Genetics of Cancer Lecture 32 Cancer II Prof Bevin Engelward MIT Biological Engineering Department Why Cancer Matters New Cancer Cases in 1997 Cancer Deaths in 1997 Genetics 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 Tissue Divits Crypts Cell Lining Epithelial Cells Most colon cancers appear to be of epithelial origin 100 TOP Inner surface of the colon um Normal Colon Tissue Definitions Crypt Somatic Stem Cell Conveyor Belt 1 Crypt 1 Clone Image from D Schauer Image by Christine Andersen Progression from Normal to Cancer Normal Colonic Epithelium Mild Dysplasia Dysplasic Crypt Cancer What are the genetic steps What does a cancer cell need to be able to do Normal Cell Metastatic Tumor Many Changes are Necessary Concept parts of figure from Hanahan and Weinberg Normal Cell Metastatic Tumor Many Changes are Necessary CANCER Definitions Apoptosis Immortal Angiogenesis Metastasis Concept parts of figure from Hanahan and Weinberg Where do cancer cells come from Survival of the Fittest Most fully blown cancers require many mutations Colon Cancer Normal Colonic Epithelium Mutation 1 Photographs C E Fuller E D Williams Br J Cancer 1990 Most fully blown cancers require many mutations Colon Cancer Normal Colonic Epithelium Mutation 1 Mutation 2 20 40 Years Additional Mutations Most of the mutations occur in somatic cells but germ line mutations can also contribute to cancer Clonal Expansion of Mutant Cells Single Mutant Cell Segment Inherited Mutation How do you figure out Which mutations promote cancer Normal Colonic Epithelium Mutation 1 Mutation 2 Additional Mutations What types of genetic changes turn a normal cell into a cancer cell Oncogenes gene that makes a cell cancerous dominant gain of function mutations Proto Oncogenes Normal genes often involved in growth regulation Oncogene mutant form of an otherwisenormal gene that when mutated gives a cancer cell a selective advantage What types of genetic changes turn a normal cell into a cancer cell Cancer is Uncontrolled Cell Proliferation Normal signaling machinery can be exploited by cancer cells Independent Go signal Mutations in Cancer Genes Transform Normal Cells into Cancer Cells Oncogenes gene that makes a cell cancerous dominant gain of function mutations Ras Ras G12D Go Growth Signal Independent Normal Ras is involved in sensing growth signals Mutant Ras gives the go signal without growth factors H Ras N Ras and K Ras Signal Transduction and Growth Regulation Definitions Ligand Receptor Signal Transduction Cytoplasmic signal transduction proteins Nuclear proteins Growth Factor Genes Signal Transduction and Growth Regulation Receptor Tyrosine Kinases Many variants many ligands NGF PDGF FGF EGF insulin Trigger different effects on different cells proliferation prosurvival Specific Receptors for Growth factors e g Her2 EGFR G proteins kinases and their targets e g RAS ABL Cytoplasmic signal transduction proteins Nuclear proteins Growth Factor Genes Transcription factors e g MYC EGFR Receptor Tyrosine Kinase Definitions Outside the cell Extracellular Domain Transmembrane Domain Cytoplasmic Domain Kinase Active Site lipid membrane Inside the cell EGFR Epidermal growth factor receptor EGFR Receptor Tyrosine Kinase EGFR Receptor Tyrosine Kinase Definitions Receptor Dimerization Kinase Activation Autophosphorylation P P EGFR Receptor Tyrosine Kinase RAS GDP SOS GRB2 SOS GRB2 P P P P P P EGFR Receptor Tyrosine Kinase SOS GRB2 RAS SOS GRB2 P GTP P P P P P Signaling by Phosphorylating Targets Go Cancer Cells Often Exploit Receptor Tyrosine Kinases EGFR GENETIC DELETION TRUNCATES THE PROTEIN ErbB P P P P P P Constitutively Active Without Need for Growth Factors Go Cancer Cells Often Exploit Receptor Tyrosine Kinases Her2 POINT MUTATION MUTATES THE PROTEIN Neu Glutamine Valine P P P P P P Constitutively Active Without Need for Growth Factors Go Constitutive Activation converts RTKs to Dominant Acting Oncogenes Zwick et al 2002 TIMM 8 17 23 Genetic 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 Receptor Mutations in Cancer Genes Transform Normal Cells into Cancer Cells Oncogenes gene that makes a cell cancerous dominant gain of function mutations Ras Ras G12D Go Growth Signal Independent Normal Ras is involved in sensing growth signals Mutant Ras gives the go signal without growth factors H Ras N Ras and K Ras Signal Transduction and Growth Regulation Specific Receptors for Growth factors e g Her2 EGFR G proteins kinases and their targets e g RAS ABL Cytoplasmic signal transduction proteins Nuclear proteins Growth Factor Genes Transcription factors e g MYC EGFR Receptor Tyrosine Kinase ON RAS GTP Point Mutations in Ras turn it from a normal protein into an oncoprotein Oncogenic mutations Lock Ras into active GTP bound state Codon 12 Normally glycine almost anything else and it is stuck ON Reminder Ras was the gene that transformed the 3T3 Cells EGFR Receptor Tyrosine Kinase ON RAS GTP Raf OFF OFF RAS GDP Raf ON MEK OFF NUCLEUS P MEK ON MAP OFF P MAP ON P MAP ON TF OFF P TF ON Transcription of Genes that push Go S Signal Transduction and Growth Regulation Specific Receptors for Growth factors e g Her2 EGFR G proteins kinases and their targets e g RAS ABL Cytoplasmic signal transduction proteins Nuclear proteins Growth Factor Genes Transcription factors e g MYC cMYC drives cells from G1 to S so pushes cells through the cell cycle Burkitts Lymphoma There are many chromosomal abnormalities in the cancer cells How do you figure out which changes promote the disease Burkitt s Lymphoma A chromosome translocation cMYC is expressed inappropriately in B cells MYC drives cells from G1 to S Another way that oncogenic transcription factors can be up regulated Gene Amplification Chromosome from a Cancer Cell Blue staining of all chromosomes Red staining of chromosome 4 Green staining of the MYC gene Two Classes of Mutations that Increase Myc Translocation A fusion gene is created Myc coding sequence is put behind a strong constitutive promoter Amplification Cell harbors many copies of Myc Normal 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 repairs Don t Die Resist
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