Explain how a virus can cause cancer

When E2F is bound to Rb, it cannot act as a transcription factor and cannot cause the cell to divide. But, if E7 binds to Rb, E2F cannot also bind to Rb and is then free to act as a transcription factor. In essence, E7 inhibits an inhibitor or cell division. When a cell makes the E7 protein, the E2F transcription factor causes the cell to divide, a critical step in cancer development.

Research in mice showed that infection with a group of human papillomaviruses beta-HPV led to a protective immune response against squamous cell skin cancer SCC. The researchers believe that the immune response against the virus somehow protects against cancers caused by exposure to ultraviolet UV radiation.

They are now looking into using HPV vaccination to protect against skin cancer. Transmission: HTLV1 can be transmitted via sexual or blood-blood contact. It can also be passed through breast milk and from mother to fetus. Tax may contribute to carcinogenesis by inducing cellular proliferation, activating cell survival proteins, and also may contribute to chromosomal instability. Several other retroviruses are also associated with cancer and the use of retroviral vectors in cancer treatment has to take into consideration the possibility that the treatments could cause major problems.

Merkel cells are located in the outer layer of skin epidermis and their exact function is not known. They appear to have sensory roles i. The images below, in clockwise order - a Merkel cell tumor, Merkel cell cancer as viewed under a microscope, virus-like particles from MCV,. Providing reliable information about cancer biology and treatment. Viruses and Cancer In addition to chemicals and radiation , another source of mutation is viruses.

Viruses can disrupt cell behavior in several different ways. The integration can disrupt important regulatory genes. The viruses may contain their own genes that disrupt the regulation of the cell. This process may be beneficial to the virus if it allows for rapid production of progeny but can be seriously detrimental to the host. Some viruses actually carry altered versions of genes that they have picked up from previous host cells. These altered genes no longer function properly, and when they are inserted into a new host cell, they cause disregulation and can lead to cancerous growth.

There are 3 steps necessary for cervical cancer development: 12 HPV Infection. HPV Persistence. Less common. If HPV infection is not cleared and persists for a long period of time a condition called cervical intraepithelial neoplasia CIN can develop. See below for more about cervical intraepithelial neoplasia. Cell Transformation and Invasion. Rare in comparison to the number of women infected by HPV. Invasion usually occurs after a long period of infection.

It is thought that severe dysplasia does not occur without certain co-factors. Jones and Bartlett Publishers, Campbell Biology 11th ed. Boccardo and LL Villa. Viral Origins of Human Cancer. Current Medicinal Chemistry. Epstein-Barr virus and Burkitt lymphoma. Postgrad Med J. Hepatitis B virus-induced oncogenesis. World J Gastroenterol. HCV-related hepatocellular carcinoma: From chronic inflammation to cancer. Clin Immunol. Epub Nov Ensoli, C. There is currently no vaccine for Epstein-Barr virus.

Hepatitis B virus HBV is spread through infected blood, semen and other body fluids. Hepatitis B is a leading cause of liver cancer. The hepatitis B vaccine is recommended for all children and adults.

Hepatitis C virus HCV is spread through infected blood. There is no vaccine against hepatitis C, but it is highly treatable. Human immunodeficiency virus HIV is spread through infected semen, vaginal fluids, blood and breast milk. It can enable other oncoviruses to cause cancer. There is no vaccine against HIV. Human herpes virus 8 HHV-8 is related to Kaposi sarcoma in people who have a weakened immune system.

That includes patients with HIV. Human papillomavirus HPV has at least 12 strains that can cause cancer in men and women, including anal, cervical, penile , throat, vaginal and vulvar cancer. Boys and girls age should get the HPV vaccine. It is spread through infected semen, vaginal fluids, blood and breast milk. The infection is rarely found in the United States. The effects of these viruses on cancer development is highly complicated.

