Journal of Molecular Medicine

, Volume 90, Issue 5, pp 535–541 | Cite as

Infection, mutation, and cancer evolution

  • Paul W. EwaldEmail author
  • Holly A. Swain Ewald


An understanding of oncogenesis can be fostered by an integration of mechanistic studies with evolutionary considerations, which help explain why these mechanisms occur. This integration emphasizes infections and mutations as joint essential causes for many cancers. It suggests that infections may play a broader causal role in oncogenesis than has been generally appreciated. An evolutionary perspective also suggests that oncogenic viruses will tend to be transmitted by routes that provide infrequent opportunities for transmission, such as transmission by sexual and salivary contact. Such routes increase the intensity of natural selection for persistence within hosts, and molecular mechanisms for persistence often compromise critical barriers to oncogenesis, particularly cell cycle arrest, apoptosis, and a cap on the total number of divisions that a cell can undergo.


Infection Mutation Cancer evolution Evolution Natural selection Oncogenic selection Oncogenesis Apoptosis Cell cycle arrest Telomerase EBV KSHV HTLV Hepatitis B Hepatitis C Papillomavirus 



The Rena Shulsky Foundation generously supported this work as part of a project to develop a unified theory of oncogenesis. John Pepper made helpful comments on this manuscript.


  1. 1.
    Aktipis CA, Maley CC, Pepper JW (2012) Dispersal evolution in neoplasms: the role of dysregulated metabolism in the evolution of cell motility. Cancer Prev Res (Phila) 5:266–275CrossRefGoogle Scholar
  2. 2.
    Arora P, Kim EO, Jung JK, Jang KL (2008) Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Lett 261:244–252PubMedCrossRefGoogle Scholar
  3. 3.
    Banerjee P, Feuer G, Barker E (2007) Human T-cell leukemia virus type 1 (HTLV-1) p12I down-modulates ICAM-1 and -2 and reduces adherence of natural killer cells, thereby protecting HTLV-1-infected primary CD4+ T cells from autologous natural killer cell-mediated cytotoxicity despite the reduction of major histocompatibility complex class I molecules on infected cells. J Virol 81:9707–9717PubMedCrossRefGoogle Scholar
  4. 4.
    Cai Q, Guo Y, Xiao B, Banerjee S, Saha A, Lu J, Glisovic T, Robertson ES (2011) Epstein-Barr virus nuclear antigen 3C stabilizes Gemin3 to block p53-mediated apoptosis. PLoS Pathog 7:e1002418PubMedCrossRefGoogle Scholar
  5. 5.
    Cai Q, Verma SC, Lu J, Robertson ES (2010) Molecular biology of Kaposi’s sarcoma-associated herpesvirus and related oncogenesis. Adv Virus Res 78:87–142PubMedCrossRefGoogle Scholar
  6. 6.
    Chen J, Sprouffske K, Huang Q, Maley CC (2011) Solving the puzzle of metastasis: the evolution of cell migration in neoplasms. PLoS One 6:e17933PubMedCrossRefGoogle Scholar
  7. 7.
    Chen L, Hu L, Li L, Liu Y, Tu QQ, Chang YX, Yan HX, Wu MC, Wang HY (2010) Dysregulation of beta-catenin by hepatitis B virus X protein in HBV-infected human hepatocellular carcinomas. Front Med China 4:399–411PubMedCrossRefGoogle Scholar
  8. 8.
    Choi YH, Kim HI, Seong JK, Yu DY, Cho H, Lee MO, Lee JM, Ahn YH, Kim SJ, Park JH (2004) Hepatitis B virus X protein modulates peroxisome proliferator-activated receptor gamma through protein-protein interaction. FEBS Lett 557:73–80PubMedCrossRefGoogle Scholar
  9. 9.
