Boc Lecture 4 the hallmarks of cancer km

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Boc Lecture 4 the hallmarks of cancer km

  1. 1. The Hallmarks of Cancer Karobi Moitra (Ph.D) NCI Frederick , NIH Cancer Inflammation Program Human Genetics Section Frederick MD.
  2. 2. Acquired Capabilities of Cancer Cells
  3. 3. 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.
  4. 4. 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
  5. 5. 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).
  6. 6. 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
  7. 7. 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)
  8. 8. 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.
  9. 9. Transcription factors: switch genes on
  10. 10. E2F is a transcription factor which can switch on genes that can cause cell division. Rb can inactivate E2F.
  11. 11. Loss of pRB tumor suppressor
  12. 12. 3. Evading Apoptosis (cell suicide)
  13. 13. Mutations in p53 can derail apoptosis (prevent cell suicide)
  14. 14. What happens when there is a ‘mistake’ or mutation in the code?
  15. 15. Mutations in p53 can derail apoptosis
  16. 16. Insulin like Growth Factors (IGFs) trigger pro-survival (anti-apoptotic) pathways
  17. 17. 4. Limitless Replicative Potential Telomere Normal cells age by shortening of chromosomes when their telomeres degrade
  18. 18. Telomerase synthesizes and maintains telomeres in cancer cells
  19. 19. 5. Sustained Angiogenesis Angiogenesis is the growth of new blood vessels
  20. 20. VEGF - Vascular endothelial growth factor and angiogenesis
  21. 21. The VEGF pathway
  22. 22. 6. Tissue invasion and metastasis
  23. 23. Cancer cells synthesize collagenase type lV
  24. 24. E-cadherin is disregulated in invasion and metastasis Loss of anchorage dependence E- Cadherin
  25. 25. Parallel Pathways Of Tumorigenesis
  26. 26. Reference: The Hallmarks of Cancer , Hanahan D and Weinberg R (2000) Cell, 100: 57-70.

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