Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Viruses and Cancer: A Walk on the Memory Lane

Curator: Demet Sag, PhD, CRA, GCP

 

One of the other mechanism where cancer and microorganisms establish a close relationship is viruses. They are vicious sometimes as they adept fast even we don’t call them a real organism since they require a living cell to survive. Vaccination against these viruses or using them as a tool to deliver genes to cure certain human diseases also become very attractive. They come various shapes, sizes, and content.

At first the discoveries of human viral cancers was done by tedious viral technology but later for the last four human cancer viruses molecular biology techniques used.

It was in 2011 Francis Peyton Rous’s landmark experiments on an avian cancer virus the connection between viruses and cancer is established yet we discover new ones. Currently we believe that about 10-215% cancers originated from viruses.

They were very interesting due to their dual actions through infections or non-infectious cancer causes with their effects on immune system, innate immunity, and tumor suppressor proteins.

Since their discoveries it was also identified that 20 % or one in five cancer cases born as a result of viral infections. Therefore, in the world now two of them have widely used vaccines, hepatitis B virus (HPV) and human papilloma virus (HPV). On the other hand, one may wonder what their efficacy is.

Of course these discoveries came with the highest recognitions:

Nobel Prizes awarded for the discoveries of viruses in timeline.

The origin of cancer viruses and cancer sometimes bring a misconception. For a virus tumors are dead end since they can’t replicate and invade the organisms unlike many thought that viruses infect the host to increase their replication. Thus, most of time only in very rare occasions they transmit to another human so the big fat truth is most if the human tumor viruses are asymptomatic. Even if they can be very mildly symptomatic, they don’t make neoplasia.

On the other hand, the question is why and how the viruses make oncogenes and why they initiate tumorogenecity begs the question. Of course, there is an evolution but also they have a common functional targets in the human genome. Like viruses human genome has various replicating sequences or inversions. When these viruses expressing oncoproteins they mainly target the RB1 and p53.  In addition, these tumor targets attack telomerase reverse transcriptase (TERT⁾, cytoplasmic PI3K–AKT–mTOR, nuclear factor-κB (NF-κB), β-catenin (also known as CTNNB1) and interferon signaling pathways.

Thus immunity and inflammation reactions present different pathways against the virulent action and initiation of tumor forming for cancer.

http://www.ncbi.nlm.nih.gov/corecgi/tileshop/tileshop.fcgi?p=PMC3&id=858389&s=38&r=1&c=2

1966  Nobel Prize awarded to Rous

Tumorigenic retroviruses have been central to cancer biology, leading to the development of focus formation assays, discovery of reverse transcription, identification of more than 20 cellular oncogenes, and ultimately Nobel Prize recognition for Rous 57 years after his initial experiments. Then these discoveries led to discoveries of oncogenes and tumor suppressor genes.

 

1975 Nobel Prize awarded to Temin, Baltimore, and Dulbeco

 

1976 Nobel Prize awarded to Blumberg

HBV, discovered shortly after EBV in the mid-1960s and leading to a Nobel Prize for Baruch Blumberg in 1976, has only recently been successfully propagated in culture and was first linked by serology to acute hepatitis rather than to cancer^25,26. The role of HBV in hepatocellular carcinoma was established more than a decade later by Beasley et al.²⁷ through longitudinal studies of Taiwanese insurance company cohorts.

 

1989 Nobel Prize awarded to Bishop and Varmus

 

2008 Nobel Prize awarded to Harald zur Hausen, François Barré-Sinoussi and Luc Montagnier.

 

Nobel Prizes awarded in 2008 for the discovery by Harald zur Hausen of high-risk HPV strains that cause cervical cancer and the discovery of HIV, an agent that does not initiate cancer but indirectly ‘sets the stage’ for malignancy through immuno suppression, by François Barré-Sinoussi and Luc Montagnier.

Furthermore, human cancer viruses span the entire range of virology and include:

• complex exogenous retroviruses
  • such as HTLV-I,
• positive-stranded RNA viruses
  • such as hepatitis C virus (HCV),
• DNA viruses with retroviral features
  • such as HBV
• both large double-stranded DNA viruses :
  • such as EBV and
  • Kaposi’s sarcoma herpesvirus

(KSHV; also known as human herpesvirus 8 (HHV8))

• small double-stranded DNA viruses
  • HPV and
  • Merkel cell polyomavirus (MCV)).

