Benign: Excessive proliferation; single mass Malignant: Cancer; invade surrounding tissue Classifications: carcinomas, sarcomas, others Benign Versus Malignant

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  • Benign: Excessive proliferation; single massMalignant: Cancer; invade surrounding tissueClassifications: carcinomas, sarcomas, othersBenign Versus Malignant Tumors

  • Tumor ProgressionDerived from single abnormal cellSomatic mutationsAccumulation of multiple mutations in lineageEvolutionary process

  • Evolution Of TumorNatural selectionCell acquiring further mutation that enhances proliferation dominates tumorHeterogeneity reflects continuing evolution

  • Stages Of Progression

  • Properties of Cancer CellsCell divisionFailure to properly differentiateFailure to undergo apoptosisDefective checkpoint controlGenetic instabilityOvercome replicative cell senescenceCell growth, biosynthesis, Warburg effect Metastasis

  • Warburg EffectImport vastly more glucoseSmall fraction for oxidative phosphorylationBuilding blocks for macromolecules

  • MetastasisInvade neighboring tissue; proliferate in new location

  • MutagensMost agents that cause cancer damage DNAChemical carcinogens, UV light, ionizing radiation, certain viruses

  • Epigenetic ChangesHeritable gene inactivation through histone modification and DNA methylation

  • Cancer Stem CellsSmall population of stem cells with indefinite self-renewalGive rise to rapidly dividing cells with limited self-renewal

  • Genes That Contribute To CancerProto-oncogenes: gain-of-function mutation in single allele drives tumor progressionTumor suppressor genes: loss-of-function mutations in both alleles drives tumor progression

  • Converting Proto-oncogenes To OncogenesMutation results in hyperactive or overexpressed protein

  • Inactivating Tumor Suppressor GenesBoth alleles can undergo inactivating somatic mutationsIndividual can inherit one inactive allele resulting in increased susceptibility to cancer Can be inactivated by epigenetic mechanisms

  • Normal Cellular Functions Of Cancer-Causing GenesInternal regulators of cell cycle progression and apoptosisMolecules involved in cell adhesion and movementsComponents of signaling pathways

  • Cancer GenomicsAbout 300 cancer-critical genesAbout 10 critical genetic or epigenetic changes in typical cancerSeveral key pathways commonly disrupted

  • Mechanisms Of RetinoblastomaHereditary form: one inherited and one somatic mutationNonhereditary form: two somatic mutations

  • Alterations To Rb PathwayOveractivation of cyclin D or Cdk4 or inactivation of p16 functionally equivalent to inactivation of Rb

  • Ras Proto-oncogeneConverted to oncogene by point mutation that abolishes GTPase activityDownstream effects independent of growth factor stimulation

  • p53 Tumor Suppressor GeneFunctions in checkpoint pathway for DNA damage or other cell stressesCan either induce apoptosis or block cell divisionInactivation leads to further genetic alterations

  • Bcl-2 Proto-oncogeneBlocks apoptosisOverexpression can contribute to cancerDiscovered from chromosomal translocation in B-cell lymphoma

  • Genes Contributing to MetastasisChanges that promote metastasis largely unknownRho-family GTPases: proto-oncogene, actin-based cell motilityE-cadherin: tumor suppressor, cell adhesion at adherens junctions

  • Commonly Mutated Genes in Colorectal Cancer

  • Apc Tumor Suppressor GeneInherited mutation in familial adenomatous polyposis coliMost colorectal tumors have somatic mutationsFunctions in Wnt signaling pathway by inhibiting b-catenin

  • Sequence of Genetic Changes in Colorectal Tumor ProgressionGeneral sequence in which common mutations often occur

  • DNA Repair GenesInactivation increases mutation rateIncreased cancer susceptibility from inheriting one inactive alleleDiseaseDefective ProcessHereditary nonpolyposismismatch repaircolon cancer

    Xeroderma pigmentosumnucleotide excision repair(susceptibility to skin cancer)BRCA-1, BRCA-2 mutationsrepair by homologous(susceptibility to breast cancer)recombination

  • Chronic Myeloid LeukemiaChromosomal translocation joining Bcr and AblHyperactive Abl tyrosine kinase

  • Treatment By Bcr-Abl InhibitorGleevec: small molecule inhibitor