Genetics of Cancer Lecture 32“Cancer II”Prof. Bevin Engelward, MIT Biological Engineering DepartmentWhy Cancer MattersNew Cancer Cases in 1997 Cancer Deaths in 1997Genetics 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?Normal Colon TissueDivits = "Crypts"TOP: Inner surfaceof the colonCell Lining = Epithelial CellsMost colon cancers appear to be of epithelial origin100 umNormal Colon TissueDefinitions:CryptSomatic Stem CellConveyor Belt1 Crypt = 1 CloneImage from D. SchauerImage by Christine AndersenCancerDysplasic 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 WeinbergNormal Cell → Metastatic Tumor: Many Changes are NecessaryCANCERConcept & parts of figure from Hanahan and WeinbergDefinitions:ApoptosisImmortalAngiogenesisMetastasisWhere do cancer cells come from?"Survival of the Fittest"Most fully blown cancers require many mutationsColon Cancer…Photographs: C.E.Fuller & E.D.Williams; Br.J.Cancer (1990)Normal Colonic EpitheliumMutation 1Most fully blown cancers require many mutationsColon Cancer…Normal Colonic EpitheliumMutation 1 Mutation 2 AdditionalMutations20 – 40 YearsMost of the mutations occur in somatic cells – but germ line mutations can also contribute to cancerClonal Expansion of Mutant CellsSingle Mutant CellSegment Inherited MutationHow do you figure outWhich mutations promote cancer?Mutation 1Normal Colonic EpitheliumMutation 2 AdditionalMutationsWhat types of genetic changes turn a normal cell into a cancer cell?Oncogenesgene that makes a cell cancerousdominant gain-of-function mutationsProto-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 advantageWhat 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!" signalMutations in Cancer Genes Transform Normal Cells into Cancer CellsOncogenesgene that makes a cell cancerousdominant gain-of-function mutations“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 factorsSignal Transduction and Growth RegulationCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesDefinitions:LigandReceptorSignal TransductionSignal Transduction and Growth RegulationCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesSpecific 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)EGFR: Receptor Tyrosine KinaseOutside the cellDefinitions:Extracellular DomainTransmembrane DomainCytoplasmic DomainKinase Active Sitelipid membraneInside the cellEGFR = Epidermal growth factor receptorEGFR: Receptor Tyrosine KinaseEGFR: Receptor Tyrosine KinaseP PDefinitions:Receptor DimerizationKinase ActivationAutophosphorylationEGFR: Receptor Tyrosine KinaseRASGDPP PP PP PGRB2SOSGRB2SOSEGFR: Receptor Tyrosine KinaseRASGTPGRB2SOSGRB2SOSP PP PP PSignaling by Phosphorylating Targets"Go!"Cancer Cells Often Exploit Receptor Tyrosine KinasesEGFRGENETIC DELETION TRUNCATESTHE PROTEINErbBP PP PP PConstitutively ActiveWithout Need for Growth Factors"Go!"Cancer Cells Often Exploit Receptor Tyrosine KinasesHer2NeuConstitutively ActiveWithout Need for Growth FactorsPOINT MUTATIONMUTATESTHE PROTEINP PP P"Go!"P PGlutamineValineConstitutive Activation converts RTKs to Dominant Acting OncogenesZwick et al, (2002) TIMM 8:17-23Genetic alterations leading to Constitutive Activation of RTKs• Deletion of extracellular domain• Mutations that stimulate dimerization without ligand binding• Mutations of the kinase domain • Overexpression of Ligand• Overexpression of ReceptorMutations in Cancer Genes Transform Normal Cells into Cancer CellsOncogenesgene that makes a cell cancerousdominant gain-of-function mutations“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 factorsSignal Transduction and Growth RegulationCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesSpecific Receptors for Growth factors e.g., Her2, EGFRG-proteins, kinases, and their targets e.g., RAS, ABLTranscription factors, e.g., MYCEGFR: Receptor Tyrosine KinaseRASGTPONPoint 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”Reminder:Ras was the gene that transformed the 3T3 CellsEGFR: Receptor Tyrosine KinaseRASGTPRaf OFFONMEKOFFMEKONPMAPOFFMAPONPTFOFFTFONPMAPONPNUCLEUSRASGDPOFFRaf ONTranscription of Genes that push Go → SSignal Transduction and Growth RegulationCytoplasmic signal transduction proteinsNuclear proteinsGrowth Factor GenesSpecific Receptors for Growth factors e.g., Her2, EGFRG-proteins, kinases, and their targets e.g., RAS, ABL, Transcription factors, e.g., MYCcMYC drives cells from G1 toS – so pushes cells through the cell cycleBurkitts LymphomaThere are many chromosomal abnormalities in the cancer cellsHow do you figure out which changes promote the disease?Burkitt’s Lymphoma: A chromosome translocation cMYC is expressed inappropriately in B-cellsMYC drives cells from G1 to SAnother way that oncogenic transcription factors can be up-regulated: Gene AmplificationChromosome from a Cancer CellBlue – staining of all chromosomesRed – staining of chromosome 4Green – staining of the MYC geneTwo Classes of Mutations that Increase MycTranslocation: A fusion-gene is createdMyc coding sequence is put behind a strong constitutive promoterAmplification:Cell harbors many copies of MycNormal Cell → Metastatic Tumor: Many Changes are Necessary“Go!” Growth Signal Independent“Don’t Stop”Resist anti-growth signals"Hurry Up!"Resist signals to wait for
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