The year 2011 marks the centenary of Francis Peyton Rous's landmark experiments on an avian cancer virus. Since then, seven human viruses have been found to cause 10–15% of human cancers worldwide. Viruses have been central to modern cancer research and provide profound insights into both infectious and non-infectious cancer causes. This diverse group of viruses reveals unexpected connections between innate immunity, immune sensors and tumour suppressor signalling that control both viral infection and cancer. This Timeline article describes common features of human tumour viruses and discusses how new technologies can be used to identify infectious causes of cancer.
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Parkin, D. M. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030–3044 (2006).
Bouvard, V. et al. A review of human carcinogens-part B: biological agents. Lancet Oncol. 10, 321–322 (2009).
Chang, M. H. et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N. Engl. J. Med. 336, 1855–1859 (1997).
Lavanchy, D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J. Viral Hepat. 11, 97–107 (2004).
Goldie, S. J. et al. Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J. Natl Cancer Inst. 96, 604–615 (2004).
Polk, D. B. & Peek, R. M. Helicobacter pylori: gastric cancer and beyond. Nature Rev. Cancer 10, 403–414 (2010).
Vennervald, B. J. & Polman, K. Helminths and malignancy. Parasite Immunol. 31, 686–696 (2009).
Rous, P. A transmissible avian neoplasm. (Sarcoma of the common fowl). J. Exp. Med. 12, 696–705 (1910).
Rous, P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 13, 397–411 (1911).
Ellerman, V. & Bang, O. Experimentelle leukämie bei hühnern. Centralbl. f. Bakteriol. 46, 595–609 (1908).
Beard, J. W. Avian virus growths and their etiologic agents. Adv. Cancer Res. 7, 1–127 (1963).
Becsei-Kilborn, E. Scientific discovery and scientific reputation: the reception of Peyton Rous' discovery of the chicken sarcoma virus. J. Hist. Biol. 43, 111–157 (2010).
Vogt, P. K. Peyton Rous: homage and appraisal. FASEB J. 10, 1559–1562 (1996).
Gross, L. Oncogenic Viruses (Pergamon, Oxford, 1970).
Epstein, M. A., Achong, B. G. & Barr, Y. M. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 15, 702–703 (1964).
Proceedings of the IARC working group on the evaluation of carcinogenic risks to humans. Epstein-Barr virus and Kaposi's sarcoma herpesvirus/human herpesvirus 8. Lyon, France, 17–24 June 1997. IARC Monogr. Eval. Carcinog. Risks Hum. 70, 1–492 (1997).
Kelly, G. L. & Rickinson, A. B. Burkitt lymphoma: revisiting the pathogenesis of a virus-associated malignancy. Hematology Am. Soc. Hematol. Educ. Program 2007, 277–284 (2007).
Bunge, M. Causality: The Place of the Causal Principle in Modern Science (Meridian Books, Cleveland and New York, 1959).
Epstein, M. A., Henle, G., Achong, B. G. & Barr, Y. M. Morphological and biological studies on a virus in cultured lymphoblasts from Burkitt's lymphoma. J. Exp. Med. 121, 761–770 (1965).
Poiesz, B. J. 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 77, 7415–7419 (1980).
Miyoshi, I. et al. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature 294, 770–771 (1981).
Yoshida, M. Discovery of HTLV-1, the first human retrovirus, its unique regulatory mechanisms, and insights into pathogenesis. Oncogene 24, 5931–5937 (2005).
Gallo, R. C. History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2. Oncogene 24, 5926–5930 (2005).
Vahlne, A. A historical reflection on the discovery of human retroviruses. Retrovirology 6, 40 (2009).
Blumberg, B. S., Alter, H. J. & Visnich, S. A “new” antigen in leukemia sera. JAMA 191, 541–546 (1965).
Prince, A. M., Fuji, H. & Gershon, R. K. Immunohistochemical studies on the etiology of anicteric hepatitis in Korea. Am. J. Hyg. 79, 365–381 (1964).
