act by phosphorylating specific target proteins whose actions are required for various stages of the cell cycle.
How do Cdk-cyclin complexes ensure that passage through key points in the cell cycle only occurs at the appropriate time? In addressing this question, we will briefly consider the behavior of the mitotic Cdk-cyclin complex (mitotic Cdk bound to mitotic cyclin), which regulates passage from G2 to M phase.
Mitotic cyclin is continuously synthesized throughout interphase and grad­ually increases in concentration during G1, S, and G2, eventually reaching a concentration that is high enough to bind to mitotic Cdk (Figure 8).
The resulting mitotic Cdk- cyclin triggers passage from G2 into M phase by phosphorylating key proteins involved in the early stages of mitosis. For example, proteins phosphorylated by mitotic Cdk-cyclin trigger nuclear envelope breakdown, chromo­some condensation, and mitotic spindle formation.
Shortly thereafter, mitotic cyclin is targeted for degrada­tion by an enzyme called the anaphase-promoting complex and mitotic Cdk becomes inactive, triggering the exit from mitosis. During the next cell cycle, mitosis cannot be triggered until the concentration of mitotic cyclin builds up again.
Besides being regulated by the availability of cyclins, the activity of the various Cdk-cyclin complexes is controlled by reactions in which Cdk molecules are altered by phosphorylation (addition of phosphate groups) and dephosphorylation (removal of phosphate groups).
Figure 9 illustrates how the mitotic Cdk-cyclin complex is regulated in this way:
In step ①, the binding of mitotic cyclin to mitotic Cdk creates a complex that is initially inactive. Before it can trigger passage from G2 into M phase, the complex requires the addition of an activating phosphate group to a particular amino acid of the Cdk molecule. Prior to adding this phosphate, however, inhibitory phosphate groups are first attached to the Cdk molecule at two other locations, preventing the Cdk from functioning (step ②). The activating phosphate group, highlighted with yellow in step ③, is then added. The last step in the activation sequence is the removal of the inhibiting phosphates by a specific enzyme called a protein phosphatase (step ④).
Once the phosphatase begins removing the inhibiting phosphates, a positive feedback loop is set up: The activated Cdk-cyclin complex generated by this reaction stimulates the phosphatase, thereby causing the activation process to proceed more rapidly. After being activated, the mitotic Cdk-cyclin complex triggers passage from G2 into M phase by catalyzing the phosphorylation of proteins required for the onset of mitosis.
Growth Factor Signaling Pathways Act on the Restriction Point by Stimulating Phosphorylation of the Rb Protein:
Now that Cdk-cyclins have been introduced, we can explain how growth factors exert their control over cell proliferation. If normal cells are placed in a culture medium containing nutrients and vitamins but no growth factors, the cells become arrested at the restriction point. Subsequent addition of growth factors is sufficient to cause the cells to start dividing again.
How do growth factors cause G1-arrested cells to resume progression through the cell cycle? The binding of a growth factor to its corresponding cell surface receptor causes the receptor to become activated, and the activated receptor then triggers a complex pathway of reactions involving dozens of different cytoplasmic and nuclear molecules that relay the signal throughout the cell. Here we are concerned only with the question- How do these pathways impinge on the cell cycle and cause cells to pass through the restriction point and into S phase?
The answer to this question is that growth factor signaling pathways trigger the production of Cdk-cyclins that in turn catalyze the phosphorylation of target pro­teins required for the transition into S phase.
A key target is the Rb protein, a molecule that normally restrains cell proliferation by preventing passage through the restric­tion point (Figure 10). After Cdk-cyclin phosphorylates Rb, it can no longer exert this inhibitory influence and cells are free to pass through the restriction point and into S phase.
Checkpoint Pathways Monitor for DNA Replication, Chromosome-to-Spindle Attachments, and DNA Damage:
The ability of growth factors to promote passage through the restriction point by stimulating the production of Cdk-cyclins that phosphorylate Rb is just one example of how the cell cycle is controlled by external and internal factors that determine whether or not a cell should divide.
Another type of cell cycle control involves a series of checkpoint pathways that prevent cells from proceeding from one phase to the next before the preceding phase has been properly completed. These checkpoint pathways monitor conditions within the cell and transiently halt the cell cycle at various points if conditions are not suitable for continuing (Figure 11).
One such mechanism, called the DNA replication checkpoint, monitors the state of DNA replication to ensure that DNA synthesis has been completed prior to proceeding with cell division. If DNA replication is not complete, the cell cycle is halted to allow DNA replication to be finished prior to entering M phase. The existence of the DNA replication checkpoint has been demonstrated by treating cells with inhibitors of DNA synthesis.
Under such conditions the final dephosphorylation step involved in activating mitotic Cdk-cyclin (step 4 in Figure 9) is blocked through a series of events triggered by proteins associated with replicating DNA. The resulting lack of active mitotic Cdk-cyclin halts the cell cycle at the end of G2 until DNA replication is completed.
A second checkpoint mechanism, called the spindle checkpoint, acts between the metaphase and anaphase stages of mitosis, the point where the two duplicate sets of chromosomes are about to be parceled out to the two new cells being formed by the process of cell division.
At the end of metaphase, the two sets of chromosomes are nor­mally lined up at the center of the mitotic spindle, a structure composed of microtubules that attach to the chromosomes and eventually pull them into the two newly forming cells. Before chromosome movement begins (the event that marks the beginning of anaphase), the spindle checkpoint mechanism is invoked to make certain that the chromosomes are all properly attached to the spindle.
If the chromosomes are not completely attached, the cell cycle is temporarily halted at this point to allow the process to be completed. In the absence of such a control mechanism for monitoring chromosome- to-spindle attachments, there would be no guarantee that each of the newly forming cells would receive a complete set of chromosomes.
A third type of checkpoint is used to prevent cells with damaged DNA from proceeding through the cell cycle. In this case, a series of DNA damage checkpoints monitor for DNA damage and halt the cell cycle at various points—including late G1, S, and late G2—by inhibiting different Cdk-cyclin complexes. A molecule called the p53 protein plays a central role in these checkpoint path­ways.
In the presence of damaged DNA, the p53 protein accumulates and triggers cell cycle arrest to provide time for the DNA damage to be repaired. If the damage cannot be repaired , p53 may also trigger cell death by apoptosis. The ability of p53 to trigger cell cycle arrest or cell death prevents cells with damaged DNA from proliferating and passing the damage on to succeeding generations of cells.
iv. Cell Cycle Control Mechanisms are Defective in Cancer Cells:
The preceding discussion of cell cycle control mechanisms has focused largely on the behavior of normal cells. How do these principles apply to the behavior of cancer cells, which grow and divide in an uncontrolled fashion? We have already seen that cancer cells often produce excessive amounts (or hyperactive versions) of growth factors, receptors, or other components of growth factor signaling pathways.
Such alterations cause an excessive production of the Cdk-cyclins that phosphorylate the Rb protein, thereby providing an ongoing stimulus for cells to pass through the restriction point and divide.
The situation is made even worse by the fact that the restriction point often fails to function properly in cancer cells. When cancer cells are grown under suboptimal conditions—for example, insufficient growth factors, high cell density, lack of anchorage, or inadequate nutrients— that would cause normal cells to become arrested at the restriction point, cancer cells continue to grow and divide without halting at the restriction point.
In other words, cancer cells exhibit a loss of restriction point control. Under extremely adverse conditions, such as severe nutritional deprivation, cancer cells die at random points in the cell cycle rather than arresting at the restriction point.
In addition to the loss of restriction point control, cancer cells frequently exhibit defects in the checkpoint pathways that would otherwise respond to internal problems, such as DNA damage, by halting the cell cycle. Failures in checkpoint pathways, along with the loss of restriction point control, allow cancer cells to continue proliferating under conditions in which the cell cycle of normal cells would stop.
The difference between cell cycle regulation in cancer cells and normal cells can be exploited experimentally using drugs that act at different points in the cycle. For example, staurosporine is a drug that halts the cell cycle at the restriction point, and camptothecin is a drug that kills cells in S phase by disrupting DNA synthesis.
As shown in Figure 12, when cultures of normal cells are exposed to staurosporine followed by camptothecin, the stauro­sporine halts cells at the restriction point and thus prevents them from entering S phase and being killed by camptothecin. If the two drugs are later removed, the cells again pass through the restriction point and resume dividing.