    Ding L, Li L, Yang J, Zhou S, Li W, Tang M, Shi Y, Yi W, Cao Y (2007) Latent membrane protein 1 encoded by Epstein-Barr virus induces telomerase activity via p16INK4A/Rb/E2F1 and JNK signaling pathways. J Med Virol 79:1153–1163PubMedCrossRefGoogle Scholar
  10. 10.
    Dyson N, Howley PM, Munger K, Harlow E (1989) The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937PubMedCrossRefGoogle Scholar
  11. 11.
    Dyson OF, Oxendine TL, Hamden KE, Ford PW, Akula SM (2008) Differential regulation of the attachment of Kaposi’s sarcoma-associated herpesvirus (KSHV)-infected human B cells to extracellular matrix by KSHV-encoded gB and cellular alphaV integrins. Cell Microbiol 10:1546–1558PubMedCrossRefGoogle Scholar
  12. 12.
    Ewald PW (2009) An evolutionary perspective on parasitism as a cause of cancer. Adv Parasitol 68:21–43PubMedCrossRefGoogle Scholar
  13. 13.
    Gewin L, Myers H, Kiyono T, Galloway DA (2004) Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes Dev 18:2269–2282PubMedCrossRefGoogle Scholar
  14. 14.
    Guasparri I, Bubman D, Cesarman E (2008) EBV LMP2A affects LMP1-mediated NF-kappaB signaling and survival of lymphoma cells by regulating TRAF2 expression. Blood 111:3813–3820PubMedCrossRefGoogle Scholar
  15. 15.
    Higgs MR, Lerat H, Pawlotsky JM (2010) Downregulation of Gadd45beta expression by hepatitis C virus leads to defective cell cycle arrest. Cancer Res 70:4901–4911PubMedCrossRefGoogle Scholar
  16. 16.
    Hino R, Uozaki H, Inoue Y, Shintani Y, Ushiku T, Sakatani T, Takada K, Fukayama M (2008) Survival advantage of EBV-associated gastric carcinoma: survivin up-regulation by viral latent membrane protein 2A. Cancer Res 68:1427–1435PubMedCrossRefGoogle Scholar
  17. 17.
    Hino R, Uozaki H, Murakami N, Ushiku T, Shinozaki A, Ishikawa S, Morikawa T, Nakaya T, Sakatani T, Takada K et al (2009) Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res 69:2766–2774PubMedCrossRefGoogle Scholar
  18. 18.
    Huang XH, Sun LH, Lu DD, Sun Y, Ma LJ, Zhang XR, Huang J, Yu L (2003) Codon 249 mutation in exon 7 of p53 gene in plasma DNA: maybe a new early diagnostic marker of hepatocellular carcinoma in Qidong risk area, China. World J Gastroenterol 9:692–695PubMedGoogle Scholar
  19. 19.
    Jiang J, Zhao LJ, Zhao C, Zhang G, Zhao Y, Li JR, Li XP, Wei LH (2012) Hypomethylated CpG around the transcription start site enables TERT expression and HPV16 E6 regulates TERT methylation in cervical cancer cells. Gynecol Oncol 124(3):534–541PubMedCrossRefGoogle Scholar
  20. 20.
    Katzenellenbogen RA, Egelkrout EM, Vliet-Gregg P, Gewin LC, Gafken PR, Galloway DA (2007) NFX1-123 and poly(A) binding proteins synergistically augment activation of telomerase in human papillomavirus type 16 E6-expressing cells. J Virol 81:3786–3796PubMedCrossRefGoogle Scholar
  21. 21.
    Kew MC (2011) Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol 26(Suppl 1):144–152PubMedCrossRefGoogle Scholar
  22. 22.
    Kim YM, Geiger TR, Egan DI, Sharma N, Nyborg JK (2010) The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription. Oncogene 29:2142–2152PubMedCrossRefGoogle Scholar
  23. 23.
    Kirk GD, Camus-Randon AM, Mendy M, Goedert JJ, Merle P, Trepo C, Brechot C, Hainaut P, Montesano R (2000) Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma from The Gambia. J Natl Cancer Inst 92:148–153PubMedCrossRefGoogle Scholar
  24. 24.
    Knight J, Sharma N, Robertson E (2005) Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiqitin ligase. PNAS 102:18562–18566PubMedCrossRefGoogle Scholar