Beasley, R. P., Hwang, L. Y., Lin, C. C. & Chien, C. S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet 2, 1129–1133 (1981).
zur Hausen, H. Condylomata acuminata and human genital cancer. Cancer Res. 36, 794 (1976).
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 80, 3812–3815 (1983).
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. 3, 1151–1157 (1984).
Choo, Q. L. et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244, 359–362 (1989).
Wakita, T. et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Med. 11, 791–796 (2005).
Chang, Y. et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 265, 1865–1869 (1994).
Feng, H., Shuda, M., Chang, Y. & Moore, P. S. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319, 1096–1100 (2008).
Lisitsyn, N., Lisitsyn, N. & Wigler, M. Cloning the differences between two complex genomes. Science 259, 946–951 (1993).
Feng, H. et al. Human transcriptome subtraction by using short sequence tags to search for tumor viruses in conjunctival carcinoma. J. Virol. 81, 11332–11340 (2007).
Xu, Y. et al. Pathogen discovery from human tissue by sequence-based computational subtraction. Genomics 81, 329–335 (2003).
Perz, J. F., Armstrong, G. L., Farrington, L. A., Hutin, Y. J. & Bell, B. P. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J. Hepatol. 45, 529–538 (2006).
Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).
Hahn, W. C. et al. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol. Cell. Biol. 22, 2111–2123 (2002).
Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999).
Purtilo, D. T., Cassel, C. K., Yang, J. P. & Harper, R. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 1, 935–940 (1975).
Kaposi, M. Idiopathic multiple pigmented sarcoma of the skin. CA Cancer J. Clin. 1982; 32, 340–347 (1872).
McGeoch, D. J., Gatherer, D. & Dolan, A. On phylogenetic relationships among major lineages of the Gammaherpesvirinae. J. Gen. Virol. 86, 307–316 (2005).
Miller, G. et al. Antibodies to butyrate-inducible antigens of Kaposi's sarcoma-associated herpesvirus in patients with HIV-1 infection. N. Engl. J. Med. 334, 1292–1297 (1996).
Gao, S. J. et al. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N. Engl. J. Med. 335, 233–241 (1996).
Simpson, G. R. et al. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 348, 1133–1138 (1996).
Gao, S. J. et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nature Med. 2, 925–928 (1996).
Kedes, D. H. et al. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nature Med. 2, 918–924 (1996).
Pellett, P. E. et al. Multicenter comparison of serologic assays and estimation of human herpesvirus 8 seroprevalence among US blood donors. Transfusion 43, 1260–1268 (2003).
Engels, E. A. et al. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS 20, 1645–1654 (2006).
zur Hausen, H. Oncogenic DNA viruses. Oncogene 20, 7820–7823 (2001).
Parsonnet, J. in Microbes and Malignancy (ed. Parsonnet, J.) 3–18 (Oxford Univ. Press, New York, 1999).
Steele, C., Cowsert, L. M. & Shillitoe, E. J. Effects of human papillomavirus type 18-specific antisense oligonucleotides on the transformed phenotype of human carcinoma cell lines. Cancer Res. 53, 2330–2337 (1993).
Tan, T. M. & Ting, R. C. In vitro and in vivo inhibition of human papillomavirus type 16 E6 and E7 genes. Cancer Res. 55, 4599–4605 (1995).
Goodwin, E. C. & DiMaio, D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc. Natl Acad. Sci. USA 97, 12513–12518 (2000).
Wies, E. et al. The viral interferon-regulatory factor-3 is required for the survival of KSHV-infected primary effusion lymphoma cells. Blood 111, 320–327 (2008).
Houben, R. et al. Merkel cell polyomavirus infected Merkel cell carcinoma cells require expression of viral T antigens. J. Virol. 84, 7064–7072 (2010).
