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Lawrence Berkeley National Lab

Lawrence Berkeley National Lab. Mary Helen Barcellos-Hoff, Ph.D Life Sciences Division. Breast Stem Cells and Cancer: Concepts, not conclusions. Tissue Specific Stem Cells. Stem cells are able to: Self renew Generate all the differentiated cell represented in the tissue.

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Lawrence Berkeley National Lab

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  1. Lawrence Berkeley National Lab Mary Helen Barcellos-Hoff, Ph.D Life Sciences Division

  2. Breast Stem Cells and Cancer: Concepts, not conclusions

  3. Tissue Specific Stem Cells Stem cells are able to: Self renew Generate all the differentiated cell represented in the tissue Stem Pluripotent Lineage Restricted Transit Terminal

  4. Mouse Mammary Development Mouse Mammary Development

  5. Mouse Mammary Gland

  6. Functional Test for Stem Cells DeOme, K. B., L. J. J. Faulkin, H. A. Bern and P. B. Blair (1959). "Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice." Cancer Res 19: 515- 520.

  7. Hypothesis: Cancer stem cells are a result of carcinogen-induced alterations in stem cells per se. OR Cancer cells use the same signals that regulate stem cell function.

  8. Signals for mammary stem cells are also critical determinants of cancer growth. SURVIVE (SCF) SELF RENEW (Notch) DIFFERENTIATE (?) Migration Signals PROLIFERATE (Wnt) STAY HERE,ADHERE (FIBRONECTIN VCAM-1) DO NOT PROLIFERATE (MIP-1a, TGF-b)

  9. Signaling Similarities between Stem Cells and Tumors Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 (2001).

  10. Prospective identification of tumorigenic breast cancer cells Breast tumor specimen (some expanded in mice) CD44+ Injection into mammary fat pads of immune-compromised mice CD44+, CD24-/low CD44+, CD24-/low, ESA+ Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. & Clarke, M.F. PNAS100, 3983-3988 (2003) Disaggregation into cells Flow cytometry sort based on cell surface markers Analysis of tumor formation frequency

  11. # injected % Tumor Take Tumorigenic Potential of Breast Cancer Cells Selected for Stem Cell Markers Al-Hajj, M.S. Wicha, A. Benito-Hernandez, S.J. Morrison, M.F. Clarke, PNAS 100, 3983-3988 (2003)

  12. Breast Stem Cells and Cancer • The biology of tissue-specific stem cells may be an important determinant of cancer susceptibility, • And/or certain aspects of stem cell biology may be recapitulated in cancer development. • Exploiting stem cell-like regulatory markers are potential means for controlling cancer.

  13. Although heterogeneous, all cells of a tumor are targets for therapy. Corollary: profiles of the entire tumor reveal therapeutic targets. ONLY cancer stem cells are targets for therapy. Corollary: analysis of the entire tumor will not reveal therapeutic targets. Therapeutic Consequences of Cancer Stem Cell Hypothesis Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature414, 105-111 (2001).

  14. Targeting stem cell pathways for therapy Tumor Cancer Stem Cell Therapies that kill non-tumorigenic cells Dormancy Therapies that kill cancer stem cells Metastasis R. Pardal, M. F. Clarke, S. J. Morrison, Nat Rev Cancer 3, 895-902 (2003)

  15. Bay Area Breast Cancer and the Environment Center

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