Viruses can leave the body through one site or multiple sites. This topic is concerned with how the virus transmits from one individual to another. Virus transmission depends on the amount of virus shed, duration of shedding, and the ability of the virus to survive in the environment until it reaches the host body and infects it.

Please feel free to contact us for any question or comment below your question and thebiomanual team will respond to your comments. July 14, July 16, TheBioManual how viruses cause disease , viral infections , virus pathogenesis , viruses. Loading Comments Evidence supporting this comes from knockdown studies in which the loss of viral proteins results in the loss of host cancer viability 54 - Hepatocellular carcinoma HCC generally arises after prolonged liver cirrhosis from chronic virus-induced cell death and regeneration 61 - HTLV-I, like most direct carcinogens, is present as a clonal infection of ATLL, but expression of its putative oncogene v-tax is frequently absent in the mature leukaemia or lymphoma cells Thus, for these viruses it remains unclear whether specific viral products maintain mature tumour cells, promote a precancerous cell phenotype or contribute to cancer solely through prolonged infection and chronic inflammation 62 , Bacterial carcinogens can also have features that are reminiscent of direct carcinogens 66 , showing that the simple dichotomization of direct and indirect carcinogens is probably inadequate.

The indirect versus direct paradigm is nonetheless very useful as it guides our thinking about which cancers are most likely to harbour a new human cancer virus. Cancers that are related to immunosuppression are candidates for being caused by tumour viruses Loss of surveillance for specific viral cytotoxic T cell epitopes without generalized immunosuppression, as might occur during ageing, is also likely to promote cancers that are caused by viruses 68 , This makes intuitive sense, particularly for direct carcinogens, as they must express at least one foreign protein in each cancer cell, but even cancers caused by indirect infectious carcinogens have an increased occurrence in immunosuppressed populations In a classic epidemiological study, Beral et al.

Similarly, analyses by Engels et al. This paradigm not only suggests where to look for human cancer viruses but also how to look for them. A cell possesses approximately , mRNA transcripts, and methods to sequence cDNA substantially beyond this level are readily available. If a direct carcinogen is present and expresses a foreign oncoprotein, carrying out DTS on cDNA from a monomorphous tumour specimen is likely to sequence a viral gene.

There are technical difficulties with this approach particularly in recognizing that a transcript belongs to a novel virus rather than being a missequenced or unannotated human transcript, as outlined elsewhere 36 that place constraints on sequencing-based virus discovery.

As genomic databases improve, molecular distinctions between self and non-self genomes will become more precise and easier to detect. Equally importantly, sequencing technologies can help to exclude a direct carcinogen if it is not present in a cancer.

Deep sequencing of four human mesothelioma tumour cDNAs failed to identify SV40 viral transcripts 74 , providing evidence against a long-standing hypothesis that SV40, a rhesus polyomavirus, is directly involved in the development of mesothelioma Although this does not exclude SV40 as a cause of human cancer, this virus would have to do so in mesotheliomas through a new and undescribed mechanism.

Tumour trasnscriptome sequencing can also be paired with sequencing of the appropriate control tissues to determine cancer cell gene expression. Therefore, if properly carried out, even negative searches for viral sequences can provide useful clues about the origins of human cancer. A common feature for human tumour viruses is that they are persistent latent or pseudo-latent infections that generally do not replicate to form infectious virus particles in tumours.

All of the viruses in TABLE 1 have the capacity to form virions and become transmissible at some point in their natural lifecycles, but within tumours these infections are generally latent so that productive virus replication also known as lytic replication is either diminished or absent Viral latency serves as an immune evasion strategy allowing the virus to hide from the immune system by turning off unnecessary viral proteins that might be sensed by cell-mediated immune recognition.

The virus persists as a naked nucleic acid, often as a plasmid or episome, which relies on host cell machinery to replicate whenever the cell divides. Viral latency should not be confused with clinical latency, which means asymptomatic infection. Latent viral infections can be symptomatic, as in viral cancers, and active lytic viral replication can be relatively asymptomatic, as occurs during the prodromal phases of HIV or HCV infection.