Godfrey, A., Anderson, J., Papanastasiou, A., Takeuchi, Y. & Boshoff, C. Inhibiting primary effusion lymphoma by lentiviral vectors encoding short hairpin RNA. Blood (2004).
Dirmeier, U. et al. Latent membrane protein 1 of Epstein-Barr virus coordinately regulates proliferation with control of apoptosis. Oncogene 24, 1711–1717 (2005).
Seeger, C. & Mason, W. S. Hepatitis B virus biology. Microbiol. Mol. Biol. Rev. 64, 51–68 (2000).
Tsai, W. L. & Chung, R. T. Viral hepatocarcinogenesis. Oncogene 29, 2309–2324 (2010).
Mason, W. S., Liu, C., Aldrich, C. E., Litwin, S. & Yeh, M. M. Clonal expansion of normal appearing human hepatocytes during chronic HBV infection. J. Virol. 84, 8308–8315 (2010).
Yasunaga, J. & Matsuoka, M. Leukaemogenic mechanism of human T-cell leukaemia virus type I. Rev. Med. Virol. 17, 301–311 (2007).
Jeang, K. T., Giam, C. Z., Majone, F. & Aboud, M. Life, death, and tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J. Biol. Chem. 279, 31991–31994 (2004).
Hatakeyama, M. Helicobacter pylori CagA - a bacterial intruder conspiring gastric carcinogenesis. Int. J. Cancer 119, 1217–1223 (2006).
Grulich, A. E., van Leeuwen, M. T., Falster, M. O. & Vajdic, C. M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370, 59–67 (2007).
Chen, L. P., Thomas, E. K., Hu, S. L., Hellstrom, I. & Hellstrom, K. E. Human papillomavirus type 16 nucleoprotein E7 is a tumor rejection antigen. Proc. Natl Acad. Sci. USA 88, 110–114 (1991).
Guihot, A. et al. Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma. J. Infect. Dis. 194, 1078–1088 (2006).
Beral, V., Peterman, T. A., Berkelman, R. L. & Jaffe, H. W. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 335, 123–128 (1990).
Engels, E. A., Frisch, M., Goedert, J. J., Biggar, R. J. & Miller, R. W. Merkel cell carcinoma and HIV infection. Lancet 359, 497–498 (2002).
Vajdic, C. M. & van Leeuwen, M. T. Cancer incidence and risk factors after solid organ transplantation. Int. J. Cancer 125, 1747–1754 (2009).
Schulz, T. F. Cancer and viral infections in immunocompromised individuals. Int. J. Cancer 125, 1755–1763 (2009).
Sugarbaker, D. J. et al. Transcriptome sequencing of malignant pleural mesothelioma tumors. Proc. Natl Acad. Sci. USA 105, 3521–3526 (2008).
zur Hausen, H. SV40 in human cancers-an endless tale? Int. J. Cancer 107, 687 (2003).
Zur Hausen, H. The search for infectious causes of human cancers: where and why. Virology 392, 1–10 (2009).
Small, M. B., Gluzman, Y. & Ozer, H. L. Enhanced transformation of human fibroblasts by origin-defective simian virus 40. Nature 296, 671–672 (1982).
Walter, P. R., Philippe, E., Nguemby-Mbina, C. & Chamlian, A. Kaposi's sarcoma: presence of herpes-type particles in a tumor specimen. Human Pathol. 15, 1145–1146 (1984).
Zhong, W., Wang, H., Herndier, B. & Ganem, D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc. Natl Acad. Sci. USA 93, 6641–6646 (1996).
Parravicini, C. et al. Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Am. J. Pathol. 156, 743–749 (2000).
Sarid, R., Flore, O., Bohenzky, R. A., Chang, Y. & Moore, P. S. Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1). J. Virol. 72, 1005–1012 (1998).
Bischoff, J. R. et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274, 373–376 (1996).
