Mary Helen BarcellosHoff, Ph.D

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Lawrence Berkeley National Lab

• Mary Helen Barcellos-Hoff, Ph.D
• Life Sciences Division

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Breast Stem Cells and Cancer Concepts, not
conclusions
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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
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Mouse Mammary Development
Mouse Mammary Development
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Mouse Mammary Gland
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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.
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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.

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Signals for mammary stem cells are also
critical determinants of cancer growth.
DIFFERENTIATE (?)
Migration Signals
PROLIFERATE (Wnt)
STAY HERE, ADHERE (FIBRONECTIN VCAM-1)
DO NOT PROLIFERATE (MIP-1a, TGF-b)
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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).
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Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A.,
Morrison, S.J. Clarke, M.F. PNAS 100,
3983-3988 (2003)
Prospective identification of tumorigenic breast
cancer cells
Disaggregation into cells
Flow cytometry sort based on cell surface markers
Analysis of tumor formation frequency
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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)
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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.

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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. Nature 414, 105-111 (2001).
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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)
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• Bay Area Breast Cancer and the Environment Center