Boc Lecture 4 the hallmarks of cancer  km
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Boc Lecture 4 the hallmarks of cancer km



Cancer Biology

Cancer Biology



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Boc Lecture 4 the hallmarks of cancer  km Boc Lecture 4 the hallmarks of cancer km Presentation Transcript

  • The Hallmarks of Cancer Karobi Moitra (Ph.D) NCI Frederick , NIH Cancer Inflammation Program Human Genetics Section 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 own growth signals.
  • Autocrine signaling : Secretion of a substance or growth factor 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’s own autocrine growth factors. Active transforming growth factor beta blocks proliferation in normal cell, while downregulation of TGF-beta in 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 structural support to the cells and performs various other functions
  • GRB2- growth factor receptor bound protein Growth signals MEK - mitogen activated protein kinase kinase ERK - Extracellular signal regulated kinase Activation of the Ras-raf pathway through integrins (integrins can mediate signals from the ECM to the cell)
  • 2. Insensitivity to Antigrowth signals If cancer cells are to survive they must block anti-growth signals. 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 genes that can cause cell division. Rb can inactivate E2F.
  • Loss of pRB tumor suppressor
  • 3. Evading Apoptosis (cell suicide)
  • Mutations in p53 can derail apoptosis (prevent cell 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 Telomere Normal cells age by shortening of chromosomes when their telomeres degrade
  • Telomerase synthesizes and maintains telomeres in 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 is disregulated in invasion and metastasis Loss of anchorage dependence E- Cadherin
  • Parallel Pathways Of Tumorigenesis
  • Reference: The Hallmarks of Cancer , Hanahan D and Weinberg R (2000) Cell, 100: 57-70.