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VIRUSES AND CANCER
The answer to the important question, "Do viruses play a role in human cancer?" is still unknown. Although many scientists think that they may play a role, straightforward attempts to isolate human tumor viruses in animals or in tissue cultures have failed. Possibly the most sensitive test object, newborn human infants, of course cannot be used as test objects, and this may explain the failure to isolate human tumor viruses. At present, it would appear that the best means of tackling the problem of viral-induced carcinogenesis is to study the basic characteristics of known tumor viruses and the basic aspects of their interactions with cells. Both RNA-containing and DNA-containing viruses, two obviously different classes of virus, can cause cancer and therefore both classes must be studied in order to obtain a complete picture of the role of viruses in causing cancer in animals and cell transformation in vitro. Such basic studies already have yielded information of great importance to general biology.A number of exciting developments have occurred in the area of virus-induced cancer. One of these is the oncogenic capacity in hamsters of certain human adenoviruses, and an intensive probe of their possible role in human cancer is in progress. Another is the detection by electron microscopy of virus-like particles in the tissues and serum of patients with leukemia. Rigid criteria have been suggested to establish etiologic significance of viruses recovered from human cancer tissues and of the virus-like particles observed by electron microscopy in serum or malignant tissues from cancer patients. If viruses are eventually found to play a role in human cancer, then perhaps the disease can be prevented by vaccines and treated with antiviral substances.
How Can Viruses Influence Cancer?
Together, microbes are estimated to underlie between 10% and 20% of all cancers worldwide. Unknown microbes may also play an additional role in tumorigenesis. In 2002, HPV accounted for the largest global cancer burden, making up 5.2% of infection-associated cancers. While it is clear that cancer is not contagious, virus-associated cancers continue to afflict populations throughout the world. Viruses aren&rsquot the only microbial culprits Helicobacter pylori, a type of bacteria, plays a role in stomach cancers, while helminths are often causal in bladder and gall bladder cancers. Microbes are thought to promote development of cancer through two routes: expression of an oncogene or induction of chronic inflammation.
Chronic inflammation leading to tissue damage is one mechanism of carcinogenesis. For example, liver cancer caused by the hepatitis C virus (HCV) is a multi-step process that begins with HCV infection. Once the virus has infected the liver, inflammatory agents such as reactive oxygen species (ROS) and cell death signals promote higher mutation rate and liver scarring. As illustrated in Figure 1, low-level inflammation increases ROS and other mutagenic compound production, genetic instability leads to unchecked cell growth, and increased immune evasion result from HCV infection. Additionally, initiation of neoplastic clones, cancer cells capable of indefinite proliferation, leads to additional tumor progression. This process can take over 20-40 years. In other studies, HCV viral proteins appear to affect the innate immune pathway, which is normally responsible for the body&rsquos first-line defense against pathogens. While HCV activates a beneficial immune response known as the interferon pathway, recent studies have shown that robust induction of the interferon pathway actually predicts treatment failure and viral persistence.
Figure 1. Pathogenesis of HCV-induced hepatocellular carcinoma (HCC). SNPs, single nucleotide polymorphism LPS, lipopolysaccharide.
Another mechanism of carcinogenesis is the expression of an oncogene, such as during RSV infection. The &ldquoprovirus hypothesis,&rdquo proposed by Howard Temin of the University of Wisconsin in 1964, reversed the flow of the central dogma of biology in which genes provide the instructions for creating proteins (namely, transcription and translation). His hypothesis stated that human cancer viruses were caused by the conversion of RNA to DNA. While this idea may not have been accepted into the scientific mainstream, some have argued that it laid the groundwork for retrovirology. The role of retrovirology in the study of cancer biology remains a topic of research.
Current cancer vaccines
Scientists develop preventative vaccines by using weakened or harmless forms of viruses to give the immune system the information it needs to recognize and attack potential threats. Therapeutic vaccines are used to compel the immune system to attack cancer cells. Here are four vaccines designed to treat or prevent cancer:
- Sipuleucel-T: This was the first therapeutic cancer vaccine to receive U.S. Food and Drug Administration (FDA) approval. Used to treat some forms of prostate cancer, sipileucel-T uses a patient&rsquos re-engineered cells that are injected back into the body to help activate the immune system.
- Bacille Calmette-Guerin (BCG): A preventive vaccine for tuberculosis, BCG is also used as a therapeutic vaccine to treat very early stages of bladder cancer. The drug is delivered directly to the bladder tumor to attract immune cells to that location.
- Hepatitis B vaccine (HBV): In 1981, HBV became the first FDA-approved vaccine to prevent cancer. The U.S. Centers for Disease Control and Prevention recommends that children receive the vaccine shortly after birth to prevent liver cancer.
- Human papillomavirus (HPV) vaccine: These preventive vaccines are designed to protect against infections from HPV strains responsible for many cancers.
Vaccines have not yet been developed to treat or prevent HIV, HCV, EBV or other cancer-related viruses.