As early as the s, investigators recognized an inverse relationship between virus replication, or permissiveness, and cell transformation for tumour viruses. SV40, for example, transforms human cells efficiently only when mutations are introduced into its replication origin to prevent viral replication The most likely explanation for the connection between virus latency and tumorigenesis is that productively replicating viruses initiate cell death, which has long been known to virologists as the cytopathic effect CPE.

Counter-intuitively, from the point of view of tumour virology, virus-induced CPE can be harnessed to kill cancer cells in viral oncolytic therapies, illustrating the anticancer activity of active lytic viral replication 82 , Although CPE is frequently thought of as a virus-induced event, it is actually a stereotypical and nonspecific innate immune response of cells to infection by many types of viruses. When latent viruses switch to producing virions, virus replication generates pathogen-associated molecular patterns from partially synthesized viral chromosomes, double-stranded RNAs and empty capsids that trigger cellular DNA damage responses and innate immune signalling 84 - For some viruses, lytic replication generates a linear viral chromosome that can be recognized as a DNA fragment 87 unless either the DNA ends are structurally hidden from DNA damage response sensors by encapsidation or these sensors are inactivated.

Activation of toll-like receptor and interferon signalling by virus infection initiates and amplifies this innate immune response Together, these cellular responses generally kill infected cells that are undergoing productive virus replication — hence the term lytic replication. Once triggered, lytic viral replication is largely irreversible and initiates a race between the virus to successfully reproduce itself and the death of the host cell.

Among viruses, latency is best understood for the herpesvirus family particularly for EBV and KSHV that have latent viral tissue culture systems , in which it is tightly regulated by transcriptional repression Latent herpesviral protein expression is limited to a few crucial, non-structural viral products that include oncogenic proteins and microRNAs miRNAs.

During herpesviral latency the viral genome is not packaged into virions but instead the viral genome replicates in tandem with the host cell using the replication machinery of the cell and is tethered to chromosomes as a naked circular genome Lytic replication to produce infectious virions is initiated through a highly stereotypical series of viral transactivator cascades, which are cued by cellular environmental signalling pathways, that leads to host cell death and the release of infectious virions Although not fully described, these cellular environmental triggers might tell the persistent virus when to initiate lytic virus replication to optimally achieve transmission to a new host and survive.

Viral control of lytic and latent replication is less well-understood for the RNA and small DNA tumour viruses, but these agents also show a similar absence of productive viral replication during malignancy. In these tumours, the viral oncoprotein TAX is thought to promote early precancerous cell expansion and survival, but it may not be required in the fully malignant T cell.

Although herpesviruses do not generally integrate into the host genome, recombination patterns for their terminal repeat sequences can also be used as markers for tumour cell clonality 94 , As viruses in tumours are generally latent, antiviral drugs targeting the viral replication machinery are ineffective in treating mature tumours.

However, antiviral therapy can in some instances prevent the development of new tumours. A possible exception to the rule for viruses being non-replicative and silent in human malignancy is HBV. This virus can infect nearly all hepatocytes in the liver during acute HBV hepatitis but most cells survive infection, eventually clearing the viral genomes without cell death It is not known whether this results from re-expanding clones of hepatocytes or whether it represents a premalignant change.

Cancers caused by viruses — such as non-infectious cancers — are biological accidents. Tumours do not increase transmissibility of viruses or enhance their replication fitness. A common misperception is that cancer viruses cause cancer to increase viral burden and transmission. Only a small proportion of people infected with any of the human tumour viruses develop tumours and, of those people who do, they rarely if ever serve as sources for ongoing transmission.

Instead, most human tumour virus transmissions are asymptomatic or mildly symptomatic but do not lead to neoplasia.

