Boc Lecture 4 the hallmarks of cancer km
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Transcript of Boc Lecture 4 the hallmarks of cancer km
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The Hallmarks of Cancer
Karobi Karobi Moitra (Ph.D)Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.
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Acquired Capabilities of Cancer
Cells
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1. Self-Sufficiency in growth signals
Normal cells require mitogenic (cell div) growth signals to move from a quiescent (resting) state into an active proliferation state. Cancer cells can generate their owngrowth signals.
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Autocrine signaling : Secretion of a substance or growthfactor that acts on a cell that produced it (i.e. IL2 signaling in monocytes )
Paracrine signaling: secretion of a substance or growth that acts on a nearby cell (i.e. neurotransmitter signaling)
Autocrine
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How do cancer cells generate their own growth signals ?
Autocrine signaling: a cancer cell can manufacture it’sown autocrine growth factors.
Active transforming growth factor beta blocks proliferation in normal cell, while downregulation of TGF-betain a cancer cell can induce proliferation by upregulation of cyclins and autocrine growth factors(hypothetical example Grimm and Rosen 2006).
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Cancer cells can also switch the types of Extracellular matrix receptors (ECM) they express favoring the
ones that transmit growth signals
ECM : extracellular part of tissue that provides structuralsupport to the cells and performs various other functions
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Activation of the Ras-raf pathway through integrins(integrins can mediate signals from the ECM to thecell)
Growth signals
MEK - mitogen activatedprotein kinase kinase
ERK -Extracellular signal regulated kinase
GRB2- growth factor receptor bound protein
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2. Insensitivity to Antigrowth signals
If cancer cells are to survive they must block anti-growthsignals. Antigrowth signals can block proliferation by a. Forcing a cell out of the cell cycle into G0.b. Inducing a cell to enter post-mitotic differentiated state.
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Transcription factors: switch genes on
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E2F is a transcription factor which can switch on genesthat can cause cell division. Rb can inactivate E2F.
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Loss of pRB tumor suppressor
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3. Evading Apoptosis (cell suicide)
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Mutations in p53 can derail apoptosis (preventcell suicide)
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What happens when there is a ‘mistake’ or mutation in the code?
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Mutations in p53 can derail apoptosis
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Insulin like Growth Factors (IGFs) trigger pro-survival(anti-apoptotic) pathways
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4. Limitless Replicative Potential
Normal cells age by shortening of chromosomes whentheir telomeres degrade
Telomere
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Telomerase synthesizes and maintains telomeresin cancer cells
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5. Sustained Angiogenesis
Angiogenesis is the growth of new blood vessels
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VEGF - Vascular endothelial growth factor and angiogenesis
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The VEGF pathway
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6. Tissue invasion and metastasis
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Cancer cells synthesize collagenase type lV
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E- Cadherin
E-cadherin is disregulated in invasion and metastasis
Loss of anchorage dependence
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ParallelPathways
OfTumorigenesis
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Reference: The Hallmarks of Cancer , Hanahan D and Weinberg R (2000) Cell, 100: 57-70.