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44 Cards in this Set

  • Front
  • Back
what percentage of human cancers are viral contributed?
major cancer types seen in viral?
liver and cervical - thus Hep B and HPV vaccines are important
fate of cellular proto oncogenes?
can become c oncs or v oncs
what do RNA tumor viruses usually do to cellular genes? DNA tumor viruses?
activate proto oncogenes. Negate cellular tumor suppressor genes
generalizations of DNA tumor viruses? RNA tumor viruses?
v oncs are essential and not acquired, no cellular homologues, inactivate tumor suppressors like Rb and p53, linked to strategy of viral replication. V onc not essential, acquires v onc via cellular genes, deregulate signalling pathways thus increasing growth, unrelated to strategy for virus replication.
in DNA viral tumor viruses, what viral genes are oncogenes?
early genes that prepare the non condusive cell for viral replication which leads to inhibition of the p53 or Rb
with DNA viruses what must occur for transformation to occur?
aborted viral life cycle, early genes expressed but viral replication (which would be cytocidal) is aborted
what are the viral oncogenes and the associated cellular targets of adenovirus (animal tumors only)? SV40 (animals only)? Polyoma? Papilloma?
E1A for Rb and E1B for p53. large T antigen for p53 and Rb. Large T Ag for Rb and middle T Ag for Src and P13K. E7 for Rb, E6 for p53 and E5 for PDGF receptor
describe possible results for a pap smear?
initial change is cervical intraepithelial neoplasia type 1: top layers have perinuclear clearing around the nucleus (called koilocytes) but you still see differentiated normal squamous epithelium, types vary depending upon amount of dedifferntiation exists, when the virus integrated into the host cell, you will see carcinoma with de many dedifferntiated cells with large nuclei
how does HPV transform the cell molecularly?
viral DNA integrates into the host cell and the viral protein E2, which keeps in check E6 and E7 (the oncogenes that affect the tumor suppressor cells), is disrupted as well as other genes needed to replicate the virus.
what is the outcome of infection with small DNA tumor viruses (non-Herpes)?
cell cycle deregulation is of no consequence if cell dies and virus completes lytic cycle, but in the rare case the cell has an abortive infection and integration of the viral genome, transformation occurs and monoclonal tumors are seen
IN GENERAL how do the tumor inducing human herpesviruses 8 - KS - causes oncogenesis?
molecular mimicry thus upregulating cell cycle, they pirate cellular oncogenes like RNA viruses
epidemiology of HHV 8 (kaposi's sarcoma)?
not ubiquitous, uncommon in general population, STD, shed in saliva, endemic KS in young children suggests vertical transmission
what are the populations that are at risk for HHV 8?
AIDS (usually MSM), italian population (usually benign), east and central africa (younger age, women, aggressive), post trasplantation KS… mainly AIDS
molecular biology of HHV 8?
B lymphos are reservoir, PCR detection in saliva, semen, prostate, peripheral blood lymphocytes, virus has pirated cellular regulatory genes that regulate angiogenesis, cell cycle, and inflammation
HHV 8 disease associations?
Kaposi's sarcoma: multiple vascular nodules in skin, mucous membranes, viscera, cytokine driven process, infiltrating inflammatory cells, proliferation of endothelial or spindle cells. Body cavity based primary effusion lymphomas: Pel lymphomas, no contiguous mass, cell surface adhesion molecules not expressed, often co infected with EBV. Multicentric Castlemen's disease: non neoplastic lymphoproliferation, generalized or as a solitary mediastinal node (can become malignant), occurs in setting of IL 6 over expression (viral or cellular)
describe what is seen in a KS tumor?
extensive neoangiogenesis, erythrocyte extravasation, infiltrating inflammatory cells, spindle and endothelial cells
describe the cellular proto oncogenes that HHV 8 pirates.
Bcl 2 (apop regulator), IL6 (stimulates B cell growth, anti apop), cyclin (D type that is very important in dodging cell stop proteins), GPCR (IL8 receptor, enhances fibroblast proliferation, has angiogenic activity related to KS), all the previous proteins are viral lytic proteins. Interferon regulatory factor (negative regulator of interferon signaling thus halts the cellular anti viral response)
treatment for KS?
highly active antiretroviral therapy (HAART) is very effective in preventing KS since AIDS is most commonly associated
T/F replication of RNA viruses is cytocidal and is required for tumorgenesis?