With cancer cells, the results are quite different. Staurosporine does not stop cancer cells in G1 because of the loss of restriction point control, so the cells proceed into S phase and are killed by camptothecin. This discovery that cancer cells can be killed by drug combinations that do not harm normal cells raises the possibility that similar strategies might eventually be devised for treating cancer patients.
4. Essay on Traits Affecting Cancer Cell Proliferation:
An unrestrained cell cycle, however, is not the only factor that contributes to the uncontrolled produc­tion of tumor cells. The number of cells that accumulate in a growing tumor is determined not just by the rate at which cells divide, but also by the rate at which they die. As in the case of the cell cycle, cell death is controlled by pathways that fail to function properly in cancer cells, thereby permitting the survival of cells that would other­wise be destroyed.
Traits that affect cancer cell proliferation by affecting the cell cycle and cell division:
i. Apoptosis is a Mechanism for Eliminating Un-Needed or Defective Cells:
Cell death seems like it would be a random, uncontrolled, undesirable event. In reality, organisms possess a precisely regulated genetic program for inducing individual cells to kill themselves when appropriate. This suicide program, called apoptosis, is designed to prevent the accumulation of unneeded or defective cells that arise during embryonic development as well as later in life.
For example, you might think that embryos would produce only the exact number of cells they need, but that is hardly the case. Embryos produce many extra cells that will not form part of the final organ or tissue in which they arise. A case in point is the human hand, which starts off as a solid mass of tissue.
The fingers are then carved out of the tissue by a process in which apoptosis is invoked to destroy the cells that would otherwise form a webbing between the fingers. Apoptosis is also important in the newly forming brain, where extra nerve cells created during embryonic devel­opment are destroyed by apoptosis during early infancy as the final network of nerve connections is established.
Another function of apoptosis is to rid the body of defective cells. For example, cells infected with viruses often invoke apoptosis to trigger their own destruction, thereby limiting reproduction and spread of the virus. Cells with damaged DNA may also trigger apoptosis, espe­cially if the damage cannot be repaired. This ability to destroy genetically damaged cells is especially useful in helping avert the development of cancer.
ii. Apoptosis is Carried Out by a Caspase Cascade:
Apoptosis is a unique type of cell death, quite different from what happens when cells are destroyed by physical injury or exposure to certain poisons. In response to such nonspecific damage, cells undergo necrosis, a slow type of death in which cells swell and eventually burst, spewing their contents into the surrounding tissue. Necrosis often results in an inflammatory reaction that can cause further cell destruction, which makes it potentially dangerous.
In contrast, apoptosis kills cells in a quick and neat fashion without causing damage to surrounding tissue. The process involves a carefully orchestrated sequence of intracellular events that systematically dismantle the cell (Figure 13). The first observable change in a cell under­going apoptosis is cell shrinkage. Next, small bubble-like protrusions of cytoplasm (“blebs”) start forming at the cell surface as the nucleus and other cellular structures begin to disintegrate.
The chromosomal DNA is then degraded into small pieces and the entire cell breaks apart, forming small fragments known as apoptotic bodies. Finally, the apoptotic bodies are swallowed up by neigh­boring cells called phagocytes, which are specialized for ingesting foreign matter and breaking it down into mole­cules that can be recycled for other purposes.
Apoptosis is carried out by a series of protein- degrading enzymes known as caspases. Normally, caspases reside in cells in the form of inactive precursors called procaspases. When a cell receives a signal to commit suicide, an initiating member of the procaspase family is converted into an active caspase.
The activated caspase catalyzes the conversion of another procaspase into an active caspase, which activates yet another procaspase, and so forth. Some members of this caspase cascade destroy key cellular proteins.
For example, one caspase degrades a protein involved in maintaining the structural integrity of the nucleus, and another caspase degrades a protein whose destruction releases an enzyme that causes frag­mentation of chromosomal DNA. Hence, the net effect of the caspase cascade is the activation of a series of enzymes that degrade the cell’s main components, thereby leading to an orderly disassembly of the dying cell.
iii. Cancer Cells are able to Evade Apoptosis:
The presence of procaspases within a cell means that the cell is programmed with the seeds of its own destruction, ready to commit suicide quickly if so required. It is therefore crucial that the mechanisms employed to control caspase activation are precisely and carefully regulated and are called into play only when there is a legitimate need to destroy an unneeded or defective cell. There are two main routes for activating the caspase cascade, an external pathway and internal pathway (see Figure 13, bottom).
The external pathway is employed when a cell has been targeted for destruction by other cells in the surrounding tissue. In such cases, neighboring cells produce molecules that transmit a “death signal” by binding to death receptors present on the outer surface of the targeted cell.
The activated death receptors then interact with, and trigger activation of, initiator procaspase molecules located inside the cell, thereby starting the caspase cascade.
The internal pathway—a pathway that is particularly relevant to the field of cancer biology—functions mainly in the destruction of cells that have sustained extensive DNA damage. Although cells possess several mechanisms for repairing DNA damage, in many cases it is safer to destroy cells in which there is any question about the integrity of their DNA.
In this way, the potential danger posed by the proliferation of mutant cells is minimized. The protein plays a pivotal role in the mechanism by which, apoptosis is induced in cells that have sustained extensive DNA damage. The presence of damaged DNA triggers the accumulation of the p53 protein, which in turn stimulates the production of pro­teins that alter the permeability of mitochondrial membranes. The altered mitochondria then release a group of proteins, especially cytochrome c, that activate the caspase cascade and thereby cause the cell to be destroyed by apoptosis.
Given that killing defective cells is one of the main functions of apoptosis, why aren’t cancer cells destroyed?
After all, cancer cells fit the definition of defective cells- They grow in an uncontrolled fashion and, as you will learn shortly, possess DNA mutations and other chromo­somal abnormalities. The reason cancer cells are still able to survive is that they have developed ways of avoiding apoptosis. One common mechanism is that many cancer cells have mutations that disable the gene coding for thereby disrupting the main internal pathway for trig­gering apoptosis.
Mutations the gene are the most common genetic defect observed in human cancers. Other genes involved in apoptosis may also be altered in cancer cells. For example, the gene coding for the Bcl2 protein, a naturally occurring inhibitor of apoptosis, is altered in some cancers in a way that causes too much Bcl2 to be produced, thereby blocking apoptosis.
5. Essay on the Role of DNA in Cancer Cell Proliferation:
i. Cancer Cells are Genetically Unstable and often Exhibit Gross Chromosomal Abnormalities:
The number of mutations accumulated by cancer cells is generally greater than would be expected in comparable populations of normal cells. This tendency to accumulate an excessive number of mutations and other kinds of DNA damage is called genetic instability.
As we have just seen, one reason for genetic instability is that cancer cells may exhibit defects in DNA repair that diminish their ability to correct DNA mutations. The net result is elevated mutation rates that can be hundreds or even thousands of times higher than normal.
Another factor is that cancer cells often exhibit defects in the pathways that trigger apoptosis in response to DNA damage. As a result, cells that have incurred extensive DNA damage that is beyond repair do not self-destruct by apoptosis as would normally be expected.
Mistakes in the handling of chromosomes during cell division also contribute to genetic instability by creating gross abnormalities in chromosome structure and number. Normally, human cells other than sperm and eggs possess 23 pairs of chromosomes, or a total of 46 chromosomes per cell.
Such cells are said to be diploid (from the Greek word diplous, meaning “double”) because two copies of each type of chromosome are present, one derived from each parent. In contrast, cancer cells are often aneuploid, which means that they possess an abnormal number of chromosomes. Aneuploidy usually involves both the loss of some chromosomes and extra copies of others.
In addition to an abnormal number of chromosomes, cancer cells often possess chromosomes whose structure has been altered by deletions (loss of long stretches of DNA) and translocations (exchange of long stretches of DNA between different chromosomes).
One of the first chromosomal abnormalities to be consistently observed in any type of cancer was the Philadelphia chromosome, an oddly shaped chromosome present in the cancer cells of nearly 90% of all individuals with chronic myelogenous leukemia (Figure 19).
The Philadelphia chromosome is produced by DNA breakage near the ends of chromosomes 9 and 22, followed by reciprocal exchange of DNA between the two chromosomes. A similar phenomenon is observed in Burkitt’s lymphoma, a cancer of human lymphocytes, in which segments derived from chromosomes 8 and 14 are exchanged. In both of these situations, scientists have iden­tified the specific gene whose alteration by chromosomal translocation leads to cancer.
Abnormalities in chromosome number and structure contribute to cancer development in various ways. Some crucial genes may be lost, other genes may become overactive, and yet other genes may become structurally altered and produce abnormal products. In contrast to mutations involving short stretches of DNA, gross chromosomal defects are extremely difficult, if not impossible, to repair.
