Viral  Carcinogenesis

Oncology  for  Scientists  2013

Irwin  H.  Gelman,  Ph.D.

Human Cancers Associated with Viral Etiology

Carcinomas Anogential HPV   Hepatocellular HBC, HCV   Nasopharyngeal EBV   Oropharyngeal HPV   Stomach EBV   Merkel Cell MCPyV

Lymphomas Post-transplant EBV   Burkitt’s EBV   Hodgkin’s EBV   Adult T-cell HTLV-I  

Sarcoma Kaposi HHV-8  

Cancer in Developing and Developed Countries: Association with Viral Etiologies  

Developed Countries Developing Countries  Site Agent # cases % all Ca # cases % all Ca.  

Liver HBV,HCV 48,000 1.0 475,000 8.2 Flukes 0 2,500

Cervix HPV 83,400 1.7 409,400 7.0

Stomach H. pylori 192,000 3.8 400,000 6.9 Kaposi HHV8 3,700 0.1 62,500 1.1 NHL HIV/EBV 9,300 0.2 26,800 0.7 Anogenital HPV 22,450 0.4 31,430 0.5 Nasopharynx EBV 6,500 0.1 71,600 1.2 Oropharynx HPV 5,600 0.1 8,800 0.2 Hodgkin L. EBV 11,500 0.2 17,100 0.3 Bladder Schistos 0 0.0 10,600 0.2

Total 389,000 7.7 1,527,000 26.3

Why Study Infection Associated Cancers?  

• Prevention - vaccines, eliminate agent  

• Diagnosis - identify precursors expressing agent  

• Treatment - anti-virals, antibiotics  

• Provides insights into mechanism  

• Important problem - large world wide burden of cancer

Principles of Oncology: Dysregulation of  The Cell Cycle

p53

Rb

Central Roles Played by p53 and Rb

Carcinogen – A substance or agent that induces cancer

Viruses as Carcinogens  

Viruses Chemicals/Radiation

Introduce foreign DNA Point Mutations/ DNA breaks  

Must persist in DNA form Hit and Run  

Continued expression of viral continued presence not required   genes necessary

Specific:1/few viral genes Random: many genes altered   expressed

DNA Tumor Viruses

Virus Oncoproteins Cellular Targets

Polyomavirus   SV40, MCPyV

Large T antigen  Small t antigen p53 and pRb tumor suppressors

Human   papillomavirus

E6  E7

P53  pRb

Bovine   papillomavirus E5 PDGFβ receptor

Adenovirus   (rodent cells)

E1A  E1B-55k

pRb  p53

Epstein-Barr   virus

LMP1  vIL10  BCL2 homolog

TRAFs  IL-10 receptor (soluble viral cytokine)  Rescues cell from apoptosis

Doorbar, J., Clinical Sci., 2006.

HPV: Many types, but only some associated with cervical cancer  

**only E6/E7 from oncogenic types bind their p53/Rb targets.

Oncogenic HPV: Early expression of E6 and E7 in basal cells à  prevents normal senescence à  cell survival and proliferation.  

2º mutations à  oncogene activation  

à Cervical cancer

10-15  years

Doorbar, J., Clinical Sci., 2006.

Gardasil: quadravalent vaccine

Quadrivalent HPV 6/11/16/18 L1 virus-like particle  • VLPs are produced in Saccharomyces cerevisiae.

Some HPV types associated with severe papilloma formation.

HBV: DNA virus HCV: RNA virus (Flavivirus)

inhibits DNA damage repair

HCV:  -induces HCC by   i) increasing ROS   ii) inducing proliferation pathways

EBV:  - induces B cell immortalization  - Rare 2⁰  mutations à lymphoma   (typically assoc with immunosuppression)

KSHV (HHV-8) and Kapsoi’s sarcoma: angiogenic disease

Acute Transforming Retroviruses:  -“extra gene” not encoding Gag, Pol or Env.  

tsRSV:  -causes transformation at the permissive temp. (35ºC) but not at the non-permissive temp. (39.5ºC). First proof of a transforming gene (“oncogene”) not required for virus replication.

Robinson, Rev. Infectious Diseases, 1982.

Acute vs. Chronic Transforming Retroviruses, con’t.

Acu

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Growth factors

Transcription factors

Membrane receptors

Signal molecules

sis,/PDGF int-2/FGF-F hst (KS3) int-1/GF

bZIP: fos, jun bHLH: myc, N-myc, L-myc lyl-1, fal, scl ZF: myl/RARA, erb-A, vav, gli-1 HD: pbx, Hox-2, Other: myb, rel, est-1, est-2, spi-1

RTK: erb-B/EGF-R Neu, ROS, Fms/CSF-1 Non-RTK: mas

src yes fps abl met mos raf ras crk

Chronic Transforming Retroviruses:  Insertional activation of endogenous oncogenes

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