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DNA viruses and cancer: insights from evolutionary biology
When it comes to understanding the exact mechanisms behind the virus induced cancers, we have often turned to molecular biology. It would be fair to argue that our understanding of cancers caused by viruses has significantly improved since the isolation of Epstein-Barr virus from Burkitt's lymphoma. However they are some important questions that remain unexplored like what advantage do viruses derive by inducing carcinogenesis? Why do viruses code for the so called oncogenes? Why DNA viruses are disproportionately linked to cancers? These questions have been addressed from the lens of evolutionary biology in this review. The evolutionary analysis of virus induced cancer suggests that persistent strategy of infection could be a stable strategy for DNA viruses and also the main culprit behind their tendency to cause cancer. The framework presented in the review not only explains wider observations about cancer caused by viruses but also offers fresh predictions to test the hypothesis.
Keywords: Carcinogenesis DNA viruses Evolutionary ecology of cancers Evolutionary medicine Infectious causes of cancer Persistent viral infections.
© Indian Virological Society 2020.
Conflict of interest statement
Conflict of interestThe author declares that he does not have any conflict of interest.
Viruses and cancer: A systematic overview
Scientists from the German Cancer Research Center systematically investigated the DNA of more than 2,600 tumor samples from patients with 38 different types of cancer to discover traces of viruses -- which they found in 13 percent of the samples studied. The researchers also identified mechanisms that the pathogens use to trigger carcinogenic mutations in the DNA. The work is part of the Pan-Cancer Analysis of Whole Genomes (PCAWG), an initiative launched by the International Cancer Genome Consortium (ICGC).
The World Health Organization (WHO) estimates that more than 15 percent of all cancers are directly or indirectly attributable to infectious pathogens. The International Agency for Research on Cancer (IARC) in Lyon has classified 11 different pathogens -- viruses, bacteria, and worms -- as carcinogenic agents and estimates that one in ten cancers is linked to viruses. Throughout the world, a total of 640,000 cancers each year are caused by human papillomaviruses (HPV) alone.
A new paper has now been published by an international team of genome researchers led by Peter Lichter from the German Cancer Research Center (DKFZ) to provide a precise overview of which viruses play a role in which cancers. The researchers also looked for viruses that have not previously been associated with carcinogenesis or even ones that were completely unknown. "The issue of which viruses are linked to cancer is highly relevant in medicine," explained Marc Zapatka from DKFZ, the lead author of the present study. "Because in virus-related cancers, real prevention is possible: If a carcinogenic virus is identified, there is a chance of avoiding infection with a vaccine and hence to prevent cancer developing."
The current work is part of the Pan-Cancer Analysis of Whole Genomes (PCAWG), a consortium of more than 1,300 researchers who have teamed up to establish which genetic mutations or patterns of DNA mutations play a role in several types of tumors. For this meta-analysis, they carried out a comprehensive bioinformatic analysis of the sequencing data of more than 2,600 tumor genomes from 38 different types of cancer.
The DFKZ team discovered traces of a total of 23 different virus types in 356 cancer patients. As expected, the known viral drivers of tumor initiation and growth were the most common: The genome of Epstein-Barr viruses (EBV), which are known to cause a number of different types of cancer, in particular lymphomas and gastric and nasopharyngeal carcinomas, was found in 5.5 percent of the cancer genomes investigated. Hepatitis B virus (HBV) DNA was found in 62 of the 330 cases of liver cancer.
The researchers primarily found human papillomaviruses, most commonly HPV16, in cervical carcinomas (in 19 of 20 cancer cases investigated) and in head and neck tumors (in 18 of 57 cases).
They were able to rule out a connection with the cancers as highly unlikely for some of the virus types detected. Thus adenoviruses and baculoviruses are often used as research tools in the field of molecular biology, for example, so the sequences found were probably due to contamination.
In a few cases, the team found other viruses already known to cause cancer, such as a retrovirus in kidney carcinoma. Other pathogens were occasionally found in tumors of the tissue type that they normally infect, such as cytomegaloviruses in gastric cancer. Despite thorough bioinformatic analysis, the researchers have not found any completely unknown viruses, however.
In some of the tumors linked to HPV and EBV, the researchers observed that the characteristic driver mutations that the cells of these cancer types normally depend on for growth were missing: The presence of the virus presumably supports malignant cell degeneration through other factors.
Viral integration into the host genome was found as as the most important mechanism that leads to mutations caused by viruses, particularly HVB and papillomaviruses. "We often observed integration of HPV DNA into the telomerase promoter: This genetic switch steers production of the 'immortality enzyme' telomerase and is mutated in many types of cancer. We have now shown that viral integration can also lead to activation of this genetic switch and can thus immortalize the cells," Marc Zapatka explained.
The DKFZ researchers identified cellular defense against viruses as another key mechanism that leads to mutations in the DNA of infected cells: The cell uses its APOBEC proteins to attack the DNA of dangerous viruses -- but this often leads to mutations of the cell's own genome too. As a result, cervical cancer and head and neck tumors may arise following HPV infection, for example.