The best solution for cells exhibiting such chromosomal problems is suicide by apoptosis. However, if cells have genetic defects that disrupt the pathways responsible for carrying out apoptosis, self- inflicted suicide is not an option and the genetically damaged cells will continue to proliferate.
ii. DNA Mutations can Lead to Cancer:
The presence of gross chromosomal defects in cancer cells was first reported almost a hundred years ago, and the smaller changes in base sequence that occur in the DNA of cancer cells have also been recognized for many years.
For a long time, it was difficult to distinguish whether such DNA abnormalities are responsible for causing cancer or whether they simply represent secondary changes that arise because cancer cells are dividing in a rapid, uncon­trolled fashion. In other words, the question was much like the classic problem of “which came first, the chicken or the egg?” Do DNA abnormalities cause cancer to arise, or does cancer cause DNA abnormalities to arise?
This issue was finally resolved in the early 1980s, when DNAs isolated from several different human cancers were shown to cause cancer under laboratory conditions. In the first studies of this type (Figure 20), DNA was extracted from human bladder cancer tissue and applied to a culture of normal mouse cells under experimental conditions that favor incorporation of the foreign DNA into the cells’ chromosomes.
The uptake of foreign DNA by cells under such artificial laboratory conditions is called transfection. In response, some of the cultured mouse cells began to proliferate excessively. When these proliferating cells were injected back into mice, the animals developed cancer.
Similar experiments using DNA extracted from normal human tissues did not produce mouse cells capable of forming tumors. It was therefore concluded that DNA obtained from human bladder cancer contains gene sequences, not present in normal DNA, that are capable of causing cancer.
Similar results were subsequently obtained using DNA isolated from other human cancers. Such studies have facilitated the identification of a number of specific genes that contribute to cancer development.
6. Essay on Immune System and Cancer Cell Proliferation:
The ability of cancer cells to proliferate in an uncontrolled fashion, combined with their capacity to spread through the body, makes them a potentially lethal hazard. Are any of the body’s normal defense mechanisms capable of protecting against such a threat? The immune system is designed to defend against infection by potentially harmful agents, such as bacteria, viruses, fungi, parasites, and it also attacks foreign tissues and cells.
Is the immune system also capable of recognizing cancer cells, and if so, how does cancer cells frequently manage to thrive despite the immune system? In addressing these questions, let us start by reviewing the basic mechanisms involved in an immune response.
i. Immune Responses are Carried Out by B Lymphocytes, T Lymphocytes, and NK Cells:
Molecules capable of provoking an immune response are referred to as antigens. To function as an antigen, a sub­stance must be recognized as being “foreign”—that is, different from molecules normally found in a person’s body. The more a molecule differs in structure from normal tissue constituents, the greater the intensity of the immune response mounted against that substance.
Antigens also need to be susceptible to degradation and processing by cells. This requirement explains why non-degradable foreign materials, such as stainless steel pins and plastic valves, can be surgically implanted into humans without eliciting an immune response. To trigger an efficient immune response, an antigen must be degraded and processed by specialized antigen-presenting cells that “present” antigens to cells of the immune system in a way designed to activate an immune response.
Macrophages and dendritic cells are among the most commonly encountered antigen-presenting cells. As shown in Figure 21, antigens engulfed by these cells are degraded into small fragments that eventually become bound to cell surface proteins called major histocompatibility complex (MHC) molecules. When an antigen fragment bound to an MHC molecule is present at the surface of an antigen- presenting cell, the MHC-antigen complex stimulates cells called lymphocytes to mount an attack against that partic­ular antigen.
The stimulated lymphocytes attack foreign antigens in two different ways. One group of lymphocytes, called B lymphocytes, produce proteins called antibodies, which circulate in the bloodstream and penetrate into extracellular fluids, where they bind to the foreign antigen that induced the immune response. Another group of lymphocytes, called cytotoxic T lymphocytes (CTLs), bind to cells exhibiting foreign antigens on their surface and kill the targeted cells by causing them to burst.
In addition to B and T lymphocytes, a small fraction of the total lymphocyte population consists of natural killer (NK) cells that possess the intrinsic ability to recognize and kill certain kinds of tumor cells (as well as virus-infected cells).
In contrast to a typical immune response involving antibody formation or cytotoxic T lymphocytes, NK cells do not need to recognize a specific antigen before attacking a target cell. Instead, they are programmed to attack a broad spectrum of abnormal cells in a relatively indiscrim­inate fashion, while leaving normal cells unharmed.
ii. Some Cancer Cells Possess Antigens that Trigger an Immune Response:
Because so many people develop cancer, it is clear that the ability of NK cells to attack tumors is often overwhelmed.
A more powerful and efficient immune response requires the participation of cytotoxic T lymphocytes, whose killing activity is selectively directed at cells containing a specific antigen. For cytotoxic T lymphocytes to become involved, however, they need to recognize an antigen as being foreign or abnormal.
The question of whether cancer cells exhibit unique antigens that can elicit such an immune response has had a long and controversial history. Part of the difficulty in reaching a consensus arises because cancers exhibit a variety of antigenic changes. In human melanomas, for example, at least three classes of antigens have been detected.
Antigens of the first type are specific both for melanomas and for the person from whom a particular melanoma is obtained. Antigens of the second type are specific for melanomas but not for the particular person who has the melanoma. Antigens of the two preceding types cannot be detected in normal cells and are therefore examples of tumor-specific antigens.
Antigens of the third type are present in both normal and melanoma cells, although their concentration in melanoma cells is greater. Such antigens which are present in higher concentration in a tumor but are not unique to tumors are more accu­rately referred to as tumor-associated antigens.
The distinction between tumor-specific and tumor- associated antigens is sometimes difficult to make. For example, a group of molecules called MAGE antigens are expressed in melanomas and several other cancers but not in most normal tissues. The MAGE antigens are therefore close to being “tumor-specific”, and an immune response directed against them would be expected to be reasonably selective, causing minimum damage to normal tissues.
Other tumor-associated antigens, such as the prostate-specific antigen (PSA) produced by prostate cancer cells, are unique to a specific tissue. Although antigens of this type are produced by normal cells as well, an immune response directed against them would be relatively selective in that it is only directed against a single tissue.
Antigens that are genuinely tumor-specific occur in cancers that produce structurally abnormal proteins. Such proteins do not appear in normal cells and thus can be recognized by the immune system as being “foreign”. There are several examples of mutant cancer cell genes that produce abnormal proteins.
These molecules can act as antigens that elicit a highly selective, cytotoxic T cell response against the tumor cells in which they are found, provided that the mutant proteins are processed and presented to the immune system in the appropriate fashion.
iii. The Immune Surveillance Theory Postulates that the Immune System is able to Protect against Cancer:
The existence of tumor-specific antigens raises an inter­esting question- Why don’t people with cancer reject their own tumors? The immune surveillance theory postulates that immune destruction of newly forming cancer cells is in fact a routine event in healthy individuals, and cancer simply reflects the occasional failure of an adequate immune response to be mounted against aberrant cells.
The validity of this theory has been debated for many years, with various kinds of evidence being cited both for and against it.
Some of the evidence involves organ transplant patients who take immunosuppressive drugs, which depress immune function and thereby decrease the risk of immune rejection of the transplanted organ. As would be predicted by the immune surveillance theory, individuals treated with immunosuppressive drugs develop many cancers at higher rates than normal (Figure 22).
Although this finding appears to support the idea that the immune system normally helps prevent cancers from developing, it is also possible that the immunosuppressive drugs are acting directly to trigger the development of cancer. For example, cyclosporin—one of the most effective and com­monly used immunosuppressive drugs—has been shown to stimulate the proliferation and motility of isolated cancer cells growing in culture.
These results indicate that direct effects of immunosuppressive drugs on newly forming cancer cells may contribute to the increased tumor growth observed in individuals taking such drugs.
A more direct approach for evaluating the immune surveillance theory involves the use of animals that have been genetically altered to introduce specific defects in the immune system. One study of this type employed mutant mice containing disruptions in Rag2, a gene expressed only in lymphocytes.
The mutant mice, which produce no functional lymphocytes, were found to develop cancer more frequently than do normal mice. An increased cancer risk was observed both for cancers that arise spon­taneously and for cancers that were induced by injecting animals with a cancer-causing chemical. Such results indicate that a normally functioning immune system helps protect mice against the development of cancer.
