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Stem Cells & Cancer

Stem Cells & Cancer. Norman Iscove M.D. Multiple kinds of blood cell. Bone marrow is a factory for blood cells. Multiple assembly lines in marrow. The neutrophil assembly line. The neutrophil assembly line. The neutrophil assembly line. The neutrophil assembly line.

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Stem Cells & Cancer

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  1. Stem Cells & Cancer Norman Iscove M.D.

  2. Multiple kinds of blood cell

  3. Bone marrow is a factory for blood cells

  4. Multiple assembly lines in marrow

  5. The neutrophil assembly line

  6. The neutrophil assembly line

  7. The neutrophil assembly line

  8. The neutrophil assembly line

  9. The neutrophil assembly line

  10. The neutrophil assembly line

  11. The neutrophil assembly line

  12. The neutrophil assembly line

  13. The neutrophil assembly line

  14. The neutrophil assembly line

  15. The neutrophil assembly line

  16. The neutrophil assembly line

  17. The neutrophil assembly line

  18. Multiple assembly lines

  19. Where do precursor cells come from?

  20. Stem cells self-renew Stem cell Committed precursors Differentiating precursors

  21. Stem cells self-renew Stem cell

  22. Stem cells self-renew Stem cell

  23. Stem cells self-renew Stem cell Committed precursor

  24. Stem cells self-renew Stem cell Committed precursor Differentiating precursor

  25. Stem cells self-renew Stem cell Committed precursors Differentiating precursors

  26. Stem cells self-renew Stem cell

  27. Stem cells self-renew Stem cell

  28. Stem cells self-renew Stem cell Committed precursor

  29. Stem cells self-renew Stem cell Committed precursor Differentiating precursor

  30. Stem cells self-renew Stem cell Committed precursors Differentiating precursors

  31. Stem cells self-renew Stem cell

  32. Stem cells self-renew Stem cell

  33. Stem cells self-renew Stem cell Committed precursor

  34. Stem cells self-renew Stem cell Committed precursor Differentiating precursor

  35. Stem cells are the key transplantable element in marrow Imaging of stem cell transplantation Stem cells can be purified 1 stem cell time Other precursors Stem cells 1 in 4,000 1 in 20,000 Cao et al., PNAS 101:221-226, 2004

  36. Normal blood cell formation • blood cells produced by maturation of precursor cells • precursor cells have finite proliferative capacity and lifespan • stem cells are multipotent • stem cells constantly replenish the precursor cells • stem cells make new stem cells - "self-renewal" • self-renewal is unique to stem cells and is essential for continued existence of blood cell production

  37. Differing biology of precursor cells and stem cells proliferative

  38. Differing biology of precursor cells and stem cells killed by anti-cancer drugs

  39. Differing biology of precursor cells and stem cells quiescent

  40. Differing biology of precursor cells and stem cells relatively resistant to anti-cancer drugs

  41. Differing biology of precursor cells and stem cells • >95% of marrow cells can be depleted by treatment with certain anti-cancer drugs • stem cells may entirely resist short-term chemotherapy Despite massive reduction in marrow bulk by chemotherapeutic agents, marrow will rapidly regenerate from surviving stem cells

  42. Stem cells in normal mammary glands 1 in 1500 mammary ductal cells can regenerate an entire gland 1 purified cell is sufficient Stingl et al, Nature 439:993, 2006

  43. Leukemia Leukemia Normal

  44. Leukemia initiating cells are rare and distinct leukemia cells human leukemia cells 1 in 50,000 cells FACS time Stem cells 1 % Remaining cells 99 % florid leukemia Dick et al, 1997

  45. Breast tumour initiating cells are rare and distinct Human breast carcinoma cells breast tumour cells FACS time Stem cells 1 % Remaining cells 99 % Breast carcinoma Clarke et al, 2003

  46. Brain tumour initiating cells are rare and distinct Human brain tumour cells brain tumour cells FACS time Stem cells 1 % Remaining cells 99 % Brain tumour Dirks et al, 2004

  47. Colon tumour initiating cells are rare and distinct Human colon carcinoma cells colon carcinoma cells FACS time Stem cells 1 % Remaining cells 99 % Colon carcinoma Dick et al, 2006

  48. Cancer stem cells • cancers, like normal tissues, constitute differentiating systems • bulk cells produced by cancer systems have abnormal properties clinical disease • bulk cells have finite lifespans • cancer stem cells are rare and physically distinct from the bulk of tumour cells • cancer stem cells are essential to the continued existence of cancer systems • the biology of cancer stem cells differs from the rest of the cells in a tumour

  49. Differing biology of precursor cells and stem cells relatively resistant to anti-cancer drugs killed by anti-cancer drugs

  50. Tumour stem cell Stem cell concepts will change treatment strategies treatment remission relapse conventional bulk reduction eventual cure stem cell targetted combined anti-stem and bulk reduction early cure Jean Wang

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