Mary Helen Barcellos-Hoff, Ph.DMary Helen Barcellos-Hoff, Ph.DLife Sciences DivisionLife Sciences Division

Lawrence Berkeley National Lawrence Berkeley National LabLab

Breast Stem Cells Breast Stem Cells and Cancer: and Cancer:

Concepts, not Concepts, not conclusionsconclusions

ER+

+

Stem Pluripotent Lineage Restricted Transit Terminal

Tissue Specific Stem CellsTissue Specific Stem CellsStem cells are able to:Stem cells are able to:

a)a) Self renewSelf renew

b)b) Generate all the differentiated cell represented Generate all the differentiated cell represented in the tissuein the tissue

Mouse Mammary Development

Mouse Mammary Development

LNLN

Endbuds

Ductal outgrowthMaturegland

Alveolar differentiationInvolution

LN

Mouse Mammary Mouse Mammary GlandGland

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.

Mammary epithelial cells

Tissue fragments

Functional Test for Stem Functional Test for Stem CellsCells

Hypothesis:Hypothesis:

Cancer stem cells are a result of Cancer stem cells are a result of carcinogen-induced alterations carcinogen-induced alterations in stem cells in stem cells per seper se..OROR

Cancer cells use the same Cancer cells use the same signals that regulate stem cell signals that regulate stem cell function.function.

Signals for mammary stem cells are Signals for mammary stem cells are also critical determinants of cancer also critical determinants of cancer

growth.growth.

Migration SignalsDIFFERENTIATE (?)

DO NOT PROLIFERATE(MIP-1a, TGF-)

PROLIFERATE(Wnt)

SELF

REN

EW

(Not

ch)STA

Y HERE,

ADHERE(F

IBRONECTIN

VCAM-1)

SURVIVE

(SCF)

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

Signaling Similarities between Stem Cells Signaling Similarities between Stem Cells and Tumorsand Tumors

Injection into mammary Injection into mammary fat pads of immune-fat pads of immune-compromised micecompromised mice

CD44+CD44+

CD44+, CD44+, CD24-/low, CD24-/low, ESA+ESA+

CD44+, CD44+, CD24-/lowCD24-/low

Breast tumor specimen (some expanded in mice)Breast tumor specimen (some expanded in mice)Disaggregation into cellsDisaggregation into cells

Flow cytometry Flow cytometry sort sort based on cell based on cell surface markerssurface markers

Analysis of tumor formation frequencyAnalysis of tumor formation frequencyAl-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. & Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. &

Clarke, M.F. Clarke, M.F. PNASPNAS 100100, 3983-3988 (2003), 3983-3988 (2003)

Prospective identification of Prospective identification of tumorigenic breast cancer cellstumorigenic breast cancer cells

Tumorigenic Potential of Breast Tumorigenic Potential of Breast Cancer Cells Selected for Stem Cell Cancer Cells Selected for Stem Cell

MarkersMarkers

Al-Hajj, M.S. Wicha, A. Benito-Hernandez, S.J. Morrison, M.F. Clarke, Al-Hajj, M.S. Wicha, A. Benito-Hernandez, S.J. Morrison, M.F. Clarke, PNASPNAS 100, 3983-3988 (2003) 100, 3983-3988 (2003)

0

20

40

60

80

100

>50,00010,0001000<500

# injected

% T

umor

Tak

e

Breast Stem Cells and CancerBreast Stem Cells and Cancer

• The biology of tissue-specific stem cells The biology of tissue-specific stem cells may be an important determinant of may be an important determinant of cancer susceptibility,cancer susceptibility,

• And/or certain aspects of stem cell And/or certain aspects of stem cell biology may be recapitulated in cancer biology may be recapitulated in cancer development.development.

• Exploiting stem cell-like regulatory Exploiting stem cell-like regulatory markers are potential means for markers are potential means for controlling cancer. controlling cancer.

Therapeutic Consequences of Therapeutic Consequences of Cancer Stem Cell HypothesisCancer 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).

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.

R. Pardal, M. F. Clarke, S. J. Morrison, R. Pardal, M. F. Clarke, S. J. Morrison, Nat Rev CancerNat Rev Cancer 3, 895-902 (2003) 3, 895-902 (2003)

Targeting stem cell pathways for Targeting stem cell pathways for therapytherapy

Cancer Stem Cell

Therapies that kill non-tumorigenic cells

Therapies that kill cancer stem cells

Metastasis

Tumor

Dormancy

Bay Area Breast Cancer Bay Area Breast Cancer and the Environment and the Environment

CenterCenter