Nonetheless, the question still exists as to the rele­vance of these findings to human cancers. If the immune system plays a significant role in protecting humans from common cancers, you would expect to see a dramatic increase in overall cancer rates in AIDS patients with severely depressed immune function.
While people with AIDS do exhibit higher rates for a few types of cancer, especially Kaposi’s sarcoma and lymphomas, increased rates for the more common forms of cancer have not been observed. Most of the cancers that do occur in higher rates in AIDS patients are known to be caused by viruses.
Such observations suggest that immune surveillance may play an important role in protecting humans from virally induced cancers but that it is less effective in preventing the more common forms of cancer.
iv. Cancer Cells have Various Ways of Evading the Immune System:
Based on the large number of people who develop cancer each year, it is clear that tumors routinely find ways of evading destruction by the immune system. One mecha­nism is based on tumor progression, which refers to the gradual changes in the makeup of cancer cell populations that occur over time as natural selection favors the sur­vival of cells that are more aggressive and aberrant.
During tumor progression, cells containing antigens that elicit a strong immune response are most likely to be attacked and destroyed. Conversely, cells that either lack or produce smaller quantities of antigens marking them for destruction are more likely to survive and proliferate. So as tumor progression proceeds, there is a continual selection for cells that invoke less of an immune response.
Cancer cells have also devised ways of actively con­fronting and overcoming the immune system. For example, some cancer cells produce molecules that kill T lymphocytes or disrupt their ability to function.
Tumors may also sur­round themselves with a dense layer of supporting tissue that shields them from immune attack. And some cancer cells simply divide so quickly that the immune system cannot destroy them fast enough to keep tumor growth in check. Consequently, the larger a tumor grows, the easier it becomes to overwhelm the immune system.
Although tumors are often successful at evading immune attack, immune rejection is not necessarily an unattainable objective. Experiments in mice have shown that immunizing an animal with tumor antigens can trigger an effective immune response under conditions in which the tumor growing in the animal had not elicited any response on its own. Observations like this one suggest that it may be possible to stop or even prevent the develop­ment of cancer by stimulating a person’s immune system to attack cancer cells.
7. Essay on Molecular Changes in Cancer Cell Proliferation:
Some of these alterations involve unique or abnormal proteins that are not ordinarily encountered in adult tissues, but most of the molecular changes seen in cancer cells proliferation are increases or decreases in the quantity or activity of normal proteins. We will examine a few such changes that are especially noteworthy.
i. Cancer Cells Exhibit Cell Surface Alterations that Affect Adhesiveness and Cell-Cell Communication:
Alterations in the makeup of the outer cell membrane (plasma membrane) are almost universally observed in cancer cells, yet it is often difficult to assess the signifi­cance of such changes because similar alterations occur in normal cells when they begin to proliferate.
For example, membrane transport proteins responsible for the uptake of sugars, amino acids, and other nutrients are frequently activated in tumor cells, but similar increases are observed in normal cells that have been stimulated to divide by adding nutrients or growth factors. It is therefore impor­tant to distinguish between membrane changes that play unique roles in cancer cells and membrane changes that are characteristic of dividing cells in general.
Among the cell surface changes that are particularly distinctive and important for the behavior of cancer cells are those that influence adhesiveness. In normal tissues, cell-cell adhesion helps keep cells in their place in cancers, this adhesiveness is diminished or missing entirely. The reduced adhesiveness of cancer cells can often be traced to defects in E-cadherin, a cell-cell adhesion protein that is located at the cell surface.
A second cell surface property altered in cancer cells is their enhanced tendency to clump together when exposed in the laboratory to proteins called lectins. A lectin is a carbohydrate-binding protein possessing two or more carbohydrate-binding sites, which means that a single lectin molecule can link two cells together by binding to carbohydrate groups exposed on the surface of each cell.
As a result, when lectins are added to a suspension of isolated cells, the lectin molecules link the cells together to form large clumps (Figure 23). It was initially thought that the increased susceptibility to lectin-induced clumping meant that cancer cells possess more cell surface carbohydrate groups to which lectins can bind.
Careful measure­ments, however, have led to the conclusion that the total number of these carbohydrate groups tends to be similar in normal and cancer cells. What does appear to differ is the mobility of carbohydrate groups within the plasma membrane, which tends to be greater in cancer cells than in normal cells. This ability of cell surface carbohydrate groups to move more readily in cancer cells apparently increases the rate at which they can bind to added lectins.
Another cell surface alteration commonly observed in cancer cells is a decrease in the number of gap junctions, which are specialized cell surface structures composed of a protein called connexin. Gap junctions play a role in cell- cell communication by joining adjacent cells together in a way that allows small molecules to pass directly from one cell to another.
The idea that gap junctions are deficient in cancer cells has come from experiments showing that small fluorescent molecules injected into normal cells move rapidly into surrounding cells that are normal but not into cells that are malignant (Figure 24). To investigate whether this deficiency plays any role in the loss of growth control, studies have been performed in which normal cells were fused with cancer cells that had lost the ability to form gap junctions.
Initially, the resulting hybrid cells produced gap junctions and exhibited normal growth control, but the gap junctions eventually disappeared from some of the hybrid cells. At that point the cells reverted to uncontrolled growth raising the interesting possibility that normal growth control is influenced by the ability of cells to com­municate through gap junctions.
ii. Cancer Cells Produce Embryonic Proteins, Proteases, and Stimulators of Blood Vessel Growth:
A great deal of effort has been expended in searching for molecules that are produced only by cancer cells and that might therefore serve as “markers” for detecting the pres­ence of cancer. Unfortunately, few of the molecules identified thus far are broadly useful as unique identifiers of cancer cells, although a number of them can be employed for detecting the presence of specific kinds of cancer. For example, some cancer cells manufacture and secrete proteins that are usually found only in embryos.
One such protein, alpha-fetoprotein, is produced by embryonic liver cells but is detectable in only trace amounts in normal adults. In people with liver cancer, the concentration of alpha-fetoprotein in the blood increases dramatically. Carcinoembryonic antigen (CEA), a protein produced in the embryonic digestive tract, and fetal hormones such as chorionic gonadotropin and placental lactogen, are also secreted by some cancers.
Blood tests for embryonic markers such as alpha-fetoprotein and carcinoembryonic antigen can therefore be used to monitor the presence of certain kinds of cancer, but the fact that these substances are made by only a few tumor types limits the applicability of this approach.
Other proteins produced by cancer cells are not unique to such cells but have provided some important insights into the behavior of malignant tumors. For example, cancer cells tend to produce proteases (protein- degrading enzymes) that facilitate the breakdown of structures that would otherwise represent barriers to cancer cell movement and invasion.
Although proteases are also secreted by certain kinds of normal cells, their enhanced production by cancer cells facilitates the ability of malignant tumors to invade surrounding tissues and enter the circulatory system. Cancer cells also produce proteins that stimulate the growth of blood vessels, thereby helping ensure that tumors have a sufficient blood supply.
The cell cycle and cancer
Recent insights in the fields of cell cycle regulation and cancer would each alone have provided prime examples of research at the “Frontiers of Science.” However, some of the most revealing information about both topics has derived from the intersection of the two fields. The intent of this summary is to introduce the basics of the cell cycle, cancer, and their overlap, and then to describe the research from two laboratories that was presented in the session. A more comprehensive treatment of these subjects, beyond this description for a general audience, is contained in several reviews (1–5).
The process of replicating DNA and dividing a cell can be described as a series of coordinated events that compose a “cell division cycle,” illustrated for mammalian cells in Fig. 1 (see legend for details). At least two types of cell cycle control mechanisms are recognized: a cascade of protein phosphorylations that relay a cell from one stage to the next and a set of checkpoints that monitor completion of critical events and delay progression to the next stage if necessary. The first type of control involves a highly regulated kinase family (2). Kinase activation generally requires association with a second subunit that is transiently expressed at the appropriate period of the cell cycle the periodic “cyclin” subunit associates with its partner “cyclin-dependent kinase” (CDK) to create an active complex with unique substrate specificity. Regulatory phosphorylation and dephosphorylation fine-tune the activity of CDK–cyclin complexes, ensuring well-delineated transitions between cell cycle stages. In the future, additional molecular definition of the cell cycle may lead to a more intricate progression than indicated in Fig. 1.
