genetics of cancer lecture 32 “cancer...
TRANSCRIPT
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Genetics of Cancer
Lecture 32
“Cancer II”
Prof. Bevin Engelward, MIT Biological Engineering Department
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Why Cancer Matters
New Cancer Cases in 1997 Cancer Deaths in 1997
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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?
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Normal Colon Tissue
Divits = "Crypts"
TOP: Inner surfaceof the colon
Cell Lining = Epithelial Cells
Most colon cancers appear to be of epithelial origin
100 um
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Normal Colon Tissue
Definitions:
CryptSomatic Stem Cell
Conveyor Belt1 Crypt = 1 Clone
Image from D. Schauer
Image by Christine Andersen
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Cancer
Dysplasic Crypt
Mild Dysplasia
Normal Colonic Epithelium
Progression from Normal to Cancer
What are the genetic steps? What does a cancer cell need to be able to do?
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Normal Cell → Metastatic Tumor: Many Changes are Necessary
Concept & parts of figure from Hanahan and Weinberg
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Normal Cell → Metastatic Tumor: Many Changes are Necessary
CANCER
Concept & parts of figure from Hanahan and Weinberg
Definitions:
ApoptosisImmortal
AngiogenesisMetastasis
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Where do cancer cells come from?
"Survival of the Fittest"
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Most fully blown cancers require many mutations
Colon Cancer…
Photographs: C.E.Fuller & E.D.Williams; Br.J.Cancer (1990)
Normal Colonic Epithelium
Mutation 1
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Most fully blown cancers require many mutations
Colon Cancer…
Normal Colonic Epithelium
Mutation 1 Mutation 2 AdditionalMutations
20 – 40 Years
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Most of the mutations occur in somatic cells – but germ line mutations can also contribute to cancer
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Clonal Expansion of Mutant Cells
Single Mutant Cell Segment Inherited Mutation
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How do you figure outWhich mutations promote cancer?
Mutation 1
Normal Colonic Epithelium
Mutation 2 AdditionalMutations
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What types of genetic changes turn a normal cell into a cancer cell?
Oncogenesgene that makes a cell cancerous
dominant gain-of-function mutations
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 advantage
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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
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Mutations in Cancer Genes Transform Normal Cells into Cancer Cells
Oncogenesgene that makes a cell cancerous
dominant gain-of-function mutations
“Go!” Growth Signal Independent
Ras Ras(G12D)
(H-Ras, N-Ras, and K-Ras)
Normal Ras is involved in sensing growth signalsMutant Ras gives the "go signal" without growth factors
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Signal Transduction and Growth Regulation
Cytoplasmic signal
transduction proteins
Nuclear proteins
Growth Factor Genes
Definitions:
LigandReceptor
Signal Transduction
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Signal Transduction and Growth Regulation
Cytoplasmic signal
transduction proteins
Nuclear proteins
Growth Factor Genes
Specific Receptors for Growth factors e.g., Her2, EGFR
G-proteins, kinases, and their targets
e.g., RAS, ABL
Transcription factors, e.g.,
MYC
Receptor Tyrosine Kinases
• Many variants & many ligands(NGF, PDGF, FGF, EGF, insulin)
• Trigger different effects on different cells (proliferation & prosurvival)
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EGFR: Receptor Tyrosine Kinase
Outside the cellDefinitions:
Extracellular DomainTransmembrane Domain
Cytoplasmic DomainKinase Active Site
lipid membrane
Inside the cellEGFR = Epidermal growth factor receptor
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EGFR: Receptor Tyrosine Kinase
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EGFR: Receptor Tyrosine Kinase
P PDefinitions:
Receptor DimerizationKinase Activation
Autophosphorylation
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EGFR: Receptor Tyrosine Kinase
RASGDP
P P
P P
P P
GRB2SOSGRB2SOS
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EGFR: Receptor Tyrosine Kinase
RASGTP GRB2SOS
GRB2SOS
P P
P P
P P
Signaling by Phosphorylating
Targets"Go!"
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Cancer Cells Often Exploit Receptor Tyrosine Kinases
EGFR GENETIC DELETION TRUNCATES
THE PROTEINErbB
P P
P P
P P
Constitutively ActiveWithout Need for Growth Factors
"Go!"
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Cancer Cells Often Exploit Receptor Tyrosine Kinases
Her2 Neu
Constitutively ActiveWithout Need for Growth Factors
POINT MUTATIONMUTATES
THE PROTEIN
P P
P P
"Go!"
P P
Glutamine
Valine
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Constitutive Activation converts RTKs to Dominant Acting Oncogenes
Zwick et al, (2002) TIMM 8:17-23
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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
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Mutations in Cancer Genes Transform Normal Cells into Cancer Cells
Oncogenesgene that makes a cell cancerous
dominant gain-of-function mutations
“Go!” Growth Signal Independent
Ras Ras(G12D)
(H-Ras, N-Ras, and K-Ras)
Normal Ras is involved in sensing growth signalsMutant Ras gives the "go signal" without growth factors
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Signal Transduction and Growth Regulation
Cytoplasmic signal
transduction proteins
Nuclear proteins
Growth Factor Genes
Specific Receptors for Growth factors e.g., Her2, EGFR
G-proteins, kinases, and their targets
e.g., RAS, ABL
Transcription factors, e.g.,
MYC
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EGFR: Receptor Tyrosine Kinase
RASGTPON
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
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EGFR: Receptor Tyrosine Kinase
RASGTP
Raf OFFON
MEKOFF
MEKON
P
MAPOFF
MAPON
PTF
OFFTFON
P
MAPON
P
NUCLEUS
RASGDPOFF
Raf ON
Transcription of Genes that push Go → S
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Signal Transduction and Growth Regulation
Cytoplasmic signal
transduction proteins
Nuclear proteins
Growth Factor Genes
Specific Receptors for Growth factors e.g., Her2, EGFR
G-proteins, kinases, and their targets
e.g., RAS, ABL,
Transcription factors, e.g.,
MYC
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cMYC drives cells from G1 toS – so pushes cells through the cell cycle
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Burkitts Lymphoma
There are many chromosomal abnormalities in the cancer cells
How do you figure out which changes promote the disease?
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Burkitt’s Lymphoma: A chromosome translocation cMYC is expressed inappropriately in B-cells
MYC drives cells from G1 to S
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Another way that oncogenic transcription factors can be up-regulated: Gene Amplification
Chromosome from a Cancer CellBlue – staining of all chromosomes
Red – staining of chromosome 4
Green – staining of the MYC gene
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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
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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 Apoptosis
“Keep Going”Be Immortal
“Feed Me”Recruit & Sustain Blood Flow
“Take Over”Escape/Invade = Metastasize
"Mutate!" Concept & parts of figure from Hanahan and Weinberg
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Where do cancer cells come from?
"Survival of the Fittest" is Happening in You Right Now
You can reduce your odds of cancer by "closing the competition":
REDUCE THE NUMBER OF CELL DIVISIONS YOU EXPERIENCE
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The Genetic Basis of Cancer and Theodor Boveri 1862 - 1915
• Established that chromosomes carry the hereditary information
• Suggested that mis-segregation of human chromosomes could be responsible for a normal cell becoming a tumor cell
Gains/Losses of Chromosomes are an important class of mutations
• Suggested that some chromosomes promote cell growth and others inhibit cell growth
Marcella O’Grady Boveri (1863-1950) also contributed