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Neoplasia, Regulated through phos'ation CDKs phos'ate proteins to proceed Critical Checkpoints at G1/S, G2/M CDK substrates:RB, DNA replication, x-factors -dependent on cyclin synth/degrad. -CDK inhibitors cyclin D:CDK4 phos-ates RB, separating from x-complex ->activates E2F x-factor (elong. factor) ->E2F->xscription of Cyclin E, A ->thru late G1 restriction point to S Key regulators: p16, CDK4, cyclin D, Rb CDK Inhibitors Cip/Kip family-p21,p27,p57 -bind to/inactivate cyclin/CDK complexes INK4a/ARF locus->proteins p16INK4,p14ARF -p16 (INK4a)-competes w/ cyclin D->tumor supp. (b/c RB unphos'ated->still bound to E2F-> can't elongate and move to S) -mutated in GI CA, melanoma, glioblastoma, Loss of suppressors->tumorigenesis Knudson Hypothesis->"2-hit Mech" -usually need 2 rare events to happen->CA -for autosomal dom. Retinoblastoma ->already had 1 rare event happen -(both alleles of RB must be inactivated) -2nd via mutation p53 p53 - 17p13.1 -mutated in ᡪ% of human tumors most common mutations-on DNA-binding domain -hypoxia can stimulate p53 activation too -homozygous loss possible in every cancer -fcns: "applies emergency brakes to damaged DNA" -cell cycle arrest-late in G1 phase->xscribe p21 - uses GADD45 for repair, arrest -apoptosis of DNA-dmged cells-if DNA can't be repaired -activates bax, IGF-BP3->apoptosis dmged DNA->inc. p53->activate p53 as x-factor Li-Fraumeni Syndrome-1 defective p53 gene inherited ->inc. risk of brain, breast CAs, sarcomas -25x more likely to hav malignancy by 25 yo mdm2- (oncogene)- down-reg p53 after DNA repair -overexpressed in some sarcomas->down-reg too much p53 ->tumor proliferation, Neoplasm-new growth-uncontrolled, progressive overgrowth of cells -w/out protective purpose, persisting after cessation of simuli Oncology-study of neoplasms '-oma' - usually denotes tumor, usually benign '-oma misnomers' -melanoma, seminoma (testicular)-malignant -choristoma-ectopic NL adrenal cells under kidney capsule -hamartoma-mass of disorganized but mature cells -doesn't grow, congenital malformation, some in breasts, Types of mutated genes: 1. Protooncogenes-growth promoting 2. Cancer suppressor (antioncogenes) 3. Apoptotic genes 4. DNA repair genes-failure can lead to other 3 -principle target of genetic dmg Oncogenes Signal Transducing Proteins -ras-mutated in 10-20% of all CAs -in GF signalling -assoc. w/ inner memb via farnesylation -activated form bound to GTP -inactivated by intrinsic GTPase activity -GTPase activity blocked in mutant -GTPase Activ. Prot doesn't fcn right ->MAP kinase pathway always active Tyrosine Kinases -c-src family -c-abl-on Chrom 9, translocated to C22 ->w/ bcr locus=Phila. Chromosome->CML -primary role-induce apop after DNA dmg, "Cancer"-aggressive and spreading Sarcoma-from mesenchymal tissues -fibrosarcoma, liposarcoma -leiomyosarcoma-sm. mm. -rhabdomyosarcoma-striated mm. Carcinoma-from epith origin -adenocarcinoma-from/forms glands SCC-recognizable squamous cells in any epith -melanoma, semimoma also malignant *but sometimes CA is not diff'ated enough Tumor Progression Stepwise acquisition of phenotype: -excessive growth -local invasiveness -(angiogenesis) -metastases -due to accum of genetic lesions -favored by DNA repair defects, Neoplasia Origin Mostly from single cell Mixed tumors-from diff cell lines -usually from same germ layer though -(pluripotential) -ex. Wilms' tumor, nephroblastoma Teratoma-parenchymal from diff. germ layers -from totipotential cells->usually in gonads, Neoplasia Characteristics Metastasis-most reliable determinant -tumor implants discontinuous of primary tumor -always marks tumor as malignant -benign does not spread -almost all cancers can metastasize -except gliomas, basal cell carcinomas of skin -though both highly invasive -if more aggressive, rapid, large- -increase likelihood of mets -strongly reduces chance of cure 3 pathways: 1.Seeding, 2.Lymphatic, 3. Hematogeneous, Loss of suppressors->tumorigenesis Knudson Hypothesis->"2-hit Mech" -usually need 2 rare events to happen->CA -for autosomal dom. Retinoblastoma ->already had 1 rare event happen -(both alleles of RB must be inactivated) -2nd via mutation BRCA Mutated in 80% of fam. BR CA BRCA-1 (17q12-21) -mutations->inc. ov, pros, colon CA BRCA-2 (13q12-13) -muts->male BR, ov, prost CA, Neoplasia Characteristics Differentiation/Anaplasia -applies to parenchyma of neoplasm -how much do tumor cells resemble NL cells? Well diff'ated-resemble mature NL cells -usually benign are well diff'ated -can make NL hormones -malig range from well to undiff'ated -"moderately well diff'ated" Anaplasia-all undiff'ated cells -hallmark of malignant transformation -not "de-differentiated," just no maturation from proliferation -pleomorphism-cells have diff sizes/shapes -usually large, hyperchromatic nuclei C:N=1:1 -large nucleoli, chromatin clumped along memb -mitotic (not necessarily malignant if mitotic) -but will have atypical mitotic figures -tumor giant cells-large, dark nucs -lose polarity-grow disorganized-like -can make random hormones, etc. Dysplasia-disordered growth like anaplastic, but normal mitotic figures -loss of uniformity and architecture -usually in epith, mitosis in other than basal cells -Carcinoma in situ-if all epith layers -preinvasive neoplasm -usually antedates cancer, but not all dys->CA, Types of mutated genes: 1. Protooncogenes-growth promoting 2. Cancer suppressor (antioncogenes) 3. Apoptotic genes 4. DNA repair genes-failure can lead to other 3 -principle target of genetic dmg Retroviruses RNA genome w/ gag-pol-env genes Acute Transforming Virus-can't replicate -but carry v-onc transforming gene Slow Transforming Virus-insertional mutagenesis-near protooncogene ->transform to oncogene->c-onc