A schematic representation of the mammalian cell cycle. In each cell division cycle, chromosomes are replicated once (DNA synthesis or S-phase) and segregated to create two genetically identical daughter cells (mitosis or M-phase). These events are spaced by intervals of growth and reorganization (gap phases G1 and G2). Cells can stop cycling after division, entering a state of quiescence (G0). Commitment to traverse an entire cycle is made in late G1. Progress through the cycle is accomplished in part by the regulated activity of numerous CDK–cyclin complexes, indicated here and described in the text.
A second type of cell cycle regulation, checkpoint control, is more supervisory. It is not an essential part of the cycle progression machinery. Cell cycle checkpoints sense flaws in critical events such as DNA replication and chromosome segregation (4). When checkpoints are activated, for example by underreplicated or damaged DNA, signals are relayed to the cell cycle-progression machinery. These signals cause a delay in cycle progression, until the danger of mutation has been averted. Because checkpoint function is not required in every cell cycle, the extent of checkpoint function is not as obvious as that of components integral to the process, such as CDKs.
Superficially, the connection between the cell cycle and cancer is obvious: cell cycle machinery controls cell proliferation, and cancer is a disease of inappropriate cell proliferation. Fundamentally, all cancers permit the existence of too many cells. However, this cell number excess is linked in a vicious cycle with a reduction in sensitivity to signals that normally tell a cell to adhere, differentiate, or die. This combination of altered properties increases the difficulty of deciphering which changes are primarily responsible for causing cancer.
The first genetic alterations shown to contribute to cancer development were gain-of-function mutations (6). These mutations define a set of “oncogenes” that are mutant versions of normal cellular “protooncogenes.” The products of protooncogenes function in signal transduction pathways that promote cell proliferation. However, transformation by individual oncogenes can be redundant (mutation of one of several genes will lead to transformation) or can be cell type-specific (mutations will transform some cells but have no effect on others). This suggests that multiple, distinct pathways of genetic alteration lead to cancer, but that not all pathways have the same role in each cell type.
More recently, the significance of loss-of-function mutations in carcinogenesis has become increasingly apparent (7). Mutations in these so-called “tumor suppressor” genes were initially recognized to have a major role in inherited cancer susceptibility. Because inactivation of both copies of a tumor suppressor gene is required for loss of function, individuals heterozygous for mutations at the locus are phenotypically normal. Thus, unlike gain-of-function mutations, loss-of-function tumor suppressor mutations can be carried in the gene pool with no direct deleterious consequence. However, individuals heterozygous for tumor suppressor mutations are more likely to develop cancer, because only one mutational event is required to prevent synthesis of any functional gene product.
It now appears that tumor suppressor gene mutations are highly likely to promote, and may even be required for, a large number of spontaneous as well as hereditary forms of cancer (5). But what are the functions of tumor suppressor gene products in a normal cell? Although this is a topic for future research, there is suggestive evidence that several tumor suppressor genes encode proteins that negatively regulate cell cycle progression. Loss of function of the tumor suppressor gene product pRb, for example, would be predicted to liberate E2F transcriptional activators without requiring phosphorylation and thus bypass a normal negative regulation controlling entry into the cycle (Fig. 1). Loss of the tumor suppressor gene product p16 would have a similar consequence, liberating E2Fs by increasing pRb phosphorylation (Fig. 1). In addition, cell cycle progression can be halted at several points by the tumor suppressor gene product p53, activated in response to checkpoints sensing DNA and possibly also chromosome damage loss of p53 would remove this brake to cycling (8).
By what molecular pathway does loss of cell cycle regulation in an organism lead to cancer? What genetic changes can cooperate to accomplish the cancer cell’s escape from the normal balance of cell growth? Tyler Jacks described results from his laboratory that addressed these questions, using mice and cell lines derived from mice that have been engineered to lack individual tumor suppressor gene products. To create “knock-out” mice, embryonic stem cells that can later be introduced back into a developing animal are subject to targeted mutagenesis of the gene of interest. Cells with one mutant gene copy are injected into early embryos, and mice that use the injected cells to form germ-line tissue are selected for breeding. Some progeny will be entirely heterozygous for the mutant gene these mice can then be bred to obtain homozygous mutant animals.
One important insight from the studies of mice lacking tumor suppressor genes is the dependence of balanced cell numbers on not only the regulation of cell proliferation but also on the regulation of cell death. In the past, cell death was regarded as an accidental failure of normal cell function. However, often the opposite is true: genetic studies of cell death indicate a requirement for active death signals and directed execution (for review of proteins involved in cell death see ref. 9). One collection of experiments illustrates the significance of combining genetic alterations that deregulate both cell proliferation and cell death (ref. 10 see also refs. 11 and 12). Inactivation of pRb during embryogenesis promotes inappropriate cell cycle activity. This follows from the role of pRb in negatively regulating entry into the cell cycle (Fig. 1). In contrast to expectations, however, the increased cell cycle activity in Rb null mice does not result in a net increase in cell number. This is due to a commensurate increase in cell death that specifically eliminates the abnormally cycling cells. This cell death is often dependent on the function of p53, as demonstrated from the analysis of RB/p53 double-mutant embryos.
The function of p53 in sentencing inappropriately growing cells to death has implications for cancer development and chemotherapy. Murine tumors with functional p53 respond to chemotherapy by promoting their own demise, but those lacking p53 typically do not (13). A balance between cell proliferation and death likely functions during development to create a finely patterned body map. This normal function of the cell death pathway and the potential for tipping the balance too much toward death in some degenerative diseases will be exciting future topics of investigation.
Clearly, the products of cell cycle regulatory genes are critical determinants of cancer progression. But precisely how do gene sequence alterations and missing regulatory components affect the functioning of the cell cycle machinery? Having in hand molecular details of the protein structures would address this question and would also suggest strategies for cancer therapy. Nikola Pavletich described research in his laboratory that has yielded high-resolution structures of p53 and of inactive and active states of CDK2. These structures were determined from the x-ray diffraction patterns of purified, crystallized proteins.
Although p53 may serve many roles in the cell, its best-characterized function is as a transcriptional activator. The residues of p53 that are frequently mutated in cancer cells are critical for DNA binding (14). A p53–DNA co-crystal structure revealed that these frequently mutated residues fold together into one region of the surface of the protein (15). Thus, cancer-promoting mutations that occur throughout the primary sequence of the protein are in fact clustered in one functional domain.
Recent studies have focused on the structural basis for regulation of the CDKs, using CDK2 as a model system (for review of CDK regulatory mechanisms see ref. 2). In mammalian cells, CDK2 functions in S-phase with cyclin A as a partner (Fig. 1). The association of cyclin A modifies the previously determined CDK2 structure (16) by reorienting a catalytically critical glutamic acid into the catalytic cleft and moving away the regulatory loop that can block access of a protein substrate to bound ATP (17). Cyclin A binding stimulates CDK2 activity, but phosphorylation of threonine-160 is required for full activation. The crystal structure of threonine-phosphorylated CDK2 complexed with cyclin A reveals conformational change in the substrate-binding site and also a strengthening of CDK2–cyclin A interaction (18).
Finally, one mechanism for the inactivation of the CDK2–cyclin A complex was examined: binding of the inhibitor p27 (19). Co-crystals of CDK2–cyclin A with the N-terminal inhibitory domain of p27 reveal that bound p27 physically blocks the active site, inserting itself into the catalytic cleft. Also, p27 association modifies the structure of the “roof” of the ATP-binding site and blocks a putative protein substrate docking region on cyclin A. With these structural modifications in mind, it may be possible to design small molecules that will have the same effect: blocking CDK activity, thus halting the cancer cell cycle in its tracks.
8.3: Cancer and the Cell Cycle - Biology
Cancer Animations (Howard Hughes Medical Institute)
From the 2003 Holiday Lectures — Learning From Patients: The Science of Medicine
A cancer tumor forms in a bed of healthy cells. The animation goes on to show how the tumor recruits blood vessels and how metastasis occurs.
Gleevec (Howard Hughes Medical Institute)
Gleevec is a drug designed to interfere with the stimulation of growth in leukemia cells. This 3D animation shows how this is achieved.
This animation illustrates how mistakes made during DNA replication are repaired.
p53 (Howard Hughes Medical Institute)
A 3D animation showing the molecule p53 binds to DNA and initiates the transcription of mRNA.
This animation demonstrates how cancerous cells could be destroyed using a modified virus.
VEGF (Howard Hughes Medical Institute)
This animation shows how a growing tumor can recruit nearby blood vessels in order to gain a supply of blood.
How Cancer Grows
All cancers begin with a genetic mutation within a body cell and advance when the cell's descendants mutate further. This feature follows the progression of a malignant tumor, beginning with the first mutation within a cell and ending with metastasis, the colonization of related tumors throughout the body. It focuses on the most common type of cancer, a carcinoma, which can originate in a particular type of tissue found in the skin, breast, prostate, and other organs.