Huang, B., Sikorski, R., Kirn, D. H. & Thorne, S. H. Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1. Gene Ther. 26 Aug 2010 (doi:10.1038/gt.2010.121).
Jacquemont, B. & Roizman, B. RNA synthesis in cells infected with herpes simplex virus. X. Properties of viral symmetric transcripts and of double-stranded RNA prepared from them. J. Virol. 15, 707–713 (1975).
Lilley, C. E., Schwartz, R. A. & Weitzman, M. D. Using or abusing: viruses and the cellular DNA damage response. Trends Microbiol. 15, 119–126 (2007).
Moore, P. S. & Chang, Y. Kaposi's sarcoma-associated herpesvirus immunoevasion and tumorigenesis: two sides of the same coin? Annu. Rev. Microbiol. 57, 609–639 (2003).
Tauer, T. J., Schneiderman, M. H., Vishwanatha, J. K. & Rhode, S. L. DNA double-strand break repair functions defend against parvovirus infection. J. Virol. 70, 6446–6449 (1996).
Bauer, S., Muller, T. & Hamm, S. Pattern recognition by Toll-like receptors. Adv. Exp. Med. Biol. 653, 15–34 (2009).
Lieberman, P. M., Hu, J. & Renne, R. in Human Herpesviruses: Biology, Therapy and Immunoprophylaxis (eds Arvin, A., Campardelli-Fiome, G., Mocarski, A. E., Moore, P. S., Roizman, B., Whitley, R. J. & Yamanishi, K.) 379–402 (Cambridge Univ. Press, Cambridge, UK, 2007).
Ballestas, M. E., Chatis, P. A. & Kaye, K. M. Efficient persistence of extrachromosomal KSHV DNA mediated by latency- associated nuclear antigen. Science 284, 641–644 (1999).
Roizman, B. in The Human Herpeviruses (eds Roizman, B., Whitley, R. J. & Lopez, C.) 1–9 (Raven Press, Ltd., New York, 1993).
Matsuoka, M. & Green, P. L. The HBZ gene, a key player in HTLV-1 pathogenesis. Retrovirology 6, 71 (2009).
Yoshida, M., Seiki, M., Yamaguchi, K. & Takatsuki, K. Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc. Natl Acad. Sci. USA 81, 2534–2537 (1984).
Raab-Traub, N. & Flynn, K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 47, 883–889 (1986).
Russo, J. J. et al. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc. Natl Acad. Sci. USA 93, 14862–14867 (1996).
Cannon, J. S., Hamzeh, F., Moore, S., Nicholas, J. & Ambinder, R. F. Human herpesvirus 8-encoded thymidine kinase and phosphotransferase homologues confer sensitivity to ganciclovir. J. Virol. 73, 4786–4793 (1999).
Martin, D. F. et al. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N. Engl. J. Med. 340, 1063–1070 (1999).
Little, R. F. & Yarchoan, R. Treatment of gammaherpesvirus-related neoplastic disorders in the immunosuppressed host. Semin. Hematol. 40, 163–171 (2003).
Mason, W. S. et al. The amount of hepatocyte turnover that occurred during resolution of transient hepadnavirus infections was lower when virus replication was inhibited with entecavir. J. Virol. 83, 1778–1789 (2009).
Levine, A. J. The common mechanisms of transformation by the small DNA tumor viruses: the inactivation of tumor suppressor gene products: p53. Virology 384, 285–293 (2009).
Oh, S. T., Kyo, S. & Laimins, L. A. Telomerase activation by human papillomavirus type 16 E6 protein: induction of human telomerase reverse transcriptase expression through Myc and GC-rich Sp1 binding sites. J. Virol. 75, 5559–5566 (2001).
Klingelhutz, A. J., Foster, S. A. & McDougall, J. K. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 380, 79–82 (1996).
Verma, S. C., Borah, S. & Robertson, E. S. Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus up-regulates transcription of human telomerase reverse transcriptase promoter through interaction with transcription factor Sp1. J. Virol. 78, 10348–10359 (2004).
