Chances of cancer increase or decrease with age? -increase 4 types of cancer derevied as hereditary? -retinoblastoma -adenomatous polypsosis coli -xeroderma pigmentosum -familial dispositions Heredity cancers with autosomal dominate pattern? -retonoblastoma -adenomatous polyposis coli -xeroderma pigmentosum Hereditive cancer, which homozygotes may develop? -xeroderma pigmentosum Sun induced skin cancer (name for)? -xeroderma pigmentosum Persistent regenerative cell replications- acquired preneoplastic or post neoplastic? -acquired preneoplastic disorder Hyperplastic and dysplastic proliferations- acquired pre or post neoplastic? -acquired preneoplastic disorder HPV associated cancer? -cervical cancer Cancers (3) derived from environmental influences? -stomach cancer -hepatocellular cancer -cervical cancer Carcinogenesis is genetic damage or non- lethal mutation. What is the cause of this? -virus -radiation -chemical -inherited -cumulative replication errors What does cancer mass develop from? -single progenitor (monoclonal expansion) What results from damaged genes? -promotion of cancer
What is tumor progression? -excessive growth local invasion metastases How are genes damaged, which promote cancer? 1. growth promoting protooncogens 2. Cancer suppressor genes (antioncogens) 3. Apoptosis regulating genes 4. Genes encoding DNA repair proteins Normal cell DNA damage (acquired environmental factors) mutations in genome of somatic cells mutations in genome of somatic cells (genetic factors- inherited mutations in genes affecting cell growth or DNA repair) 1. Activating of growth promoting oncongenes- alterations of genes that regulate apoptosis- inactivation of cancer suppressor genes expression of altered gene products and loss of regulatory gene products (clonal expansion additional mutations (progression) heterogeneity) malignant neoplasm In a genome, what to proto oncongenes result in? -regulation of cell proliferation or apoptosis In a genome, what do non oncogenic genes result in? -do not regulate cell proliferation What encodes oncoproteins? -oncogenes What do oncoproteins resemble? -normal products of proto- oncogenes Oncoproteins make up consists of? -growth factors -growth factor receptors -signal transducing proteins critical for mitogenesis What is a result of mutations of genes encoding growth factors? -renders them oncogenic by causing their over expression What is generated in mutant oncogenic receptor proteins of growth factor receptors? -continued mitotic signal What is an example of a mutation of oncogenic growth factor receptor proteins generating a continued mitotic signal? -EGF gene c-erb B1 What is an example of a signal transducing protein?
-c- ras gene Where are signal transducing proteins located? -inner leaflet of membrane What do signal transducing proteins encode? -GTP What does encoding of GTP binding protein of a signal transducing protein activate? -other cellular protein kinases What does the encoding of GTP binding of signal transucing proteins, activating other cellular protein kinases result in? -mitosis What is GTPase activity enhanced by? -GAP (GTPase activating protein) When are ras family of proteins inactive? -when intrinsic GTPase activity cleaves GTP-> GDP Mutations in the gene sequence that reduces or abolishes GTPase activity activates what? -RAS protein What does activating the RAS protein result in? -unregulated mitosis What may be activated when mutations of GAP gene, which reduce GTPase activity? -RAS What is an example of a point mutation? -ras protein What activates oncogenes? -point mutations -chromosomal translocations -gene amplification. How do point mutations cause intrinsic GTPase activity to decline? -constitutively activates protein What do chromosolam translocations result in? -over expression In gene amplification, what does over expression result from? -increased copies of gene in genome
What is an example of gene amplification? -N-myc protein in neuroblastoma What do cancer suppressor genes inhibit? -cell proliferation What are proteins that normally bind to external receptors and inhibit growth? -growth inhibitory factors What type of cancer suppressor gene molecule regulates cell proliferation? -molecules that regulate cell adhesion What is an example of a molecule that regulate cell adhesion? -E- cadherin What type of cancer suppressor gene molecules attenuate growth promoting signals? -molecules that regulate signal transduction What is an example of a molecule that regulate signal transduction? -NF-1 gene What does a molecule that regulates signal transduction encode (NF-1fene? -encodes GAP protein What is an example of a molecule that regulates nuclear transcription and cell cycle? -retinoblastoma gene What do molecules that regulate nuclear transcription and cell cycle encode? -encodes transcription factor binding protein What does an unphosphorylated state of transcription factor binding protein do? -actively binds transcription factors and prevents cell division What does a phosphorylated state of transcription factor binding protein do? -releases transcription factors What does HPV bind to (transcription)? -HPV binds to hypophosphorylated protein, thereby displacing transctiption factors What does this result in? -cancer of cervix What gene example inhibits apoptosis? -bcl-2
