Tumor Viruses: Causes and Mechanisms of Tumor Formation

1. 4. ไวรัสที่ก่อให้เกิดเนื้องอก (Tumor Viruses) วัตถุประสงค์ • สามารถยกตัวอย่างไวรัสที่ก่อให้เกิดเนื้องอกได้ • สามารถอธิบายกลไกในการก่อให้เกิดเนื้องอกของไวรัสได้ Content 4.1 Tumor Viruses 4.2 How Tumor Viruses Cause Cancer

2. 4.1 Tumor Viruses • Tumor viruses can force host cells to proliferate uncontrollably. -----> can create cancer 4.1.1 Cancer viruses were initially discovered in animal • Peyton Rous (1911) discovered that sarcomas could be transmitted between chickens by injection of filtered tumor extracts. -----> Rous Sarcoma Virus (RSV) Weinberg, R.A. The Biology of Cancer. 2007. Garland Science, Taylor & Francis Group, LLC, New York. p.59. • Richard Shope (1933) showed that he could transmit skin cancer between rabbits using tumor extracts containing no intact cells. -----> Shope papillomavirus

3. Dozens of additional oncogenic DNA and RNA viruses were discovered. DNA Tumor Viruses Kleinsmith LJ. Principles of cancer biology. Pearson Internatonal Edition. Benjamin Cummings, San Francisco. 2006. p.121.

4. RNA Tumor Viruses Kleinsmith LJ. Principles of cancer biology. Pearson Internatonal Edition. Benjamin Cummings, San Francisco. 2006. p.121.

5. http://www.nasa.gov/mission_pages/station/science/ experiments/Epstein-Barr.html http://www.beliefnet.com/healthandhealing/images/ si2073_ma.jpg http://www.nationaljewish.org /imgs/ewebeditor/burkitts.jpg http://www.frtomskids.org/images/burkitts1.jpg 4.1.2 Epstein-Barr viruses (EBV) - EBV is associated with Burkitt’s Lymphoma and several other proliferative disorders of lymphocytes. - EBV is a member of the DNA-containing Herpesvirus group, discovered by two virologists, Michael Anthony Epstein and Yvonne Barr. - Denis Burkitt, British surgeon, observed large numbers of children came to Burkitt’s clinic in Africa with massive swellings of the jaw.

6. Several lines of evidence support the idea that EBV causes Burkitt’s lymphoma. 1) DNA sequences and proteins encoded by EBV have been found in tumor cells obtained from patients with Burkitt’s lymphoma but not in normal cells from the same individuals. 2) Adding EBV to cultures of normal human lymphocytes stimulates cell proliferation and causes the lymphocytes to acquire some of the traits of cancer cells. 3) Injecting EBV into monkeys triggers the development of lymphomas. Why is Burkitt’s lymphoma prevalent in central Africa? ----> Malaria can depress immune function and thereby allows EBV infections to proceed unchecked by an effective immune response. Half of the patients with Hodgkin’s disease, a lymphoma characterized by the presence of Reed-Sternberg cells, have EBV DNA sequences in their tumor cells. EBV infection can also trigger a nonmalignant proliferation of lymphocytes known as infectious mononucleosis. www.jamesline.com/.../CDR0000576466_full.jpg

7. EBV infection is also associated with Nasopharyngeal carcinoma and a few other epithelial cancers. Nasopharyngeal carcinoma is a tumor of the nasal passages and throat that is frequent in Southeast Asia. ----> heredity or dietary factors • A small percentage of individuals with stomach or breast cancer do have EBV DNA sequences in their cancer cells, but the precise role played by EBV in such cases is not clear. ---> EBV protein binds to Nm23-H1, a metastasis suppressor. http://info.cancerresearchuk.org/images/gpimages/cs_inf_f4.2

8. ~ 90% of all cancers of the uterine cervix involve infection with at least one of the high-risk types. HPV = a DNA virus implicated in the cancer of the uterine cervix(cervical cancer) and in several other cancers of the anal and genital area, including cancer of the penis. HPV 16 is the most common form of HPV to be detected in cervical cancer. 4.1.3 Human Papillomavirus (HPV) • High-risk types: HPV 16, HPV18, HPV45, HPV31 -------> cervical cancer • Low-risk types: HPV 6, HPV11 -------> genital warts (nonmalignant conditions) http://kirstyne.files.wordpress.com/ 2008/02/hpv_small.jpg

9. Hepatitis = inflammation of the liver ------> toxic effects of alcohol or drug consumption ------> Viruses At least 6 hepatitis viruses are known to exist. ------> two of them are strongly linked to the development of liver cancer ------> Hepatitis B virus (HBV) and Hepatitis C virus (HCV) Hepatitis B virus = DNA virus transmitted by exchange of bodily fluids ------> responsible for more than 75% of the world’s cases of liver cancer ------> prevalent in Southeast Asia, China, Africa, Alaska, Northern Canada, Amazon river basin of South America 4.1.4 Hepatitis B and Hepatitis C viruses ----> are responsible for most liver cancers.