Kataoka, H. et al. Immortalization of immunologically committed Epstein-Barr virus-transformed human B-lymphoblastoid cell lines accompanied by a strong telomerase activity. Differentiation 62, 203–211 (1997).
Terrin, L. et al. Latent membrane protein 1 of Epstein-Barr virus activates the hTERT promoter and enhances telomerase activity in B lymphocytes. J. Virol. 82, 10175–10187 (2008).
Buchkovich, N. J., Yu, Y., Zampieri, C. A. & Alwine, J. C. The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K-Akt-mTOR signalling pathway. Nature Rev. Microbiol. 6, 266–275 (2008).
Mosialos, G. et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80, 389–399 (1995).
Sarid, R., Olsen, S. J. & Moore, P. S. Kaposi's sarcoma-associated herpesvirus: epidemiology, virology and molecular biology. Adv. Virus Res. 52, 139–232 (1999).
Liu, L. et al. The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Iκ B kinase complex. J. Biol. Chem. 277, 13745–13751 (2002).
Fujimuro, M. et al. A novel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma-associated herpesvirus latency. Nature Med. 9, 300–306 (2003).
Moore, P. S. & Chang, Y. Antiviral activity of tumor-suppressor pathways: clues from molecular piracy by KSHV. Trends Genet. 14, 144–150 (1998).
McCance, D. J., Kopan, R., Fuchs, E. & Laimins, L. A. Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc. Natl Acad. Sci. USA 85, 7169–7173 (1988).
Munger, K. et al. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J. 8, 4099–4105 (1989).
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).
Duensing, S. et al. The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc. Natl Acad. Sci. USA 97, 10002–10007 (2000).
Hein, J. et al. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. J. Virol. 83, 117–127 (2009).
Liang, C., Lee, J. S. & Jung, J. U. Immune evasion in Kaposi's sarcoma-associated herpes virus associated oncogenesis. Semin. Cancer Biol. 18, 423–436 (2008).
Nakamura, H., Li, M., Zarycki, J. & Jung, J. U. Inhibition of p53 tumor suppressor by viral interferon regulatory factor. J. Virol. 75, 7572–7582 (2001).
Gwack, Y. et al. Kaposi's sarcoma-associated herpesvirus open reading frame 50 represses p53-induced transcriptional activity and apoptosis. J. Virol. 75, 6245–6248 (2001).
Park, J. et al. The K-bZIP protein from Kaposi's sarcoma-associated herpesvirus interacts with p53 and represses its transcriptional activity. J. Virol. 74, 11977–11982 (2000).
Zhang, Q., Gutsch, D. & Kenney, S. Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr latency. Mol. Cell. Biol. 14, 1929–1938 (1994).
Sarid, R., Klepfish, A. & Schattner, A. Virology, pathogenetic mechanisms, and associated diseases of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8). Mayo Clin. Proc. 77, 941–949 (2002).
Pfeffer, S. et al. Identification of microRNAs of the herpesvirus family. Nature Methods 2, 269–276 (2005).
Gottwein, E. et al. A viral microRNA functions as an orthologue of cellular miR-155. Nature 450, 1096–1099 (2007).
Choy, E. Y. et al. An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J. Exp. Med. 205, 2551–2560 (2008).
Young, L. S. & Rickinson, A. B. Epstein-Barr virus: 40 years on. Nature Rev. Cancer 4, 757–768 (2004).
Friborg, J., Kong, W., Hottiger, M. O. & Nabel, G. J. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402, 889–894 (1999).
Radkov, S. A., Kellam, P. & Boshoff, C. The latent nuclear antigen of kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene hras transforms primary rat cells. Nature Med. 6, 1121–1127 (2000).
Cloutier, N. & Flamand, L. Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen inhibits interferon (IFN) β expression by competing with IFN regulatory factor-3 for binding to IFNB promoter. J. Biol. Chem. 285, 7208–7221 (2010).