If we discard the idea that viruses are evolutionarily programmed to cause cancer, then why do tumour viruses encode oncogenes? There is strong selection to maintain viral genes that can initiate tumorigenesis, as diverse viruses including, non-tumour viruses show remarkable convergence to target the same tumour suppressor pathways FIG. For example, most of the human tumour viruses encode oncoproteins that target RB1 and p53, although they do so through different and unique mechanisms Most of these viral proteins are evolutionarily distinct from each other and have unique mechanisms for regulating or ablating these signalling pathways.

Two widely held views exist for the teleology of viral oncogenes FIG. The first hypothesis originated from the biology of small DNA tumour viruses such as HPV and SV40 and was based on the presumed need for these viruses to re-initiate the cell cycle entry of differentiated cells to set conditions for viral replication , Because the host replication machinery and nucleotide pools are limited in the G0 cell cycle phase of differentiated cells, these viruses might force unscheduled S phase entry to generate the cellular resources that are needed for viral genome replication.

Disruption of cell cycle regulation, however, also activates cell death signalling pathways, such as p53, and so apoptotic signalling should also be inhibited to allow the efficient manufacture and export of viruses before cell death. Viral tumourigenesis is a by-product of the molecular parasitism by viruses to promote their own replication. Cells respond to virus infection by activating RB1 and p53 to inhibit virus replication as part of the innate immune response To survive, tumour viruses have evolved the means for inactivating these and other immune signalling pathways that place the cell at risk for cancerous transformation.

This view holds that many tumour suppressor proteins have dual functions in preventing cancer formation and virus infection. Non-tumorigenic viruses, which constitute the overwhelming majority of viruses, target many of the same innate immune and tumour suppressor pathways as tumour viruses but do so in ways that do not place the host at risk for carcinogenesis. Apart from p53, RB1 and p, additional proteins are likely to have both tumour suppressor and innate immune functions.

This is illustrated by the lifecycle of HPV, which infects basal epithelial cells that differentiate into arrested squamous epithelium. A commonly held view of HPV targeting of tumour suppressor pathways is that as the infected keratinocyte differentiates, the HPV E7 oncoprotein inactivates RB1 signalling to drive quiescent, infected cells back into a proliferative state, thus allowing viral genome replication Simultaneously, the HPV E6 protein induces ubiquitin-mediated degradation of p53, preventing the premature apoptosis that would otherwise limit the efficiency of virus production Under normal circumstances, these virus-deregulated cells will typically be sloughed off together with infectious virions.

Rare mutations, however, that disrupt this lifecycle such as an HPV integration event that results in the loss of early viral gene regulation can set the stage for this molecular parasitism to turn into cancer cell transformation. By targeting the cell cycle checkpoints and anti-apoptotic machinery that are involved in genomic proofreading, viral oncogenes also induce cellular genomic instability and aneuploidy, which in turn contribute to carcinogenesis , In summary, the most commonly held view for the function of viral oncogenes is that these genes target cellular tumour suppressor pathways to promote productive viral replication and only contribute to cancer when random mutations disrupt this equilibrium.

However, studies on the large DNA tumour viruses such as EBV and KSHV suggest a more complex interaction between the viral oncogenes and the host cell that may have more to do with evading immune responses during latency than ensuring viral genome replication 86 , , During lytic viral replication, these viruses also hijack the cell cycle regulation machinery to promote their own genomic replication. The oncogenic herpesviruses encode proteins to inhibit p53, RB1 and other tumour suppressor checkpoints during active lytic viral replication - , and also possess virally encoded DNA synthesis enzymes These viral genes, like their counterparts among the small DNA tumour viruses, set the stage for the rapid replication and amplification of viral genomes by generating an S phase-like cellular state that can replicate viral DNA once lytic replication is initiated.

But the viral proteins and virus-encoded miRNAs that drive herpesviral tumours are expressed during latency, and these viral oncogenes can not directly contribute to productive viral replication , - Herpesvirus oncoproteins are expressed at the wrong time for them to be involved in generating the cellular resources needed for virus genome replication.

