Cancer Cancer originates in dividing cells –Intestinal lining (colon)...

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Transcript of Cancer Cancer originates in dividing cells –Intestinal lining (colon)...

  • CancerCancer originates in dividing cellsIntestinal lining (colon)Lung tissueBreast tissue (glands/ducts)Prostate (gland)White blood cells (leukemia)Stem cellsSkin (melanoma)LiverHematopoietic (myeloma)Does not occur in quiescent cells

  • Cells and Their Half-LivesIntestinal cells Less than a weekErythrocytes100 daysWhite blood cellsBrief life spansLiverInfrequently replacedMuscleIrregular activation NeuronsLittle or no replacementSkin cellsRegularly replacedEndothelial cellsFrequently replaced

  • CancerLoss of cell-cycle controlCloned cells divide uncheckedResults from multiple genetic mutationsCell cycle genesDNA repair genesApoptosis genesGrowth regulation genesClassified as carcinomas, sarcomas or leukemias (200 types recognized)

  • Benign TumorsGenerally localized and smallFairly common (warts, colon polyps, etc.)Do not break out of originating organFunction very much like cells of originGenerally are easily removed by surgery

  • Malignant TumorsRemain localized for a time but then invade surrounding tissueSpread by forming metastasesCells travel through circulationCan invade any other body tissuesProduce few markers of original tissueVery difficult to treat

  • Cancer MetastasisBasal lamina normally provides barrierMalignant tumor cells can:Break free of attachments to adjoining cellsAttach to basal laminaSecrete enzymes that digest extracellular proteinsMigrate into circulatory systemPenetrate back out of circulatory system to colonize another tissueRare cells succeed (1 in 106)

  • Tumor Angiogenesis106 cells is a mass of ~2mmCan not grow more without blood supplyMalignant cells overcome this limitationSecrete growth factors that stimulate angiogenesis (FGF, VEGF,etc.)Requirement for vascular supply suggests possible treatment approach

  • Cancer is Caused by DNA MutationsDNA from transformed cells can transform normal cellsMore than 1 mutation is requiredE.g., 3T3 cells that already lack p16 (cyclin dependent kinase inhibitor) and then develop mutation to overproduce growth-promoting signal (ras) becomes cancerousMammals have evolved to prevent accumulated mutations

  • Genes Associated with CancerOncogenesMutated forms of proto-oncogenesOverproduction or over activity is associated with cancerGain-of-function agentsE.g., Myc Transcription factor that leads to progression through cell cycleMutation in one allele is adequate to cause cancer risk

  • Genes Associated with CancerTumor suppressor genesEncoded proteins that inhibit cell cycle progression or promote apoptosisE.g., APC or RbLoss of function agentsMutations in both alleles are required

  • Inherited MutationsSome mutations pass through germ lineCauses hereditary predispositionInsufficient alone to cause cancer~10% of all cancers have hereditary componentE.g., Inherited dysfunctional APC gene leads to colon polyps early in lifeE.g., Inherited dysfunctional Rb gene leads to hereditary retinoblastoma early in life

  • Cell Cycle ProblemsOver expression of Cyclin DLoss of p16 functionLoss of Rb function

  • Loss of DNA Repair Problemsp53 is an essential checkpoint proteinPrevents proliferation with damaged DNALoss of function associated with of all cancersCells with p53 arrest in G1 after irradiationActivated only after cell stress or damageInduces p21 to inhibit Cdk-cyclin complexesFalls off to low level if DNA repair is successfulActive as tetramer of 4 unitsMutation in one allele creates loss of function

  • P53 Mutation Frequency in Various Cancers

  • Chemical CarcinogensDirect acting vs. indirectIndirect results from non-reactive chemicals being metabolized in liver to carcinogenOxidative reactions by p450 enzyme complexes rid body of fat soluble toxinsActive carcinogen binds to DNA and causes mutations (e.g., benzopyrene in cigarette smoke causes G to T transversions in DNA causes mutations of p53 at codons 175, 248 and 273)

  • Initiators vs. PromotersInitiatorsCarcinogens that interact with and cause mutations in DNAPromotersInteract with cells to promote growth, block differentiationLeads to additional permanent changes after initiator damageDoes not cause cancer by itselfNo reliable test yet found to identify promoters

  • Radiation MutationsUltraviolet radiationIonizing radiationGamma- and X-raysParticle radiation (alpha, beta)Electromagnetic radiationPower lines, cell phones, etc.May act as promoter

  • Cancer TreatmentsSurgeryChemotherapyRadiation therapyPhotodynamic therapyMagic bulletsAngiogenesis inhibitorsTransplantation of hematopoietic stem cellsWhole body radiation to treat metastasesGene therapyReintroduce p53 or other tumor suppressor genesMust get into each and every cancer cell