Chang, Y. et al. Cyclin encoded by KS herpesvirus. Nature 382, 410 (1996).
Verschuren, E. W., Klefstrom, J., Evan, G. I. & Jones, N. The oncogenic potential of Kaposi's sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell 2, 229–241 (2002).
Sarid, R., Wiezorek, J. S., Moore, P. S. & Chang, Y. Characterization and cell cycle regulation of the major Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) latent genes and their promoter. J. Virol. 73, 1438–1446 (1999).
Shah, K. M. & Young, L. S. Epstein-Barr virus and carcinogenesis: beyond Burkitt's lymphoma. Clin. Microbiol. Infect. 15, 982–988 (2009).
Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).
Chin, Y. E. et al. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science 272, 719–722 (1996).
Takaoka, A. et al. Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424, 516–523 (2003).
Sadler, A. J. & Williams, B. R. Interferon-inducible antiviral effectors. Nature Rev. Immunol. 8, 559–568 (2008).
Senger, K. et al. Gene repression by coactivator repulsion. Mol. Cell 6, 931–937 (2000).
Harada, H. et al. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 259, 971–974 (1993).
Lee, H. R., Kim, M. H., Lee, J. S., Liang, C. & Jung, J. U. Viral interferon regulatory factors. J. Interferon Cytokine Res. 29, 621–627 (2009).
Gao, S. J. et al. KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15, 1979–1985 (1997).
Chatterjee, M., Osborne, J., Bestetti, G., Chang, Y. & Moore, P. S. Viral IL-6-induced cell proliferation and immune evasion of interferon activity. Science 298, 1432–1435 (2002).
Lee, H. et al. Deregulation of cell growth by the K1 gene of Kaposi's sarcoma- associated herpesvirus. Nature Med. 4, 435–440 (1998).
Rivas, C., Thlick, A. E., Parravicini, C., Moore, P. S. & Chang, Y. Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53. J. Virol. 75, 429–438 (2001).
Wies, E. et al. The Kaposi's Sarcoma-associated Herpesvirus-encoded vIRF-3 Inhibits Cellular IRF-5. J. Biol. Chem. 284, 8525–8538 (2009).
Iwakiri, D. & Takada, K. Role of EBERs in the pathogenesis of EBV infection. Adv. Cancer Res. 107, 119–136 (2010).
Yang, X. J., Ogryzko, V. V., Nishikawa, J., Howard, B. H. & Nakatani, Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382, 319–324 (1996).
Bhattacharya, S. et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-α. Nature 383, 344–347 (1996).
Lane, D. P. p53, guardian of the genome. Nature 358, 15–16 (1992).
Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).
Hornung, V. & Latz, E. Intracellular DNA recognition. Nature Rev. Immunol. 10, 123–130 (2010).
Ranjan, P. et al. Cytoplasmic nucleic acid sensors in antiviral immunity. Trends Mol. Med. 15, 359–368 (2009).
Stracker, T. H., Carson, C. T. & Weitzman, M. D. Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 418, 348–352 (2002).
Lilley, C. E., Carson, C. T., Muotri, A. R., Gage, F. H. & Weitzman, M. D. DNA repair proteins affect the lifecycle of herpes simplex virus 1. Proc. Natl Acad. Sci. USA 102, 5844–5849 (2005).
Shin, Y. C. et al. Inhibition of the ATM/p53 signal transduction pathway by Kaposi's sarcoma-associated herpesvirus interferon regulatory factor 1. J. Virol. 80, 2257–2266 (2006).
Wu, Z. H. & Miyamoto, S. Many faces of NF-κB signaling induced by genotoxic stress. J. Mol. Med. 85, 1187–1202 (2007).
Shuda, M. et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc. Natl Acad. Sci. USA 105, 16272–16277 (2008).