10. Hepatitis C virus = RNA virus transmitted by direct contact with contaminated blood ------> HCV is more difficult to transmit than HBV but triggers long-term, chronic infections. ------> prevalent in the US (1.8 % of the population) ------> ~5% of the people with chronic HCV infections eventually develop liver cancer, although it usually requires several decades to appear Retrovirus = RNA virus with reverse transcriptase to synthesize a DNA copy Human T-cell Lymphotropic Virus-I (HTLV-I) is the only one retrovirus that causes cancer in human (adult T-cell leukemia/lymphoma). ------> transmitted mainly through sexual contact, through blood products, and from mother to child during breast-feeding Adult T-cell leukemia/lymphoma is prevalent in Japan, Africa, and the Caribbean. Cancer develops in only a few percent of infected individuals; it usually arises many decades after initial infection. 4.1.5 The HTLV-I Retrovirus ---> HTLV-I is associated with adult T-cell Leukemia and Lymphoma.

11. Kaposi’s sarcoma arises from blood vessels in the skin. Kaposi’s sarcoma-associated herpesvirus (KSHV) was discovered in specimens of Kaposi’s sarcoma tissue. HIV-infected individuals are at increased risk for Kaposi’s Sarcoma and several other viral cancers. HIV represents an indirectcancer risk because of its destructive effects on the immune system. Relative incidence = the rate for each type of cancer in HIV infected individuals divided by the rate in the general population 4.1.6 Kaposi’s Sarcoma-associated herpesvirus

12. 4.1.7 SV40 =Simian virus 40 (monkey virus) SV40 is an animal cancer virus that contaminated early batches of Polio Vaccine. SV40 DNA sequences are sometimes detectable in the cancer cells of individuals with non-Hodgkin’s lymphoma, mesothelioma, brain cancer, or bone cancer. However, we do not know how much (if any) cancer risk was created by the inadvertent exposure of humans to SV40. The 3 broad mechanisms : 1) Increase cancer risk indirectly by interfering with immune function ----> HIV 2) Create tissue destruction and chronic inflammation ----> HBV, HCV 3) Directly stimulate the proliferation of infected cells 4.2 How Tumor Viruses Cause Cancer 4.2.1 Chronic infections trigger the development of cancer through indirect as well as direct mechanisms.

13. 4.2.2 DNA and RNA viruses employ different mechanisms for latently infecting Cells. Infection by a latent DNA virus

14. Infection by a latent RNA virus

15. Genes like v-src, which trigger the development of cancer, are referred to as oncogenes. DNA sequences that are very similar to the Rous v-src gene have been detected in the normal cellular DNA of a wide variety of organisms, including salmon, mice, cows, birds, and humans. 4.2.3 Retroviral oncogenes are altered versions of normal cellular genes

16. Model for the proposed origin of retroviral oncogenes

17. Protein kinases play roles in various signaling pathways for controlling cell proliferation and survival. 4.2.4 Retroviral Oncogenes code for proteins that function in growth factor signaling pathways

18. V-Src protein kinase -----> tyrosine kinase V-Src tyrosine kinase is constitutively active and persistently catalyze the phosphorylation of target proteins that activate cell proliferation. V-Src tyrosine kinase is the first example of an oncoprotein (protein that contributes to the development of cancer). Oncoproteins produced by dozens of viral oncogenes have been identified. -----> tyrosine kinases, growth factor, growth receptors, or other proteins involved in growth signaling pathways

19. Slow-acting viruses lack oncogenes --alter the expression of normal cellular genes --insertional mutagenesis --Avian leukosis virus (ALV) ----> Chicken retrovirus --ALV can insert its proviral DNA at a variety of different locations in the host chromosomal DNA. -----> Cancer only arises when ALV inserts itself near a cellular gene called the MYC gene. 4.2.5 Insertional mutagenesis allows viruses with no oncogenes to cause cancer by activating cellular proto-oncogenes Oncogenic retroviruses can be subdivided into two classes based on how quickly and efficiently they trigger cancer in animals. 1) Acutely transforming retroviruses --cause animals to develop tumors rapidly, often within days of injection. -----> RSV --possess oncogenes 2) Slow-acting retroviruses --require months or years to induce cancer --do not possess oncogene

20. MYC gene is a proto-oncogene and thus has the potential to be converted into an oncogne. Myc protein stimulates the transcription of genes required for cell proliferation. The long terminal repeats (LTRs) of the proviral DNA contain sequences that promote transcription.

21. 2) Insertion of viral v-myc oncogene (Avian myelocymatosis virus) 3) Chromosomal translocation (EBV : Burkitt’s lymphoma) 4.2.6 Abnormalities involving the Myc protein arise through several mechanisms in viral cancers 1) Insertion of viral DNA in the vicinity of MYC gene (Avian leukosis virus)

22. 4.2.7 Several oncogenic DNA viruses produce oncoproteins that interfere with p53 and Rb function HPV contains oncogenes called E6 and E7, which produce proteins that disrupt the activity of p53 protein and Rb protein.

23. High-Risk strains of HPV integrate their viral DNA into a host chromosome, thereby placing the viral genes in an environment that causes them to produce larger amounts of the E6 and E7 oncoproteins.

24. 4.2.8 The ability of viruses to cause cancer has created problems for the field of gene therapy One type of gene therapy uses specially modified viruses to transfer copies of normal genes into cells possessing defective genes. SCID (severe combined immunodeficiency) patients are extremely vulnerable to infectious diseases. (Retroviral vector causes cancer.) “Boy in the bubble syndrome”