  25. 25.
    Li ZH, Tang QB, Wang J, Zhou L, Huang WL, Liu RY, Chen RF (2010) Hepatitis C virus core protein induces malignant transformation of biliary epithelial cells by activating nuclear factor-kappaB pathway. J Gastroenterol Hepatol 25:1315–1320PubMedCrossRefGoogle Scholar
  26. 26.
    Limpaiboon T, Pooart J, Bhattarakosol P, Niruthisard S, Chantratita W, Lulitanond V (2000) p53 status and human papillomavirus infection in Thai women with cervical carcinoma. Southeast Asian J Trop Med Public Health 31:66–71PubMedGoogle Scholar
  27. 27.
    Liu H, Luan F, Ju Y, Shen H, Gao L, Wang X, Liu S, Zhang L, Sun W, Ma C (2007) In vitro transfection of the hepatitis B virus PreS2 gene into the human hepatocarcinoma cell line HepG2 induces upregulation of human telomerase reverse transcriptase. Biochem Biophys Res Commun 355:379–384PubMedCrossRefGoogle Scholar
  28. 28.
    Liu WK, Chu YL, Zhang F, Chen P, Cheng F, Wang H, Jia YY, Ma TY (2005) The relationship between HPV16 and expression of CD44v6, nm23H1 in esophageal squamous cell carcinoma. Arch Virol 150:991–1001PubMedCrossRefGoogle Scholar
  29. 29.
    Liu YC, Chen CJ, Wu HS, Chan DC, Yu JC, Yang AH, Cheng YL, Lee SC, Harn HJ (2004) Telomerase and c-myc expression in hepatocellular carcinomas. Eur J Surg Oncol 30:384–390PubMedCrossRefGoogle Scholar
  30. 30.
    Luan F, Liu H, Gao L, Liu J, Sun Z, Ju Y, Hou N, Guo C, Liang X, Zhang L et al (2009) Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT. Gut 58:1528–1537PubMedCrossRefGoogle Scholar
  31. 31.
    Medema RH, Klompmaker R, Smits VA, Rijksen G (1998) p21waf1 can block cells at two points in the cell cycle, but does not interfere with processive DNA-replication or stress-activated kinases. Oncogene 16:431–441PubMedCrossRefGoogle Scholar
  32. 32.
    Merlo LM, Pepper JW, Reid BJ, Maley CC (2006) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6:924–935PubMedCrossRefGoogle Scholar
  33. 33.
    Mileo AM, Piombino E, Severino A, Tritarelli A, Paggi MG, Lombardi D (2006) Multiple interference of the human papillomavirus-16 E7 oncoprotein with the functional role of the metastasis suppressor Nm23-H1 protein. J Bioenerg Biomembr 38:215–225PubMedCrossRefGoogle Scholar
  34. 34.
    Moore PS (2007) KSHV manipulation of the cell cycle and apoptosis. In: Arvin A et al (eds) Human herpesviruses biology, therapy, and immunoprophylaxis, p (online book; Cambridge University Press, Cambridge
  35. 35.
    Moss SF, Blaser MJ (2005) Mechanisms of disease: inflammation and the origins of cancer. Nat Clin Pract Oncol 2:90–97, quiz 91 p following 113PubMedCrossRefGoogle Scholar
  36. 36.
    Murakami Y, Saigo K, Takashima H, Minami M, Okanoue T, Brechot C, Paterlini-Brechot P (2005) Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 54:1162–1168PubMedCrossRefGoogle Scholar
  37. 37.
    Parroche P, Touka M, Mansour M, Bouvard V, Thepot A, Accardi R, Carreira C, Roblot GG, Sylla BS, Hasan U et al (2011) Human papillomavirus type 16 E6 inhibits p21(WAF1) transcription independently of p53 by inactivating p150(Sal2). Virology 417:443–448PubMedCrossRefGoogle Scholar
  38. 38.
    Paterlini-Brechot P, Saigo K, Murakami Y, Chami M, Gozuacik D, Mugnier C, Lagorce D, Brechot C (2003) Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 22:3911–3916PubMedCrossRefGoogle Scholar
  39. 39.
    Portis T, Longnecker R (2004) Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway. Oncogene 23:8619–8628PubMedCrossRefGoogle Scholar