 

 

The human cancer viruses:

Virus	Genome	Notable cancers	Year first described
Epstein–Barr virus (EBV; also known as human herpesvirus 4 (HHV4))	Double-stranded DNA herpesvirus	Most Burkitt’s lymphoma and nasopharyngeal carcinoma, most lymphoproliferative disorders, some Hodgkin’s disease, some non-Hodgkin’s lymphoma and some gastrointestinal lymphoma	1964 PMID:14107961 Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;15:702–703.
Hepatitis B virus (HBV)	Single-stranded and double-stranded DNA hepadenovirus	Some hepatocellular carcinoma	1965 PMID:14239025 Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. JAMA. 1965;191:541–546.
Human T-lymphotropic virus-I (HTLV-I)	Positive-strand, single-stranded RNA retrovirus	Adult T cell leukaemia	1980 PMID:6261256 Poiesz BJ, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl Acad. Sci. USA. 1980;77:7415–7419.
High-risk human papillomaviruses (HPV) 16 and HPV 18 (some other α-HPV types are also carcinogens)	Double-stranded DNA papillomavirus	Most cervical cancer and penile cancers and some other anogenital and head and neck cancers	1983–1984 PMID:6304740 Durst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc. Natl Acad. Sci. USA. 1983;80:3812–3815. PMID:6329740 Boshart M, et al. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J. 1984;3:1151–1157.
Hepatitis C virus (HCV)	Positive-strand, single-stranded RNA flavivirus	Some hepatocellular carcinoma and some lymphomas	1989 PMID:2523562 Choo QL, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244:359–362.
Kaposi’s sarcoma herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8))	Double-stranded DNA herpesvirus	Kaposi’s sarcoma, primary effusion lymphoma and some multicentric Castleman’s disease	1994 PMID:7997879 Chang Y, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;265:1865–1869.
Merkel cell polyomavirus (MCV)	Double-stranded DNA polyomavirus	Most Merkel cell carcinoma	2008 PMID:18202256 Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–1100.

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Common cellular targets for unrelated tumour virus oncoproteins

An incomplete but diverse list of animal and human tumour virus proteins that target RB1, p53, interferon and PI3K–mTOR signalling pathways. Most of these viral proteins are evolutionarily distinct from each other and have unique mechanisms for regulating or ablating these signalling pathways. Convergent evolution of tumour viruses to target these (and other cellular signalling pathways (not shown), including interleukin-6 (IL-6)–signal transducer and activator of transcription 3 signalling, telomerase and nuclear factor-κB (NF-κB) signalling pathways) reveals commonalities among the cancer viruses in tumour supressor and oncoprotein targeting. CBP, cAMP-response element binding protein; CDKI, cyclin-dependent kinase inhibitor; EBV, Epstein–Barr virus; HCV, hepatitis C virus; HPV, human papillomavirus; HTLV, human T-lymphotropic virus; IFNR, interferon receptor; IRF, interferon regulatory factor; KSHV, Kaposi’s sarcoma herpesvirus; LMP, latent membrane protein; miRNA, microRNA. Nat Rev Cancer. Author manuscript; available in PMC 2013 Jul 22.

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Two views for the origins of viral oncoproteins

a | The tumour virus proteins target RB1 and p53 to drive a quiescent G0 cell into S phase of the cell cycle, allowing viral access to the nucleotide pools and replication machinery that are needed for replication and transmission¹⁰⁰. 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 response⁸⁶. 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. b | An illustration of the overlap between intracellular innate immune and tumour suppressor signalling. Under typical circumstances, viruses do not cause cancers except in the settings of immunosuppression and/or complementing host cell mutations. 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 p300, additional proteins are likely to have both tumour suppressor and innate immune functions.

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The molecular evolution of a human tumour virus

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 cells¹⁶¹. If a rare integration mutation into the host cell genome occurs³⁴, the MCV T antigen can activate independent DNA replication from the integrated viral origin that will cause DNA strand breaks in the proto-tumour cell¹⁵⁷. 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.

Glossary

Antibody panning	cDNA from a tumour is used to express proteins in bacteria and transferred to replicate filters. Antibody screening of the filters can then be used to identify colonies expressing the specific cDNA encoding an antigen.
Bayesian reasoning	A scientific approach developed from Bayes theorem, combining features of the Logical Positivist and Kuhnian schools of science philosophy, and describing how the probability of a hypothesis (in this case, virus A causes cancer B) changes with new evidence. In simple terms, it can be described as the repeated application of the scientific method to falsify a hypothesis such that the hypothesis has a high probability of being either true or false.
Digital transcriptome subtraction	DTS. Method to discover new viruses by exhaustively sequencing cDNA libraries and aligning known human sequences by computer leaving a smaller candidate pool of potential viral sequences for analysis36.
Endogenous retrovirus	ERV. Retrovirus that has inserted into the metazoan germline genome over evolutionary timescales and is now transmitted to offspring as a genetic element through Mendelian inheritance. Approximately 8% of the human genome is estimated to be derived from retroviral precursors.
High-risk papillomaviruses	More than 160 different genotypes or strains of HPV have been described but only a few genotypes belonging to a high-risk carcinogenic clade of the α-HPV genus are responsible for invasive HPV-related anogenital cancers211.
Longitudinal study	Virus infection is measured initially in a cohort of patients who are then followed over time to determine cancer occurrence.
Prodromal phase	An early set of nonspecific symptoms that occur before the onset of specific disease symptoms.
Representational difference analysis	A PCR-based subtractive hybridization technique that can subtract common human sequences from a tumour genomic library using a control human tissue genomic library35.
Serology	The measurement of antibodies against viruses in blood or bodily fluids. This usually does not distinguish ongoing infections from past viral infections.