Kean, J. M., Rao, S., Wang, M. & Garcea, R. L. Seroepidemiology of human polyomaviruses. PLoS Pathog. 5, e1000363 (2009).
Tolstov, Y. L. et al. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int. J. Cancer 125, 1250–1256 (2009).
Carter, J. J. et al. Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma. J. Natl Cancer Inst. 101, 1510–1522 (2009).
Pastrana, D. V. et al. Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLoS Pathog. 5, e1000578 (2009).
Touze, A. et al. Generation of Merkel cell polyomavirus (MCV)-like particles and their application to detection of MCV antibodies. J. Clin. Microbiol. 48, 1767–1770 (2010).
Shuda, M. et al. Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int. J. Cancer 125, 1243–1249 (2009).
Sastre-Garau, X. et al. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J. Pathol. 218, 48–56 (2009).
Schowalter, R. M., Pastrana, D. V., Pumphrey, K. A., Moyer, A. L. & Buck, C. B. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 7, 509–515 (2010).
Kwun, H. J. et al. The minimum replication origin of merkel cell polyomavirus has a unique large T-antigen loading architecture and requires small T-antigen expression for optimal replication. J. Virol. 83, 12118–12128 (2009).
Allander, T. et al. Identification of a third human polyomavirus. J. Virol. 81, 4130–4136 (2007).
Gaynor, A. M. et al. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog. 3, e64 (2007).
D'Souza, G. et al. Case-control study of human papillomavirus and oropharyngeal cancer. N. Engl. J. Med. 356, 1944–1956 (2007).
Parkin, D. M. et al. Part I: cancer in Indigenous Africans-burden, distribution, and trends. Lancet Oncol. 9, 683–692 (2008).
Rous, P. The possible role of viruses in cancer. Opening remarks. Cancer Res. 20, 672–676 (1960).
Temin, H. M. & Rubin, H. Characteristics of an assay for Rous sarcoma virus and Rous sarcoma cells in tissue culture. Virology 6, 669–688 (1958).
Baltimore, D. RNA-dependent DNA polymerase in virions of RNA tumour viruses. Nature 226, 1209–1211 (1970).
Temin, H. M. & Mizutani, S. RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 226, 1211–1213 (1970).
Chang, H. W. et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276, 1848–1850 (1997).
Bishop, J. M. Nobel Lecture. Retroviruses and oncogenes II. Biosci. Rep. 10, 473–491 (1990).
Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).
Coffin, J. M., Hughes, S. H. & Varmus, H. E. Retroviruses (CSHL Press, Cold Spring Harbor, 1997).
Weiss, R. A. The discovery of endogenous retroviruses. Retrovirology 3, 67 (2006).
Ebbesen, P. in Viruses Associated with Human Cancer (ed. Phillips, L. A.) 369–409 (Marcel Dekker, New York, 1983).
Klein, G. The Athiest and the Holy City: Encounters and Reflections (MIT Press, 1992).
Linzer, D. I. & Levine, A. J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17, 43–52 (1979).
Lane, D. P. & Crawford, L. V. T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261–263 (1979).
Arnaud, F., Varela, M., Spencer, T. E. & Palmarini, M. Coevolution of endogenous betaretroviruses of sheep and their host. Cell. Mol. Life Sci. 65, 3422–3432 (2008).
Contreras-Galindo, R. et al. Human endogenous retrovirus K (HML-2) elements in the plasma of people with lymphoma and breast cancer. J. Virol. 82, 9329–9336 (2008).
Urisman, A. et al. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2, e25 (2006).
Hohn, O. et al. Lack of evidence for xenotropic murine leukemia virus-related virus(XMRV) in German prostate cancer patients. Retrovirology 6, 92 (2009).
Weiss, R. A. A cautionary tale of virus and disease. BMC Biol. 8, 124 (2010).
Koch, R. in Source Book of Medical History (ed. Clark, D. H.) 392–406 (Dover Publications, Inc, New York, 1942).