Animation by Rick Groleau and Lexi Krock
GM-CSF/Tumor Vaccine Strategy
Summer 2003 The Biology of Cancer Teacher Animations (HHMI)
Flash creations from Summer 2003 Outreach High School Teacher Participants Storyboards.
Cancer and Cell Cycle
1-Cancer and Chemical Poisons, 2-Cancer and Your Family History, 3-Cancer and Radiation Exposure, 4-Cancer and UV Light.
Cancer as a Multistep Process - Simulator
The Hit Simulator allows you to observe how mutation rate and the number of mutations (hits) required for the development of cancer affect the incidence of cancer in a population.
This hour-long program is divided into eight chapters. The Experimental Drug, Starving Cancer, Angiogenesis in Action, Preventing Angiogenesis, New Use for an Old Drug, How Cancer Spreads, Finding New Inhibitors, Clinical Trials
Cancer Caught on Video
As chronicled in the NOVA program "Cancer Warrior," one of Dr. Judah Folkman's most significant findings in a career rife with discoveries was that cancerous tumors appear to trigger the growth of new blood vessels, which the tumors need to thrive. Here we present a series of remarkable microscope views of various stages in cancer growth and angiogenesis, or growth of new blood vessels. Shot during experiments with laboratory chicken embryos and mice, the clips follow a natural progression of cancer spread, from early events up to the point when a tumor requires angiogenesis to keep growing. The images, some color and some black-and-white, were shot by Dr. Ann Chambers and her colleagues at the University of Western Ontario using a microscope outfitted with a video camera. In many of the clips, you'll notice the camera focus changing. Dr. Chambers wrote the captions that accompany each clip.
Documentary on Cancer Biology
The CancerQuest Documentary is an 11min video-animation that describes the biological processes that are involved with cancer.
Tumor Biology Animation/Video Series
The CancerQuest Video Series includes animations describing the biological processes that are involved with cancer. This interface takes a serial approach for adequately describing all the complicated cancer biology. Step through each selectable topic on the left side of the interface and watch the associated animation/video.
The polyphenolic compound resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring phytochemical and can be found in approximately 72 plant species, including food products like grapes, peanuts, and various herbs (1) . Its exact physiological function is not known, but it may have roles in protecting plants against fungal infections and in conferring disease resistance. Red wine (1.5–3 mg/liter) and grapes (50–100 μg/g grape skins) are probably its main sources in Western diets. One of its richest sources is the herb Polygonum cuspidatum, which has been used in Asian folk medicine. Previous investigations have demonstrated its antioxidant and anti-inflammatory activities, its ability to induce phase II drug-metabolizing enzymes, and its ability to inhibit cyclooxygenase activity and transcription thus, it has activity in regulating multiple cellular events associated with carcinogenesis (for review, see Ref. 1 ). It may also have in vivo activity in modulating indices of platelet activity and lipid metabolism, which could explain the epidemiological evidence that red wine may decrease coronary heart disease mortality (for a review of its potential benefits in atherosclerotic heart disease, please refer to Ref. 2 ).
Resveratrol has been shown to have growth-inhibitory activity in several human cancer cell lines and in animal models of carcinogenesis. In HL60 promyelocytic leukemia cells, treatment with resveratrol led to growth inhibition, induction of apoptosis, S-G2-phase cell cycle arrest, and myelomonocytic differentiation (3 , 4) . Resveratrol also displayed antiproliferative activity in JB6 mouse epidermal, CaCo-2 colorectal, and A431 epidermoid carcinoma cell lines (5, 6, 7) . Its effects in breast cancer cell lines are more complicated. Whereas some investigators have demonstrated antiproliferative effects in the MCF7, MDA-MB-231, KPL-1, MKL-F, and T47D cell lines (3 , 8 , 9) , others have demonstrated growth enhancement in T47D and MCF7 cells (10 , 11) . The latter effect appears to be due to the potential estrogenic effects of resveratrol (10, 11, 12) . Resveratrol inhibited tumor formation in several animal models of carcinogenesis, including mouse 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin cancers (1) , azoxymethane-induced colon cancers (13) , and transplanted Yoshida rat ascites hepatomas (14) . In the mouse skin carcinogenesis model, resveratrol inhibited the three major steps of carcinogenesis, initiation, promotion, and progression (1) . However, the precise mechanisms by which resveratrol exerts these antitumor effects are not known.
Limited epidemiological and clinical evidence suggest that resveratrol is well tolerated during human consumption and that it may offer benefits with respect to atherosclerotic heart disease. In a small study of 24 healthy male volunteers, trial participants tolerated the consumption of resveratrol-enriched beverages, but the effects of this compound on lipid metabolism and platelet activity were unimpressive (15 , 16) . Although resveratrol is available commercially as a dietary supplement, there are no published controlled clinical studies demonstrating either its efficacy or safety in the treatment or prevention of cancer or coronary artery disease.
In the present study, we used a spectrum of six human cancer cell lines to further examine the range of antitumor activity of resveratrol. To obtain insights into its mechanism of action, we examined the effects of resveratrol on cell proliferation, cell cycle distribution, apoptosis, and on the levels of expression of several cell cycle control proteins. Our results provide support for the use of resveratrol in clinical chemoprevention and chemotherapy trials. In addition, we have identified potential surrogate biomarkers, which may serve as intermediate clinical end points in these trials.
This week we will be studying the cell cycle and mitosis.
This cycle is important to us for so many reasons!
Your job this week is to take a look at what happens when the cell cycle does not proceed as it is supposed to. What happens to our cells and our bodies as a result?
1) Do some internet research.
2) Summarize in a paragraph what happens when the cell cycle is out of control.
3) Also, give us some specific examples/cases that show what you are telling us. Feel free to use examples from sites you find OR personal examples if something like this has happened in your family/friends.
4) Don't forget to respond or reply to others. You will probably read some interesting things!
This is due Friday (11/10) by midnight!
ok obviously this condition is a very likely sign that the cells are cancerous. however there are chemical signals that control all stages of cell replication. so like if we cold learn to control these signals then we could probally elimate cancer in theory of course
By the bye, Mrs. B, Friday is the ninth. Saturday is the tenth.
When the cell cycle goes out of control, the cells can ignore the inhibitors that cause the cell to stop or at least slow down multiplying, causing the cell to divide constantly. Cancerous cells do not function normally, all they do is divide. They can form benign tumors that do not spread, or malignant tumors that spread like a plague. Several stimuli can cause cancer: smoking, overexposure to UV sunlight, alcoholism, et cetera.
Both of my grandparents on my mother's side died from cancer - my grandmother form lung cancer and my grandfather from brain cancer. My grandmother died not only from the lung cancer (no doubt from smoking for much of her life) but also a bad case of pneumonia. My grandfather ended up having more than one tumor on his brain, in too deep to be removed. I forget what it was they showed us, I only got a glimpse, but I did see a few blobs of dense white on something like an x-ray that was the cancer.
When the cell cycle begins to go wrong, cancerous cells could be formed. A cancer cell is a cell that grows out of control. Unlike normal cells, cancer cells ignore signals to stop dividing, to specialize, or to die and be shed. They grow in an uncontrollable manner and are unable to recognize their own natural boundaries, the cancer cells may even spread to areas of the body where they do not belong,a process called metastasis.
The cancerous cells can cause various bodily problems, the most common being a tumor. The tumor can be benign (not spreading) or malignant (spreading all over the body. The cancerous cells can spread using the body's lymphatic and vascular systems, making it possible to have an outbreak in any part of your body.
Many of my older family members have met with cancer before they passed away. For example, my grandpa's brother had developed lung cancer, and this coupled with his diabetes ended up killing him. Another example could me my mother on my father's side's sister. She developed a brain tumor, that while small enough to remove, was only a temporary fix. About 2 years later, the cancer resurfaced in another tumor that cant be removed. Ironic that the smallest living unit in nature can cause some of the biggest health problems there are? eh? Now i'll go ahead and leave off here. You're all probably ready for me to shut up and go do something useful. and i think i will. as soon as i find something. :-P
In response to Bobby (masterhuskie), the cells already control the cycle, cancer cells just slip past these signs, and the cell is helpless to stop itself once it begins producing the bad cells. Theoretically, if we find a way to fortify cells against cancer causing agents or allow them to recognize the prescense of an abnormal cell, then perhaps we can make some progress. But lets be realistic those solutions are decades away. We've been working on an AIDS cure since the 90's, and its only a Retrovirus. Imagine the poblems we'll encounter trying to fight a genetic disease.