"When analyzing the whole cancer genome, we discovered traces of viruses in considerably more tumors than in earlier studies that were based on investigating the RNA only. Nevertheless, we were not able to confirm the common speculation that other, as yet unknown viruses are associated with cancer," remarked principal investigator Peter Lichter, summarizing the results of the study. "However, in many cases we now have a clearer idea of how the pathogens cause malignant mutations in cells."
Human T-lymphotrophic virus-1 (HTLV-1)
HTLV-1 has been linked with a type of lymphocytic leukemia and non-Hodgkin lymphoma called adult T-cell leukemia/lymphoma (ATL). This cancer is found mostly in southern Japan, the Caribbean, central Africa, parts of South America, and in some immigrant groups in the southeastern United States.
In addition to ATL, this virus can cause other health problems, although many people with HTLV-1 don’t have any of them.
HTLV-1 belongs to a class of viruses called retroviruses. These viruses use RNA (instead of DNA) for their genetic code. To reproduce, they must go through an extra step to change their RNA genes into DNA. Some of the new DNA genes can then become part of the chromosomes of the human cell infected by the virus. This can change how the cell grows and divides, which can sometimes lead to cancer.
HTLV-1 is something like HIV, which is another human retrovirus. But HTLV-1 cannot cause AIDS. In humans, HTLV-1 is spread in the same ways as HIV, such as unprotected sex with an HTLV-1-infected partner or injection with a needle after an infected person has used it. Mothers infected with HTLV-1 can also pass on the virus to their children, although this risk can be reduced if the mother doesn’t breastfeed.
Infection with HTLV-1 is rare in the United States. Fewer than 1% of people in the US are infected with HTLV-1, but this rate is much higher in groups of people at high risk (such as injection drug users). Since 1988, all blood donated in the United States has been screened for HTLV-1. This has greatly reduced the chance of infection through transfusion, and has also helped control the potential spread of HTLV-1 infection.
Once infected with HTLV-1, a person’s chance of developing ATL can be up to about 5%, usually after a long time with no symptoms (20 or more years).
Special Issue Editor
RNA viruses are important class of human pathogens that causes an array of human diseases. RNA viruses can also act as oncoviruses to promote cancer development (oncogenesis). For example, retrovirus like Human T lymphotrophic virus type 1 (HTLV-I) has been associated to T-cell leukemia, while hepatitis C virus (HCV) has been linked to development of liver cancer. Several RNA viruses also possess anti-cancer property. Known as oncolytic viruses, these viruses specifically “kills” cancer cells, but not normal cells. RNA viruses that possess oncolytic activity are vesicular stomatitis virus (VSV), measles virus, respiratory syncytial virus (RSV), Newcastle disease virus (NDV), mumps virus, reovirus, coxsackie virus, poliovirus. In the last decade major stride has been made in understanding the mechanism of oncogenesis by HTLV-I and HCV. These have led to development of treatment regimen to combat virus-associated cancers. Similarly, research with oncolytic viruses has illustrated the possible usage of these natural or genetically engineered “anti-cancer” viruses to treat various cancers and solid tumors either alone or in combination with other non-virus cancer agents (radiation, chemotherapy etc). This has culminated in major progress for development of safe and efficacious oncolytic viruses that can specifically target cancer cells (and tumors). This special issue will publish original research papers and review articles on RNA oncovirues (HTLV-I and HCV) and oncolytic viruses that possess RNA genome.
Prof. Dr. Santanu Bose
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The Microbiome and Cancer Treatment
The impact of the human microbiome on cancer treatment is just beginning to be explored. Recent studies have highlighted the importance and potential impact of microbes on disease recovery.147 Interestingly, the microbiome can support the immune system in the fight against cancer.15 For example, cyclophosphamide (a drug used to treat leukemia and lymphomas) was found to influence the microbes living in the gut.15 These gut microbes responded by promoting the creation of immune cells, which seems to enhance cyclophosphamide efficacy.15 As we have seen in the previous sections, microbes have been shown to promote cancer development by inducing inflammation. This inflammatory response can also have a beneficial impact on cancer treatments.14 Some therapies, such as platinum chemotherapy and CpG-oligonucleotide immunotherapy, are dependent on inflammation.14 Mice that were treated with antibiotics (which killed the gut micobiome) did not respond as well to platinum chemotherapy or CpG-oligonucleotide immune therapy compared to mice with intact gut microbes.14 These results suggest that the gut microbiome enhances the effects of therapies that are dependent on inflammation.14
Resistance to cancer treatments has been linked to the presence of specific kinds of bacteria in the gut. Researchers looking at drug resistance in colorectal cancer patients found an increase in Fusobacterium nucleatum in the gut. The bacterium was shown to block death ( apoptosis ) of the cancer cells and trigger autophagy, a survival tool for the cancer cells.16
How microbes promote immunity and affect cancer development and treatment responses is still being investigated. It is clear, however, that the microbiome can play an important role in both cancer development and treatment responses. Ultimately, researchers hope to identity and harness microbes that fight cancer and develop ways to eliminate those which promote cancer development.7