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Cancer Biology
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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.
Acquired Capabilities of Cancer
Cells
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.
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
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).
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
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
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.
Transcription factors: switch genes on
E2F is a transcription factor which can switch on genesthat can cause cell division. Rb can inactivate E2F.
Loss of pRB tumor suppressor
3. Evading Apoptosis (cell suicide)
Mutations in p53 can derail apoptosis (preventcell suicide)
What happens when there is a ‘mistake’ or mutation in the code?
Mutations in p53 can derail apoptosis
Insulin like Growth Factors (IGFs) trigger pro-survival(anti-apoptotic) pathways
4. Limitless Replicative Potential
Normal cells age by shortening of chromosomes whentheir telomeres degrade
Telomere
Telomerase synthesizes and maintains telomeresin cancer cells
5. Sustained Angiogenesis
Angiogenesis is the growth of new blood vessels
VEGF - Vascular endothelial growth factor and angiogenesis
The VEGF pathway
6. Tissue invasion and metastasis
Cancer cells synthesize collagenase type lV
E- Cadherin
E-cadherin is disregulated in invasion and metastasis
Loss of anchorage dependence
ParallelPathways
OfTumorigenesis
Reference: The Hallmarks of Cancer , Hanahan D and Weinberg R (2000) Cell, 100: 57-70.
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