What gene opposes bcl- 2 gene? -bax gene What do relative levels of expression regulate? -cell death What is repair DNA damage caused by? -extrinsic agents -errors in replications Can a single oncogene transform cells? -no What does multistep carcinogenesis require? -multiple genetic alterations Can a tumor outgrow blood supply? -no What are angiogeneic factors in tumor angiogenesis produced by? -tumor What is tumor progression caused by? -subpopulation of cells What type of cells is most chemotherapy only effective on -cycling cells What are the most susceptible tumors for chemo? -tumors with higher growth fraction What is an example of a cancer, which chemotherapy is most effective on? -high- grade lymphoma How is the extracellular matrix invaded? -detachment of tumor cells attachment of cells to ECM degradation of ECM migration of tumor cells What are in circulation tumor cells subject to? -immunodestruction
How do tumor cells aggregate? -attaching to each other -attachment to platelets
-attachment to leykocytes Do tumor cells migrate individually or with a friend? -individually What is the mtastatic site preticted by -primary site What is organ tropism known as? -homing Why is the metastatic site predicted by primary site? -due to drainage Are chemicals direct acting, cancer causing? -yes What are procarcinogens? -a chemical substance that becomes a carcinogen only after it is altered by metabolic processes. What are most chemicals that are carcinogenic? What are they? -electrophiles -A chemical compound or group that is attracted to electrons and tends to accept electrons. What are the two DNA ocogenic viruses? -HPV -HBV How many serotypes does HPV have? -over 50 What is the cause of HPV? -benign squamous papillomas (warts) and/or cervical CA What proteins is HPV due to? -E7 -E6 What is the function of E7? -E7 interferes with Rb binding of transcription factors
What is the function of E6? -E6 inactivates p53
What does EBV cause? -Can cause no symptoms mono burkitts lymphoma (b-cell proliferation) nasopharengeal CA What problems can both malignant and benign tumors create (symptoms)? -Impingement on adjacent structures - Hemorrhage - Infections secondary to necrosis - Hormonal activity What is cancer cachexia? -Cachexia (wasting) syndrome common in PTs with CA What do cancer neoplastic syndromes exclud? -cachexia What percentage of pts have pareneoplastic syndromes? -10-15% What are the most common paraneoplastic syndromes and what are they? -hypercalcemia -elaboration of PTH -cushings syndrome -ectopic production of ACTH -hypercoaguability What is grading and staging necessary for? -to predict outcome What does grading establish? -estimate of aggressiveness What is grading based upon? -cytologic features -mitotic activity What is staging based on? -based on size of primary, extent of lymph node involvement and presence or absence of mets What is the TNM system?
-TO-4 -size of primary -NO-3 -involvement of nodes -MO1 -presence or absence of mets What are the tumor markers? -PSA -CEA (carcinoembryotic antigen) -Alpha- fetoprotein When is PSA elevated? -prostatic CA -benign conditions How often are CEA levels elevated in colorectal CA? -60% - 90% How often are CEA levels elevated in pancreatic cancer? -50% - 80% When is CEA elevated in malignant conditions?? -colorectal cancer -pancreatic cancer When is CEA elevated in benign conditions? -ETHOH cirrhosis -hepatitis -IBD What does CEA lack, which is required for screening test? -lacks sensitivity and specificity What is screening tests with CEA useful for? -detection of CA recurrences What does alpha- fetoprotein cancer arise from? -liver and yolk sac remnants in gonads What are benign conditions of alpha- fetoprotein? -chirrhosis -hepatitis -pregnancy with fetal distress
What does alpha- fetoprotein lack in screening tests? -sensitivity and specificity When is there a presumptive diagnosis for alpha- fetoprotein? -levels of alpha- fetoprotein are too high Terminology: Benign v Malignant Metastasis -benign- do not do -malignant- requently present Differentiation -benign-well differentiated (look like normal counterparts) (myolyoma) -malignant-lack differentiation with anaplasia (atypical structure) Rate of growth (mitotic index) -benign - progressive and slow- mitotic figures are rate and normal -malignant -erratic and may be slow to rapid- mitotic figures may be numerous and normal
Local invation -benign - usually cohesive and expansile- well demarcated masses that do not invade or infiltrate the surrounding normal tissues -