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Breast Cancer Stem cells: NCAB 2/07/06 Implications for Prevention and Therapy. Recent decrease in UK and USA breast cancer mortality at ages 50­69 years. Peto et al. Lancet 355:1822, 2000. Breast Cancer Development. Normal. Pre-neoplastic. Neoplastic. Metastatic. Local.

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Breast Cancer Stem cells: NCAB 2/07/06 Implications for Prevention and Therapy

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Breast Cancer Stem cells: NCAB 2/07/06

Implications for Prevention and Therapy


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Recent decrease in UK and USAbreast cancer mortality at ages 50­69 years

Peto et al. Lancet 355:1822, 2000


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Breast Cancer Development

Normal

Pre-neoplastic

Neoplastic

Metastatic

Local

Systemic

GeneticsRisk Assessment

Prevention

Detection

Therapy


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CANCER STEM CELL HYPOTHESIS

  • Cancers Arise From Tissue Stem Or Progenitor Cells

  • Cancers Are “Driven” By Cells With Stem Cell Properties


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Characteristics of Stem Cells

  • Self Renewal

  • Multi-Lineage Differentiation


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Development of the Mammary Glandand Mammary Tumors

Stem Cell

Stem Cell

Proliferating Tumor

Stem Cell

Early Progenitors

Proliferating Tumor

Stem Cell

Late Progenitors

Ductal Epithelial

Alveolar

Myoepithelial


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Pathways Involved in Stem CellSelf Renewal and Cancer

  • Notch

  • Hedgehog

  • Bmi-1

  • Wnt


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Hedgehog Target Gli-2 Promotes Ductal Hyperplasia


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CANCER STEM CELL HYPOTHESIS

  • Cancers Arise From Tissue Stem Or Progenitor Cells

  • Cancers Are “Driven” By Cells With Stem Cell Properties


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Models of Tumor Heterogenity

Stochastic model

Cancer stem cell model

CSC

CSC

CSC

CSC

Cancer cells are heterogeneous, but most cells can proliferate extensively and form new tumors.

Cancer cells are heterogeneous, and only rare cancer stem cells have the ability to proliferate extensively and form new tumors.


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The Isolation of Human Cancer Stem Cells

dissociate

CSC

CSC

stain with

antibodies

Y

Y

CSC

Y

Y

Y

Flow-cytometry

Y

Y


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Tumorigenicity of Cancer Cell Subsets

Cells / injection5x1051055x1042x1041045x103103200

Unsorted (T1)4/44/46/6-2/6-0/6-

B38+CD44+CD24+ ---0/50/50/50/5-

B38+CD44+CD24- ---5/55/55/55/5-

ESA+CD44+CD24- ------8/84/4

Unsorted (T2)4/44/44/4-1/6-0/6-

B38+CD44+CD24+ ---0/50/50/50/5-

B38+CD44+CD24- ---5/55/55/55/5-

Tumor 1 was derived from a metastatic pleural effusion and Tumor 2 was

derived from a primary breast tumor.


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Tumor Formation by Human Breast Cancer Cells in Mouse Model

CD44+;B38.1+CD24+

CD44+;B38.1+CD24-


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Both Non-Tumorigenic Cancer Cells and Cancer Stem Cellshave a Malignant Appearance, but Only Stem Cells Give Rise to New Tumors

Non-tumorigenic cells

Cancer stem cells

Tumorigenic

Isolated

human

breast

cancer

cells

Injection

sites in

the mice


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Breast Cancer Stem Cells give rise to Phenotypically Diverse Tumors after Transplantation

Initial tumor

CSCs from initial tumor

Secondary tumor

T1

X

T2

Y


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Hedgehog Activation & Bmi-1 Expression in Cancer Stem Cells


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Mammary stem cell self-renewal pathways

Normal

Tumor

Shh, Ihh, Dhh

DSL

Notch signaling pathway

Hedgehog signaling pathway

Cyclopamine

GSI

Gli1

Gli2

Bmi-1

Self-renewal

Self-renewal

Deregulation

Normal Stem cell

Normal Stem cell

Tumorigenic Stem cell

Tumorigenic Stem cell

↑PTCH1

↑Ihh

↑Bmi-1

Differentiation

Differentiation

Differentiated cells

Non-tumorigenic cells

Figure 10


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BMI-1 “Stem-Cell” Signature and Patient Survival

Glinsky et al. JCI 115:1503, 2005


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Implications of TSC – Profiling/Diagnosis/Prevention

  • Cell of origin may determine molecular profile

  • Molecular profiling may miss important TSC genes

  • Significance of TSC in metastasis

  • Identification of TSC in situ may have diagnostic/prognostic value

  • Elimination of mutated stem/progenitor cells important prevention strategy


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Normal Development

Carcinogenesis

Cancer stem cell

Cancer stem cell

Cancer stem cell

ER-

Stem cell

Self-renewal

Self-renewal

ER-

Basal

ER-

ER-

Aberrant limited differentiation

Progenitor cell

Differentiation

ER-

Paracrine signals

?

Cancer stem cell

Self-renewal

?

ER-

Myoepithelial progenitor

?

ER+ progenitor cell

Luminal

B

Differentiation

ER-

ER+

Ductal luminal progenitors

Cancer stem cell

Cancer stem cell

Self-renewal

ER+

Myoepithelial cell

Luminal

A

ER+

ER+

Differentiation

ER-

ER+

Ductal epithelial cell

Alveolar cell


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No Metastases

CSC

Metastases in months to few years

Subsequently to other sites

TDC

TDC

TDC

TDC

TDC

TDC

Dormancyfollowed by Metastases after many years:

Cancer Stem Cells: Implications For Metastasis

TDC only

CSC=Cancer Stem Cell

TDC=Terminally Differentiated Cell

NO CSC

1o Tumor

CSC with FULL malignant potential

CSC with PARTIAL malignant potential

Secondary Oncogenic “Hits” and/or Changes in Microenvironment


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Drugs that killcancer stem cells

Tumor looses itsability to generatenew cells

CSC

Drugs thatkill cancer cellsbut not CSCs

CSC

Tumor degenerates,patient is cured

CSCs regenarate

tumor

CSC

The Implications of Human CancerStem Cells (CSCs) for Treatment

Tumor regresses

Tumor recurs


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Implications of TSCTherapeutics

  • Tumor regression inadequate endpoint

    • Preclinical models

    • Phase II clinical trials

  • TSC may be resistant to therapy (apoptosis)

  • Effective therapies should target TSC while sparing normal cells

  • Genes in TSC self-renewal pathway may provide new therapeutic targets


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Evidence for “ Stem Cells”in Human Cancer

  • Breast Cancer

  • Leukemia

  • Multiple Myeloma

  • Brain Cancer

  • Lung Cancer

  • Prostate Cancer

  • Melanoma


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