Genetics of Cancer Lecture 32“Cancer II”Prof. Bevin Engelward, MIT Biological Engineering DepartmentBased on a lecture by Prof. Leona SamsonNew Cancer Cases in 1997 Cancer Deaths in 1997Why Cancer MattersUnless things improve…. • 1/3 of the people in this room will get cancer• Many cancers are quite treatable; others are notGenetics of Cancer:Today: What types of genetic changes turn a normal cell into a cancer cell?Next Class: Where do these genetic changes come from?Divits = "Crypts"Cell Lining = Epithelial CellsTOP: Inner surfaceof the colonNormal Colon TissueMost colon cancers appear to be of epithelial origin100 umImage by Christine AndersenImage from D. SchauerNormal Colon TissueDefinitions:CryptSomatic Stem CellConveyor Belt1 Crypt = 1 CloneCancerDysplasic CryptMild DysplasiaNormal Colonic EpitheliumProgression from Normal to CancerWhat are the genetic steps? What does a cancer cell need to be able to do?Normal Cell → Metastatic Tumor: Many Changes are NecessaryConcept & parts of figure from Hanahan and Weinberg"Mutate!"“Go!”Growth Signal Independent“Don’t Stop”Resist anti-growth signals“Don’t Die”Resist Apoptosis“Keep Going”Be Immortal“Feed Me”Recruit & Sustain Blood Flow“Take Over”Escape/Invade = Metastasize"Hurry Up!"Resist signals to wait for repairsDefinitions:ApoptosisImmortalAngiogenesisMetastasisNormal Cell → Metastatic Tumor: Many Changes are NecessaryConcept & parts of figure from Hanahan and WeinbergCANCER"Mutate!"“Go!”Growth Signal Independent“Don’t Stop”Resist anti-growth signals“Don’t Die”Resist Apoptosis“Keep Going”Be Immortal“Feed Me”Recruit & Sustain Blood Flow“Take Over”Escape/Invade = Metastasize"Hurry Up!"Resist signals to wait for repairsWhere do cancer cells come from?"Survival of the Fittest" is Happening in You Right NowMost fully blown cancers require many mutationsColon Cancer…Normal Colonic EpitheliumMutation 1Photographs: C.E.Fuller & E.D.Williams; Br.J.Cancer (1990)Most fully blown cancers require many mutationsColon Cancer…Mutation 120 – 40 YearsNormal Colonic EpitheliumMutation 2 AdditionalMutationsMost of the mutations occur in somatic cells – but germ line mutations can also contribute to cancerGermline Mutation:All Cells Harbor Cancer-Promoting MutationSomatic Mutation:Mutation arises within a tissueMutation During Development followed by Clonal Expansion: Cells within a tissue region share the same mutationSingle Mutant CellSegment Inherited MutationClonal Expansion of Mutant CellsHow do you figure outWhich mutations promote cancer?Mutation 1Normal Colonic EpitheliumMutation 2 AdditionalMutationsColon Cancer - can see every stage –compare stages and look for shared changesWhat types of genetic changes turn a normal cell into a cancer cell?Proto-Oncogenes = Normal genes (often involved in growth regulation)Oncogene = mutant form of an otherwise-normal gene that when mutated gives a cancer cell a selective advantageOncogenesgene that makes a cell cancerousdominant gain-of-function mutationsWhat types of genetic changes turn a normal cell into a cancer cell?Cancer is Uncontrolled Cell ProliferationNormal signaling machinery can be exploited by cancer cells:Independent "Go!" signalOncogenesgene that makes a cell cancerousdominant gain-of-function mutationsMutations in Cancer Genes Transform Normal Cells into Cancer Cells“Go!”Growth Signal IndependentRasRas(G12D)(H-Ras, N-Ras, and K-Ras) Normal Ras is involved in sensing growth signalsMutant Ras gives the "go signal" without growth factorsCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesSignal Transduction and Growth RegulationDefinitions:LigandReceptorSignal TransductionAdapted from L. SamsonCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesSignal Transduction and Growth RegulationSpecific Receptors for Growth factors e.g., Her2, EGFRG-proteins, kinases, and their targets e.g., RAS, ABLTranscription factors, e.g., MYCReceptor Tyrosine Kinases• Many variants & many ligands(NGF, PDGF, FGF, EGF, insulin)• Trigger different effects on different cells (proliferation & prosurvival)Adapted from L. SamsonOutside the cellInside the cellDefinitions:Extracellular DomainTransmembrane DomainCytoplasmic DomainKinase Active Sitelipid membraneEGFR: Receptor Tyrosine KinaseEGFR = Epidermal growth factor receptorP PDefinitions:Receptor DimerizationKinase ActivationAutophosphorylationEGFR: Receptor Tyrosine KinaseRASGTPGRB2SOSGRB2SOSP PP PP PEGFR: Receptor Tyrosine KinaseRASGTPGRB2SOSGRB2SOSP PP PP PSignaling by PhosphorylatingTargetsEGFR: Receptor Tyrosine Kinase"Go!"Definitions:Signal TransductionAdaptor ProteinsKinase ActivationCancer Cells Often Exploit Receptor Tyrosine KinasesEGFRErbBP PP PP PConstitutively ActiveWithout Need for Growth Factors"Go!"GENETIC DELETION TRUNCATESTHE PROTEINSlide adapted from L. SamsonCancer Cells Often Exploit Receptor Tyrosine KinasesHer2NeuPOINT MUTATIONMUTATESTHE PROTEINP PP P"Go!"P PGlutamineValineDefinitions:Proto-oncogene Receptor ProteinOncogenic MutationOncoproteinZwick et al, (2002) TIMM 8:17-23Constitutive Activation converts RTKs to Dominant Acting OncogenesSlide adapted from L. SamsonGenetic alterations leading to Constitutive Activation of RTKs• Deletion of extracellular domain• Mutations that stimulate dimerizationwithout ligand binding• Mutations of the kinase domain • Overexpression of Ligand• Overexpression of ReceptorSlide from L. SamsonCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesSignal Transduction and Growth RegulationSpecific Receptors for Growth factors e.g., Her2, EGFRG-proteins, kinases, and their targets e.g., RAS, ABLTranscription factors, e.g., MYCSlide adapted from L. SamsonEGFR: Receptor Tyrosine KinaseONRASGTPReminder:Ras was the gene that transformed the 3T3 CellsPoint Mutations in Ras turn it from a normal protein into an oncoproteinOncogenic mutations “Lock” Ras into active GTP bound stateCodon 12 - Normally glycine; almost anything else and it is stuck “ON”EGFR: Receptor Tyrosine KinaseRASGTPRaf OFFONMEKOFFMEKONPMAPOFFMAPONPTFOFFTFONPMAPONPNUCLEUSRASGDPOFFRaf ONTranscription of Genes that push Go → SCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesSignal Transduction and Growth RegulationSpecific Receptors for Growth factors e.g., Her2, EGFRG-proteins, kinases, and their targets e.g., RAS, ABL, Transcription factors,
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