The KSHV-encoded cyclin is another latent viral oncoprotein , that is expressed in a cell cycle-dependent manner Studies from the herpesviruses raise the question: what are the viral oncoproteins doing if they are not preparing the cell for virus replication? Over the past decade, increasing evidence has indicated that the evasion of innate immunity also plays a fundamental part in viral tumorigenesis.

Humans, as well as most complex metazoans, are chimeric for numerous viruses. In some cases, mammals may even exploit latent viral infections to beneficially regulate their own innate immune systems So, it is not surprising that major portions of the eukaryote cell are devoted to protecting the host genome from foreign viral sequences.

Innate immune signalling shares many similarities to tumour suppressor signalling, as both processes initiate cell cycle arrest and prime apoptotic pathways.

Key effector proteins such as the p21 cyclin-dependent kinase inhibitor and p53 REF. This suggests that targeting of tumour suppressor pathways by viruses may actually represent an immune evasion response that disables antiviral pathways but inadvertently places the infected cell at risk for cancerous transformation known as the anti-antivirus hypothesis 86 , The dual nature of innate immune signalling in antivirus and anticancer functions is illustrated by interferon regulatory factors IRFs , a family of induced and immediate-early transcription factors that regulate interferon transcriptional responses - This implies that infected cells can sense latent virus infection and must deactivate cell cycle arrest and pro-apoptotic pathways to survive in the hostile environment of the cell.

Although a role for oncoproteins in innate immune evasion is best characterized for herpesviruses, other viral oncoproteins, such as the human adenovirus E1A oncoprotein that causes cancer in rodents, also dually inhibit interferon signalling and tumour suppressor pathways by targeting the histone acetyltransferases p and CBP , , which participate in interferon-induced transcription.

The relationship between tumour suppression and cellular antiviral activity was described by Takaoka and colleagues who showed that knock out of Trp53 encoding p53 causes immune deficiency to virus infection, and that virus-induced inflammatory cytokines prime cellular pro-apoptotic signalling pathways Other cellular pathways FIG.

Cellular sensors for DNA and RNA ends are generally studied as triggers for the repair of somatic mutations but they also have a role in sensing viral nucleic acids , DNA damage responses are activated during viral uncoating and replication 65 , - that can lead to cell cycle arrest and inflammatory signalling activation Disarming the antiviral targeting of tumour suppressor signalling may allow the prolonged persistence of viral infection but also carries obvious risks for generating a cancer.

Despite evidence for a relationship between innate immune and tumour suppressor signalling FIG. The examples we describe above mainly come from the first six human tumour viruses. How does the most recently discovered virus, MCV, compare?

Similar to SV40 and murine polyomaviruses, MCV encodes a multiply spliced tumour T antigen protein complex that targets several tumour suppressor proteins Within infected tumours, the T antigen is only expressed in tumour cells, as predicted for a direct viral carcinogen Given these features, the strongest evidence to support MCV causing MCC comes from its random clonal integration into Merkel cell tumours 34 , and knockdown studies showing that T antigen expression is required for the survival of virus-positive Merkel cell lines Although skin carriage of the virus is common , no other tumours except MCC have yet been convincingly linked to MCV infection.

As SV40 and related polyomaviruses have been workhorses for cancer research from the early s, studies on these viruses can be directly applied to MCV, allowing rapid progress in understanding its biology in humans. MCV is intriguing because the precise molecular events leading to cancer have been described and they help to explain why this common childhood infection can lead to a rare cancer that is associated with sun exposure FIG.

MCC principally occurs in the elderly and immunocompromised, and those people developing MCV-related MCC have greatly increased antibodies to MCV structural proteins, suggesting that the loss of cellular immune control over the virus may allow viraemia before the development of the tumour , , Merkel cell polyomavirus MCV , which has tumour-specific truncation mutations, illustrates common features among the human tumour viruses involving immunity, virus replication and tumour suppressor targeting.

