Characteristics of stemearly progenitor cells

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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 3551822, 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 / injection 5x105 105 5x104 2x104 104 5x103
103 200 Unsorted (T1) 4/4 4/4 6/6 - 2/6 - 0/6 -
B38CD44CD24 - - - 0/5 0/5 0/5 0/5 - B38CD44
CD24- - - - 5/5 5/5 5/5 5/5 - ESACD44CD24-
- - - - - - 8/8 4/4 Unsorted (T2) 4/4 4/4 4/4 -
1/6 - 0/6 - B38CD44CD24 - - - 0/5 0/5 0/5 0/
5 - B38CD44CD24- - - - 5/5 5/5 5/5 5/5 -
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
CD44B38.1CD24
CD44B38.1CD24-
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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
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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
Tumorigenic Stem cell
Normal Stem cell
Tumorigenic Stem cell
Normal 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 1151503, 2005
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Implications of TSC Profiling/Diagnosis/Preventi
on

• 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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Cancer Stem Cells Implications For Metastasis
TDC only
CSCCancer Stem Cell TDCTerminally
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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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 Cellsin Human Cancer

• Breast Cancer
• Leukemia
• Multiple Myeloma
• Brain Cancer
• Lung Cancer
• Prostate Cancer
• Melanoma