When cells divide uncontrollably, cancer occurs. I learned this last year in Biomedical Technology. Cancer is very interesting to me, so I would really like to go into pediatric oncology. Cancer is described as uncontrolled cell mutation. The mutating cells take over the healthy cells, and it is usually too widespread to cure if it goes undetected for a long amount of time.
Recently, in August, I lost a friend of the family to cervical cancer. Her fear of the doctor caused her to acquire the disease, and it progressed rapidly as a result. Her cancer went into remission, but came back, this time in her lymph nodes. It proved to be fatal.
Cancer causing agents, or carcinogens, can come in many forms. Tobacco, too much exposure to UV rays, and genetics are common carcinogens. Even artificial UV rays, such as tanning beds, can cause cancer if there is too much exposure. Yes, tanning beds can kill you.
In response to rosenkreuz and desert, it is very sad that you both lost older family members to cancer, but the family friend that I lost was sadly, only 36 years old. Cancer has no knowledge of age, race, or gender, so we all need to take preventative measures, such as wearing sunblock to decrease or chances.
If the cell cycle were to get out of control, then the cells would constantly divide, mainly those that are cancerous. They do not tend to spread around the body, causing tumors to form. There is no inhibitor that tells them when to stop because the cancerous cells don't function normally. Thus, the cell cycle cannot complete itself like it normally would.
My aunt had suffered from a brain tumor that led to her death. The abnormal amount of glial cells built up in her. Also, tobacco contributes to this situation. It causes lung cancer to develop.
When the cell cycle gets out of control, then the cell becomes cancerous. This means that the cell grows and divides without heeding the signals to stop and/or die. Sometimes the cancer can spread to other tissues, which can kill the organism that's unlucky enough to have it.
My grandma had cancer removed from her face 4 years ago. It left a scar on her cheek and she has to go back every so often to get the new pieces that come to the surface burned off (with silver nitrate, not fire). The doctor believes it will be there for the rest of her life, and likely what kills her.
ok so the obvious response to this is cancer. Cells that do not respond to any of the usual regulation are considered cancerous. These cells tend to multiply uncontrollably and are located in various areas of the body. They show up as tumors and will be either malignant or benign. That means cancerous or non-cancerous.
In my life, a great deal has happened dealing with cancer. Most of my family has had it some time in their life. that's on both sides. My grandfather died shortly through an operation to eradicate cancer but i guess you can say "awoke" again. My grandmother has multiple myloma. My great-grandfather died of the same thing and that really tore our family up. He was like, the head of our family. My maw-maw has tumors in her breasts and under her arms. My paw-paw had what we thought were tumors but turned out to just be like, 4 hernias in his stomach. My family history is basically swamped with cancer so i look foward to getting over that obstacle. lol.
when the cell cycle does not proceed as it is supposed to, it affects us dramatically. Sometimes, you can get cancer, lumps, or tumors if the cell cycle is out of control.the cells can ignore the inhibitors that cause the cell to stop or at least slow down multiplying, causing the cell to divide constantly. Cancerous cells do not function normally, all they do is divide
As you get older the cell cycle slows down. This means that some of the cells will die naturally, but they won't grow back at all or they will grow back very slowly. This could mean that your skin will get thinner, or your spine can shrink.
My cousin had sking cancer a couple years back and she is only 30 something years old.
In reponse to Kara and David I know how you feel it is very sad that you both lost older family members to cancer, Cancer can come at any unexpected time, and we all need to take measures to prevent and protect ourselves from these diseases
Then the cell cycle goes out of control cancerous cells are formed. These cells do not function except to continuously divide and make more cells. 6 or 7 years ago my grandpa got cancer. He survived but he was in the hospital for a couple weeks and had to continuosuly have scans after he was released to make sure that the cancer was completely killed.
OK so the cell cycle going "out of control" is a sign of cancer. When cancer occurs, the cancerous "original cell" divides and spreads rapidly, which is uncommon in regular cells. Eventually, a tumor is formed that is a compilation of the numerous copies of the cancerous cell. The cancerous cell divides but it does not respond the normal signaling system so even though the cells cause damage to the body, they continue to reproduce. Also, because cancer cells do not stick together as regular cells do, they become free and can move and damage other parts of the body. Cancer does not really run in my family, were more diabetes. However, I did lose a grandmother on my fathers side to lung cancer a little less than two years ago.
In response to Kara, your exactly right about how cancer can affect everyone. I went to middle school with a girl who developed cancer in the seventh grade. However, through chemotherapy, she beat it and now she is fine.
Oh, and before I forget, I wholeheartedly agree with Kara and Paige about their information on the disruption of the cell cycle and caner's effects.
Here is another question I want to ask as you are discussing this issue.
Do you think cancer has always been around and we just haven't known enough to diagnose and treat it. maybe why people in early history died of "old age". or is cancer really becoming more common??
What do you think. is there any research out there on this??
Cells grow at a normal rate continously but die off keeping a balance. When cancer cells grow, they grow non-stop rapidly intil a tumor forms. Cancer cells are formed when genes are abnormal. These genes will ignore the signals that tell it to stop replicating and will grow till it kills the victim. Fortunaltly, no one thatI know has died of cancer.
When the cell cycle goes worng, cancer and tumors can form.
If protein detect a mutation in DNA, it will try to repair it. If this does not suceed, it will bring about apoptosis. Cancer cells are brought up when apoptosis does not initrate.
These cancer cells grow out of control. They do not respond normally to the body's control mechanisms, therefore, they keep dividing even though the body tells them not to. When these cells divide at a faster rate than normal, tumors are created from the pile up.
My grandmother died of liver cancer. I am glad that I was able to learn more about cancer and how it comes about. It has helped me to cope with the situation better. =] It is unexpected but I think it is important that everyone is informed about it.
When the cell cycle goes out of control, cells divide without stopping. This leads to the growth of tumors and cancer. Many different things can cause the cell cycle to go out of control such as: smoking, drinking too much alcohol, harmful UV rays, etc.
Three years ago, one of my aunts was diagnosed with breast cancer. The doctors had found it fairly quickly, and were able to remove it in surgery. However, she found another lump about eight months later, and her cancer was back. By the time they found it, it had already spread to other parts of her body (brain, lungs, throat). She died three months later.
Her sister also had breast cancer, but the doctors removed it and it has not came back luckily.
Cancer has been around since mutinous DNA cells have exsisted.
The earliest recorded cases of cancer date back to Ancient Egypt over 5,000 years ago. While they did not know what it was, ancient recordings of symptons are synonomous with what we know as symptons of cancer today. They also used cauterization as a way to reduce the symptons and they showed little signs of understanding benign or malignant tumors.
Whether or not cancer is more common is hard to say since scientits don't know EVERY cause of cancer. It could be all those weird perservatives and stuff they do to our food nowadays or it could be in the water OR it could be a result of the human race screwing the enviornment and nature is getting back at us.
It's also hard to tell because statistics show that some cancers, such as skin, prostate, and breast cancer are on the rise while others, such as lung and colon cancer are decreasing. These numbers change every few years so its hard to say if its becoming more common or not.
When the cell cycle is out of control, cancer is usually the obvious result. Cancer is the rapid division of cells, that is unable to stop. The stop and go signals that usually control the cell cycle no longer function correctly and the cancer invades your body.
Although I have never lost a family member to cancer, I once read a series by Lurlene McDaniel called 'Too young to die' it was about a 13 year old girl named Dawn Rochelle who was diagnosed with Lukemia. Throughout the series, she had to have many operations and met other teens with Lukemia too, although most of them did not make it. The book covered many symptoms of Lukemia and was very informative and interesting at the same time.
I agree with what Kara said, cancer doesn't care about age, race, or gender and we have to take protective measures starting right now.
A normal cell cycle is one without mutations, but cancer cells have mutations in the genees that control the cell cycle. The cancer cells grow uncontrollably. The cell can become cancerous at various staeges in the cell cycle and start as a primary tumor. One thing I found interesting was that cancers are clones, and it doesn't matter how many cells are present in the cancer they are all from a single ancestral cell.
