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Viruses Cause Cancer

--benign or malignant
--in many species incl. frogs, fish, birds, mammals
--only a few viruses cause tumors in humans
--not proven that virus is causative except in a few cases
--viruses produce tumors faster & more reliably than chemicals or radiation
--viruses don't have many genes
--retroviruses have 3, 4 or 5 genes
--"malignant transformation" = changes in growth properties, shape, etc in tumor cell
--transformation is permanent
--viral gene transcription is temperature sensitive in some cases
--two types of tumorigenesis: provirus and oncogene

--cells de-differentiate and get disorganized, pile on top of each other due to loss of contact inhibition
--cells grow in vitro at lower serum concentration than normal cells (they don't need much blood)
--cells grow well in suspension (normal cells like to be anchored to something)
--cells are easily cloned, grow into big colony
--tumor virus infection of a cell makes cells live too long (normal cells divide about 50 times then die by apoptosis, cancer cells don't)
--DNA synthesis is induced by tumor virus, resting cells in G1 phase go straight to S phase
--karyotype is altered (changes in number & shape of chromosomes)
--new antigens appear (viral proteins or cellular proteins not usually produced)
--agglutination by lectins is enhanced
--cAMP levels are lower than normal (add cAMP and cells revert to normal behavior)
--secrete more plasminogen activator than normal, causes enhanced dissolution of fibrin clots
--increases anaerobic glycoysis --> increased lactic acid (cancer uses up your energy stores without waiting for oxygen availability)
--glycoproteins and glycolipids in membranes look different

--provirus = gene that gets in cell with viral invasion
--provirus theory supported when transforming DNA is only in virus infected cells

--oncogene = gene that's already in there, either because it's part of the host genome, or because it has been introduced into the genome by a virus in a previous generation and handed down to offspring (you can inherit viral genes from your parents!)
--fibroblast growth factor is an oncogene that encourages cell growth
--something (chemicals, radiation, virus) activates cellular oncogene and it overproduces growth factors
--cellular and viral oncogenes are similar but not identical, it appears that viruses got theirs from us
--cellular oncogenes have introns & exons, viral oncogenes don't
--more than 20 cellular oncogenes have been identified, and many of the same genes are found in fruit flies, rodents and humans
--viral oncogenes can code for protein kinase, growth factor
--overproduction or inappropriate expression of ANY of these factors can result in malignant transformation: growth factors, receptors, G proteins, tyrosine kinases, cytoplasmic proteins and second messengers.
--two mechanisms activate a "proto-oncogene" into an oncogene: mutation & increased expression
--anti-oncogenes: stop overproduction of something and resist tumor formation, ex: tumor suppressor genes
--HPV and SV40 virus inactivate a protein encoded by the retinoblastoma gene (a tumor suppressor) allowing a retinoblastoma to form
--HPV also inactivates a protein encoded by the p53 gene (a tumor suppressor and apoptosis promoter) which is how it causes cervical cancer
--in colon cancers p53 and DCC (deleted in colon carcinoma) genes are inactivated
--more than half of human cancers have a mutated p53 gene in the DNA of malignant cells!!
--in most cases, tumor viruses (such as HPV) transform only cells in which they do not replicate, these cells are "nonpermissive" because they do not permit viral replication
--permissive cells are killed and not tumors are formed
--the essential step for a DNA tumor virus (such as SV40) to cause malig transform. is expression of the "early" genes (prior to replication) which produce the T antigens
--large T antigen is necessary and sufficient to induce transformation, binds SV40 virus DNA at site of initiation of viral DNA synthesis
--T antigen is mostly in nucleus but some on cell membrane where it is detected as TSTA, tumor specific transplatation antigen
--TSTA induces immune response against transplantation of virally transformed cells !!! kills metastases???
--little is known about small T antigen
--can use induction to determine if tumor viruses are present in human cancer cells, used iododeoxyuridine to induce virus from leukemic cells and discovered HTLV
--iododeoxyuridine is a nucleoside analog, not sure how it induces
--can also use a "helper" cell to find a tumor virus: fuse a transformed, nonpermissive cell with a permissive cells, forming a heterokaryon, and the tumor virus is induced and infectious virus is produced. mechanism unknown.
--treatment of NORMAL, UNINFECTED embryonic cells with nucleoside analogues reulted in the production of retroviruses (again, you can inherit viral genes from your parents)
--vertical vs horizontal transmission of tumor virus DNA
--vertical: from parents, virus crossed placenta, or virus in breast milk
--horizontal: by virus infection, if immunocompetent then Ab's vs virus and cancer frequency is low
--you probably won't get a carcinogenic viral infection from a cancer patient

--HPV and HTLV are the only two human tumor viruses (officially)
--HTLV-1 and 2 associated wtih leukemias and lymphomas (liquid tumors), tropical spastic paraparesis (autoimmune causing leg weakness)
--HTLV-1 induces leukemia by unique mechanism, stimulates mRNA synthesis, induces NF-kB which stimulates IL-2 and IL-2R (it's receptors) to be produced, causing division of all naive immune cells
--HTLV-1 is exogenously acquired: you get it from the virus, not from your parents
--HTLV-1 is not sufficient to cause cancer by itself, and is endemic in parts of Africa, some Caribbean islands, and in the southeastern US antibody titers are high
--HTLV-2 is 60% homologous with 1, also trans via blood & semen, also infects CD4 cells
--HPV causes benign warts that can progress to cancer esp with immunocompromise
--HPV carcinogenesis involves two proteins E6 and E7 that interfere with proteins encoded by two tumor suppressor genes (p53 and Rb {retinoblastoma})
--HPV has 100+ types, 1-4 cause plantar warts on the soles of feet, 6 & 11 cause anogenital warts & laryngeal papillomas, 16 & 18 implicated in cervical cancer (90% of anogenital cancers contain DNA of these types)
--EBV is a herpesvirus, was isolated from someone with Burkitt's lymphoma, causes MONOnucleosis, causes lymphomas in marmoset monkeys, causes nasopharyngeal carcinoma in humans (mostly in China) and thymic carcinoma and B-cell lymphoma in the US
--some US pts with Burkitt's lymphoma show no signs of EBV, when there is EBV the DNA is usu not integrated but rather is in closed circles in the cytoplasm
--HEP B is much more common in pts with primary heptaocellular carcinoma (#1 cancer cause of death worldwide)
--HEP C also predisposes to liver cancer, is an RNA virus with no oncogene but causes chronic hepatitis
--HHV-8 aka Kaposi's sarcoma associated herpesvirus (KSHV) seems to be causative
--polio vaccines were contaminated with SV40 virus but pts innoculated have no more tumors than those not

--papovaviruses incl polyomavirus and SV40
--rodents get lots of tumors with polyoma
--both undergot a permissive, lytic phase in host
--when infect cells of heterologous species, nonpermissive cycle --> malignant transformation
--heterologous = different but related species
--adenoviruses, human serotypes 12, 18, 31 induce sarcomas in newborn hamsters and transform rodent cells in culture (is this why so many people's pets get tumors? adenovirus is a common cause of the cold in humans)
--herpesvirus, four species cause lymphomas in nonhuman primates, chims, baboons
--a herpesvirus of chickens causes Marek's dz, kills chickens fast and is highly contagious
--herpesvirus also causes kidney cancer in frogs
--poxviruses: two cause tumors in animals, rabbits, monkeys
--not many genes
--snakes, birds, mammals incl nonhuman primates
--genes are integrated and transcription is induced, possibly increase expression of host oncogenes



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