Although MCV is a common infection, loss of immune surveillance through ageing, AIDS or transplantation and subsequent treatment with immunosuppressive drugs may lead to resurgent MCV replication in skin cells If a rare integration mutation into the host cell genome occurs 34 , the MCV T antigen can activate independent DNA replication from the integrated viral origin that will cause DNA strand breaks in the proto-tumour cell A second mutation that truncates the T antigen, eliminating its viral replication functions but sparing its RB1 tumour suppressor targeting domains, is required for the survival of the nascent Merkel tumour cell.

Exposure to sunlight possibly ultraviolet UV irradiation and other environmental mutagens may enhance the sequential mutation events that turn this asymptomatic viral infection into a cancer virus. The virus then undergoes at least two mutations, the first being non-homologous recombination with the host chromosome. As with other tumour viruses, clonality of integration in primary tumours and their metastases shows that this occurs before the tumour cell begins to proliferate As MCV has no mechanism to excise its genome, the virus cannot replicate and is no longer transmissible, and this is analogous to HPV in most cervical carcinomas.

MCV integration, however, generates a problem for the nascent tumour cell. The viral large T antigen not only targets tumour suppressor molecules, such as RB1, but it is also required for productive virus replication. During a typical infection by MCV, the large T antigen protein binds to the viral genome and its helicase domain unwinds the viral origin to allow DNA replication If the full-length large T antigen protein is expressed in tumour cells with an integrated virus, it initiates unlicensed DNA synthesis at the integration site causing replication fork collisions and DNA break responses that could lead to cytopathic cell death All MCV genomes that have been obtained from tumours so far, however, have inactivating secondary mutations in the T antigen gene that eliminate its DNA replication capacity.

Whether additional cellular mutations are required for the successful outgrowth of MCV-infected MCC tumours is currently unknown. Molecular evolution of MCV in MCC tumours illustrates many of the common features that have been described for the other human tumour viruses. Most notably, tumour formation is a rare, accidental occurrence in the lifecycle of this otherwise innocuous virus. The recent discovery of additional new human polyomaviruses , , provides the opportunity to determine whether other members of this group share a similar potential for contributing to human viral cancers.

The reduced cost and increased accuracy of sequencing technologies has created the opportunity for most research groups to search for cancer viruses. Only a snippet of unique nucleic acid sequence is needed to discover a new human tumour virus and to begin characterizing it, so the pool of cancer-causing candidates is almost certain to grow in the coming decade. Equally importantly, the reliability of human sequence databases has matured to a level at which certain classes of cancer agents might be excluded when none is found.

Identifying a new virus, however, is only the beginning in determining whether it causes human cancer. Cancer causation theories work well for uncommon viruses that are uniformly present in a particular type of cancer 64 , Head and neck squamous cell carcinomas and MCCs 34 are examples of cancers that were previously assumed to be homogenous cancers but are now recognized as likely to be caused by both infectious and non-infectious or at least not identified infectious aetiologies.

Epidemiologists will be increasingly pressed to determine whether a candidate viral agent might cause only a small but important portion of a type of tumour. New epidemiological methods that make better use of molecular biologic data will be key to resolving the causes for these cancers.

Viruses have had a chequered history in cancer biology over the past century. Depending on the time and the fashion, viruses have been either sought out as the primary cause for cancer, or ignored as inconsequential to this disease. We are now entering a more mature phase of research with the realization that a considerable proportion of cancers are indeed caused by viruses. For these cancers, infection is only one component in their ultimate cause. But failure to recognize the importance of viral cancers has led to overlooked opportunities in cancer control.

Despite EBV being the first discovered human tumour virus, there is no EBV vaccine and little enthusiasm for its development. KSHV has emerged as a leading cause of adult cancer in sub-Saharan Africa but no movement has yet been made in developing clinical interventions against this virus or its cancers.