Fredericks, D. N. & Relman, D. A. Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates. Clin. Microbiol. Rev. 9, 18–33 (1996).
Hill, A. B. Environment and disease: association or causation? Proc. R. Soc. Med. 58, 295–300 (1965).
Henle, W., Diehl, V., Kohn, G., Zur Hausen, H. & Henle, G. Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Science 157, 1064–1065 (1967).
Ernberg, I. & Klein, G. in Human Herpesviruses: Biology, Therapy and Immunoprophylaxis (eds Arvin, A. et al.) 514–539 (Cambridge Univ. Press, Cambridge, UK, 2007).
Saemundsen, A. K. et al. Documentation of Epstein-Barr virus infection in immunodeficient patients with life-threatening lymphoproliferative diseases by Epstein-Barr virus complementary RNA/DNA and viral DNA/DNA hybridization. Cancer Res. 41, 4237–4242 (1981).
Epstein-Barr Virus and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus 8 (ed. IARC) (World Health Organization, 1997).
Shope, R. E. & Hurst, E. W. Infectious papillomatosis of rabbits: with a note on the histopathology. J. Exp. Med. 58, 607–624 (1933).
Bittner, J. J. Some possible effects of nursing on the mammary gland tumor incidence in mice. Science 84, 162 (1936).
Gross, L. “Spontaneous” leukemia developing in C3H mice following inoculation in infancy, with AK-leukemic extracts, or AK-embrvos. Proc. Soc. Exp. Biol. Med. 76, 27–32 (1951).
Gross, L. A filterable agent, recovered from Ak leukemic extracts, causing salivary gland carcinomas in C3H mice. Proc. Soc. Exp. Biol. Med. 83, 414–421 (1953).
Eddy, B. E., Borman, G. S., Grubbs, G. E. & Young, R. D. Identification of the oncogenic substance in rhesus monkey kidney cell culture as simian virus 40. Virology 17, 65–75 (1962).
Trentin, J. J., Yabe, Y. & Taylor, G. The quest for human cancer viruses. Science 137, 835–841 (1962).
Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men-New York City and California. MMWR Morb. Mortal. Wkly Rep. 30, 305–308 (1981).
Barre-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).
Baer, R. et al. DNA sequence and expression of the B95–98 Epstein-Barr virus genome. Nature 310, 207–211 (1984).
DeCaprio, J. A. et al. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54, 275–283 (1988).
Dyson, N., Howley, P. M., Munger, K. & Harlow, E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934–937 (1989).
Werness, B. A., Levine, A. J. & Howley, P. M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76–79 (1990).
Albrecht, J.-C. et al. Primary structure of the herpesvirus saimiri genome. J. Virol. 66, 5047–5058 (1992).
Cesarman, E., Chang, Y., Moore, P. S., Said, J. W. & Knowles, D. M. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N. Engl. J. Med. 332, 1186–1191 (1995).
Cesarman, E. et al. In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood 86, 2708–2714 (1995).
Schiffman, M., Clifford, G. & Buonaguro, F. M. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect. Agent. Cancer 4, 8 (2009).
The authors would like to thank G. Klein and O. Gjoerup for helpful comments and corrections to the manuscript; M. Melbye at the Danish Statens Serum Institut, and T. Söderqvist and his staff at the Medical Museion, University of Copenhagen, Denmark, for materials; and F. Zappa for help in preparing the manuscript. The authors are supported by NIH CA136363, CA120726, the Al Copeland Foundation, and American Cancer Society Research Professorships.
The authors hold numerous patents that are related to KSHV and MCV that have been assigned to Columbia University, USA, and the University of Pittsburgh, USA.
- 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.
The measurement of antibodies against viruses in blood or bodily fluids. This usually does not distinguish ongoing infections from past viral infections.
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Moore, P., Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer 10, 878–889 (2010). https://doi.org/10.1038/nrc2961
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