F it is not cytocidal nor is it required for tumorgenesis
in retrovirus, expression of the integrated provirus is under control of what?
viral transcriptional regulatory sequences (LTRs)
mechanisms of cell transformation by RNA tumor viruses?
retroviral transduction of oncogene, oncogene activation by retroviral insertion (cis acting retrovirus), oncogenesis mediated by essential retrovirus proteins (trans activating retrovirus)
mechanisms of transducing onvogenes?
structurally alter gene or overexpress it, remember they are replication defective and need helper virus to start it up
voncs encode for what?
external signal molecules or growth factors, cellular receptors, second messengers in signaling cascades, txn factors
what are the structural changes in acquired v-onc outcome of retroviral transduction?
single hit carcinogenesis, polyclonal: tumor growth initiated in every infected cell, tumors wi days, characteristic of animal retroviruses
how do retroviruses activate cellular proto oncogenes by insertion (cis acting retroviruses)?
they stick a promoter or enhancer next to proto oncogene
properties of cis acting retroviruses?
do not carry the oncogenes, retain all viral genes, are replication competent
what is the outcome of oncogene activation by retrovirus insertion?
transformation is rare bc it is chance that it inserts near potential oncogene, monoclonal tumors (integrated proviral sequences remain in same spot in progeny cells), tumors induced more slowly since tumors are derived from a single cell
problem in gene therapy for X linked SCID?
used retorvirus with the gene for interleukin 2 receptor which is absent in SCID kids, then put them in the CD34+ hematopoeitec T stem cells, but the LMO2 (leukemia virus vector) blocked T cell differentiation and the transduced ILR2 facilitated cell division, made the perfect storm for leukemia.
what virus is the exception to the paradigm of retroviral oncogenesis and what mechanism does it use?
human T cell leukemia virus (HTLV1), oncogenesis is mediated by essential retrovirus proteins (trans activating retro virus). HTLV1 uses the nonstructural protein TAX which is essential for viral replication and is not cell derived.
what morphology of retroviruses is HTLV1?
C type: most common type, made at cytoplasmic membrane, no precursor particle, maturation while budding, central core
HTLV1 epidemiology?
endemic to Japan, caribbean, Africa, middle east, Australia, Melanesia, widespread in central and south america, not indigenous to NA or europe
HTLV 1 transmission?
sexual (60% male to femal vs 1 % female to male), breastfeeding, blood products, infection occurs by transmission of infected T cells, rarely by free virus
in the US, when they started screening blood samples for HTLV1, what did they find?
seroprevalence of HTLV 3x greater than HIV, but it was HTLV2 that is common in IV drug abusers and does not cause cancer, unsure of its disease associations
disease associations of HTLV1?
adult T cell leukemia/lymphoma. HTLV1 associated myelopathy (progressive demyelinating disease), inflammatory diseases: arthropathy, uveitis, pneumonitis, dermatitis in kids, polymyositis)
characteristics of adult T cell leukemia/lymphoma from HTLV1.
20 to 40 yrs after primary infection, life long carriers have a 2 to 4% risk, dx by monoclonal integration of HTLV1 (usually in CD4 cells), chemo not too helpful, fulminant type kills in 6 mos, indolent type kills 50% in 4 yrs, lymphadenopathy, skin involvement, hepatosplenomegaly, elevated serum calcium with lytic bone lesions (over expression of PTH type protein - TAX)
what classification of retroviruses is HTLV?
complex, has more genes than just pol-gag-env; also has tax and some others
fact to remember: HTLMV has 97% genomic homology WW, and it replicates like EBV by chilling in the genome and letting the cell do the work, no lytic phase
boo yah casha
what protein from the minus strand of HTLV inhibits tax?
HBZ the basic leucine zipper
describe the activities of TAX.
whore of a transactivator, transactivates everything! Regulates expression of viral genes, binds cellular txn factors to enhance their binding to cellular promoters, dissociates NF-kB from its inhibitor so it can increase survivial, upregulates a shit ton of interleukins, receptors, growth factos... also targets cell cycle regulatory proteins: inactivates p53 (G1/S restriction pt control), binds mitotic arrest defective protein which messes up G2/M progression, chromosomal segregation, and post mitotic nuclear assembly (results inaneuploidy usually)
what is the typical presentation on a smear of the HTLV CD4 cancer cells?
flower cells from elevated levels of alpha chain IL2 receptor and perturbation of chromosomal segregation via MAD1 all from TAX. Found in CSF too
describe the activities of HTLV HBZ gene.
shuts down tax bc it is a potent target for CD8 T cells, then the RNA for HBX activates the E2F pathway to keep the cells replicating
some facts about HTLV1 induced oncogenesis.
latency period indicates more things need to happen than just infection, multistep process, tax involved in tumor initation but no viral gene expression in the tumor itself. Monoclonal in terms of a specefic tumor, but integration site varies among patients
is HBZ expressed in ATL?