  40. 40.
    Saha A, Bamidele A, Murakami M, Robertson ES (2011) EBNA3C attenuates the function of p53 through interaction with inhibitor of growth family proteins 4 and 5. J Virol 85:2079–2088PubMedCrossRefGoogle Scholar
  41. 41.
    Saha A, Murakami M, Kumar P, Bajaj B, Sims K, Robertson ES (2009) Epstein-Barr virus nuclear antigen 3 C augments Mdm2-mediated p53 ubiquitination and degradation by deubiquitinating Mdm2. J Virol 83:4652–4669PubMedCrossRefGoogle Scholar
  42. 42.
    Sieburg M, Tripp A, Ma JW, Feuer G (2004) Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 tax oncoproteins modulate cell cycle progression and apoptosis. J Virol 78:10399–10409PubMedCrossRefGoogle Scholar
  43. 43.
    Sinha-Datta U, Horikawa I, Michishita E, Datta A, Sigler-Nicot JC, Brown M, Kazanji M, Barrett JC, Nicot C (2004) Transcriptional activation of hTERT through the NF-kappaB pathway in HTLV-I-transformed cells. Blood 104:2523–2531PubMedCrossRefGoogle Scholar
  44. 44.
    Sprouffske K, Pepper JW, Maley CC (2011) Accurate reconstruction of the temporal order of mutations in neoplastic progression. Cancer Prev Res (Phila) 4:1135–1144CrossRefGoogle Scholar
  45. 45.
    Stearns SC, Nesse RM, Haig D (2008) Introducing evolutionary thinking for medicine. In: Stearns SC, Koella JC (eds) Evolution in health and disease. Oxford University Press, New YorkGoogle Scholar
  46. 46.
    Su JM, Lai XM, Lan KH, Li CP, Chao Y, Yen SH, Chang FY, Lee SD, Lee WP (2007) X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter. Hepatology 46:402–413PubMedCrossRefGoogle Scholar
  47. 47.
    Tommasino M, Accardi R, Caldeira S, Dong W, Malanchi I, Smet A, Zehbe I (2003) The role of TP53 in cervical carcinogenesis. Hum Mutat 21:307–312PubMedCrossRefGoogle Scholar
  48. 48.
    Trevathan WR, Smith EO, McKenna JJ (2008) Introduction and overview of evolutionary medicine. In: Trevathan WR et al (eds) Evolutionary medicine and health. Oxford University Press, New York, pp 1–54Google Scholar
  49. 49.
    Tsai WL, Chung RT (2010) Viral hepatocarcinogenesis. Oncogene 29:2309–2324PubMedCrossRefGoogle Scholar
  50. 50.
    Tungteakkhun SS, Duerksen-Hughes PJ (2008) Cellular binding partners of the human papillomavirus E6 protein. Arch Virol 153:397–408PubMedCrossRefGoogle Scholar
  51. 51.
    Verma SC, Borah S, Robertson ES (2004) 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 78:10348–10359PubMedCrossRefGoogle Scholar
  52. 52.
    Williams GC, Nesse RM (1991) The dawn of Darwinian medicine. Q Rev Biol 66:1–22PubMedCrossRefGoogle Scholar
  53. 53.
    Xu M, Katzenellenbogen RA, Grandori C, Galloway DA (2010) NFX1 plays a role in human papillomavirus type 16 E6 activation of NFkappaB activity. J Virol 84:11461–11469PubMedCrossRefGoogle Scholar
  54. 54.
    Yi F, Saha A, Murakami M, Kumar P, Knight JS, Cai Q, Choudhuri T, Robertson ES (2009) Epstein-Barr virus nuclear antigen 3 C targets p53 and modulates its transcriptional and apoptotic activities. Virology 388:236–247PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang X, Dong N, Zhang H, You J, Wang H, Ye L (2005) Effects of hepatitis B virus X protein on human telomerase reverse transcriptase expression and activity in hepatoma cells. J Lab Clin Med 145:98–104PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of BiologyUniversity of LouisvilleLouisvilleUSA

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