Ashley, I didn't know your grandmother had cancer! =[ I do not have direct relationship with anyone that had cancer.
when the cell cycle helps grow or replace cells. Stop and go signals are sent to cells, which make them start growing, or multiplying. sometimes it gets out of control. Sometimes this signals are sent without a purpose or arent sent at all. This causes uncontrolled cell division.
so, i'm feeling very repetitive. but anyway, moving on.
when the "cell cycle" does not perform properly, cells divide uncontrollably, usually resutling in cancerous cells. The cancerous cells take over the healthy cells and also "latch onto" whatever organs are nearby. By the time your body realizes the cells have not divided properly, it's too late for your body to fight off.
I also learned about all this in bio. med-tech last semester.
Carcinogens are usually things we don't even think about. For example, exposure to sunlight. And for those of us who burn really easily (coughcough) it's worse, because we're fair skinned. If kids have really bad sunburns as kids, they're much more likely to develop skin cancer when they're older. Other agents include inheritance, smoking, drinking, etc.
And to the whole, "has cancer always been around or is it becoming more common?" -In my opinion, I think it's becoming MUCH more common. I think a long time ago, people didn't smoke, drink, or tan nearly as much as our society does. Personally, I think most girls don't use enough sunblock, because everyone wants to be tan. =] Like, way back in the day, women covered up their bodies and wore big hats and carried around umbrellas(what the heck?) to shield the sun. And now everyone just doesn't care.
so. surprise! danielle's late blogging again! yes, i know. it's 1:24 in the a.m., but at least i'm getting it done!
so, everyone basically stole my idea! so i'm gonna do a good job of paraphrasing what everyone else said, since we all have the same answer. =]
when the cell cycle doesn't operate as planned, cells psychotically divide. Overproduction/"Overdivision" of cells causes cancer.
i definitely believe that cancer cases have become so much higher when just looking at even the past 50 years or so. because our environmenthas changed so much, there are so many more stimuli for cancer than there were years ago. people stayed covered up (preventing skin cancer), didn't smoke cigarettes (and whatever else) (preventing lung cancer), etc.
luckily for me, cancer doesn't run in my family.
in kenyan culture, my "grandma," which in american culture is my "great aunt," i think, died of cancer when she was in her forties or early fifties.
on of my other "great aunts" was diagnosed a few weeks ago, and is really sick, but she's getting treatment now.
my mom had cancer from the middle of last year to early this year, too.
as far as i know, we've only had 3 cancer victims in my family.
unfortunately, it has definitely become a familiar thing to many people.
that's supposed to say, "one of my other 'great aunts'. "
Cancer. This happens when cells grow and spread very fast. Normal body cells grow and divide and know to stop growing. Over time, they also die. Unlike these normal cells, cancer cells just continue to grow and divide out of control and don't die.
Cancer cells usually group or clump together to form tumors. A growing tumor becomes a lump of cancer cells that can destroy the normal cells around the tumor and damage the body's healthy tissues.
My grandmother on my mother's side, had breast cancer but fortunately was removed. It took her left breast and left her a huge scar. She visits the doctor often and with the help of my aunts she follows an extremetely healthy diet.
In response to Kara's post. It is true that Cancer is not racist nor sexist. It is very important that we take important decisions to prevent Cancer. Smoking, taning beds, alchohol, porr diet, and lack of exercise and some of the main risk factors for cancer.
4 Answers 4
Tumors can be benign (they don't bother you at all eg: a mole which does not change) and malignant (also called cancer).
The difference is based on:-
- Degree of differentiation - How much the tumor cells resemble the normal cells
- Rate of growth - In general (over generalised) benign tumors are slow growing while malignant tumors are fast growing
- Spread to nearby tissues - Benign growth don't cross tissue planes as defined by basement membranes/fascias, while malignant tumors invade across tissue planes
- Metastasis - Spread to a remote location in the body through blood, lymph vessels, transcoelomic (peritoneal, pleural, pericardial spaces) routes - This is ONLY seen in malignant tumors.
Coming specifically to rate of growth, these factors must be considered:
- What is stated above in 2 is the general case:
- Malignant tumors a.k.a cancers grow fast
- Benign tumors are slow growing That being said some benign tumors grow faster that malignant tumors. Eg: Fibroid - grows very rapid under the influence of estrogen as in pregnancy
- The rate of growth of malignant cancers depend on their degree of differentiation (look point 1 above).
- Well differentiated cancers grow slow - Cancers that are very similar to normal cells are considered to be well differentiated
- Poorly differentiated cancers grow faster based on the "poorness" of differentiation,i.e. the worse the degree of differentiation, the faster the growth. Totally undifferentiated (unidentifiable as any tissue type) are called anaplastic cancers and these grow the fastest
- The rate of growth of cancers may vary over time
- Due to excessive division probability of mutation is high and a sub-clone may emerge with faster rate of division thus a previously slow growing cancer could suddenly start growing fast
- Due to the same process some cancers may suddenly decrease in their growth rate and may eventually even vanish! (become necrotic and get cleared away)
This is taken from Robbin's Text book of Pathology,Ed.8, chapter 6
Edit 1: To know the numbers you need, you have to find out the rate of increase in volume (by measuring size at two points in time) and divide it by the approximate volume of one cell. This will give you the number of cells that has newly divided within the two measured points (growth in interval). Which can then be converted to cell divisions per second.
As pointed out, the rate is going to vary extremely, based on the cancer type.
Different cancers divide at different rates. One way to qualitatively visualize this is observe hair loss in patients who are undergoing chemotherapy. Commonly, a drug like cisplatin will be administered which will cross-link DNA, inhibiting cell division by activating apoptosis. Tissues which are killed most readily by cisplatin are those which are dividing most rapidly: intestines, head hair, red and white blood cells, tumors.
Despite the loss of hair on the head, many patients do not lose slower growing hair on their arms, eyebrows, eyelashes, etc. Likewise, though cell death in the intestinal lining may be dramatic on cisplatin, the skin may not show lesions as it is a more slowly dividing population of cells.
The rate of cell division correlates with the rate of cell death while taking the chemotheraputic drug cisplatin.
You may make a rough visual survey of the cells in the body which divide so rapidly that they die, and divide so slowly that they largely survive chemotherapy.
The rate of cell division of head hair and other body hair spans the rate of cell division over which cisplatin effectively acts on tumor cells.
I think you should start with immortalized cell lines and so in vitro division rates by perfect conditions. This is easier to measure than in vivo division rates. E.g. HeLa has a division time of 23 hours. MDA-MB-231 and A549 division times are around 28 hours.
So I assume there is a physical barrier somewhere around one division per day or so, and it simply cannot grow faster. While bacterial division times are much lower (down to 20min), they also depend on special mechanisms (see this question/answer) and are orders of magnitude smaller than mammalian cells, so they don't count as a counter argument to this.
If you check zygote division times (10-12h, 14-16h, 22-24h, . ), you can see that they highly depend on the cell size. After some divisions the zygote depleted the reserves necessary to divide at higher rates, so after that it is limited by the
Same 24h data here by rapidly proliferating cells.
So we can assume that 1/24h is the maximum rate of cell division by cancer. Let's read more about cancer in vivo, because it behaves completely different than immortalized cell lines in in vitro tests.
Originally tumours were thought to grow because they consisted of cells that multiplied more rapidly than cells in the surrounding tissue. In fact the average cell cycle of 48 hours for human tumour cells is slightly longer than the cycle of non-malignant cells. .
When a normal cell divides, it does os only to replace a cell that has been lost and in this way a constant cell population is maintained. In tumour cells the control mechanism appears to have been lost: as the cell divides it adds to existing numbers of cells and increases the total population. .
A measure of the rate of tumour growth is the time taken for a given population of malignant cells to double in size (doubling time). If the cell cycle takes between 15 and 120 hours, the doubling time can be between 96 hours and 500 days, depending on the histological type of the tumour, its age and whether it is a primary or metastatic growth. A shorter doubling time (less than 30 days) can be between is seen with teratomas, non-Hodgkin's lymphomas, and acute leukaemias common solid tumours such as squamous cell carcinoma of the bronchus and adenocarcinoma of the breast and bowel have doubling times in excess of 70 days. In the patient the growth of a cacncer is only detectable and observable during the last 10-14 of its 35-40 doubling times.
So according to this book the division rate of cancer cells are similar to healthy cells.
According to another book this statement is from Dougherty & Bailey 2001, but I wasn't able to find the scientific article. :S
Tumour cells appear to have lost control mechanisms which prevent cells from growing until replacement is required. Human tumour cells are thought to have an average cycle time of 48 hours. This is not more rapid than the cycle of most normal cells. The reason tumours become larger is because their cell division creates additional cells rather than replacements (Dougherty & Bailey 2001).