Cancer Stem Cell Xie Li & Li Rutian

Beginning of the Cancer Stem Cell Concept  1937: Jacob Furth and Morton Kahn: a single leukaemic cell was able to transmit the systemic disease when transplanted into a mouse.  1960s: Robert Bruce and Hugo Van der Gaag: only a small subset of primary cancer tissue was able to proliferate in vivo.  Not every cell is able to proliferate to form a colony in vitro or to give rise to a tumor when transplanted in vivo.

Definition  A CSC is a cancer cell that has the ability to self-renew; dividing to give rise to another malignant stem cell and a cell that gives rise to the phenotypically diverse tumour cell population. Enriched for tumorigenic ability. Enable serial propagation in vivo. Regenerate phenotype diversity (differentiation)

Metastasis CXCR4

CSC in solid tumors  BREAST CANCER:  CD44 + CD24 -/low ESA + Cells

Identification of CSCs  Prospective purification using cell surface markers followed by tumorigenic assays.  FACS ( Fluorescence-Activated Cell Sorting ) enrichment of side populations.

Ex vivo and in vivo assays for tumor cells

Markers of Normal and Malignant Adult Tissue Stem Cells OrganNormal TissueCancer Hematopoietic CD34 + CD38 - Thy1 + c-kit + IL-3R  - CD34 + CD38 - Thy1 - c-kit - IL-3R  + Breast Lin - Sca1 low CD24 med CD49f high OR Lin - CD29 hi CD24 + CD44 + CD24 -/low Lineage - Brain CD133 + Lung Sca-1 + CD34 + Skin CD20 + Prostate CD44 + /  2  1 hi /CD133 +

SPs C6 Glioma MCF7 breast Cancer B104 neuroblastoma Hela Side Population hoechst33342

Orignation of CSCs  Adult or Embryonic Stem Cells that turn malignant?  Malignant Cells that display “ stem-like ” property?

Orignation of CSCs Cell–cell fusion Horizontal gene-transfer

Special Signaling Pathways

NICHE  Microenvironmental cells that nurture stem cells and enable them to maintain tissue homeostasis

NICHE  primarily inhibitory signals for both proliferation and differentiation  transient signals for stem cell division to support ongoing tissue regeneration  proliferation-inhibiting proliferation-promoting

Reciprocal interactions between CSC and Niche

Vascular niche

NICHE-----signaling  SDF o(∩_∩)o  MMP (*^__^*)

CSCs and drug-resistance  cell cycle kinetics  DNA replication and repair mechanisms  antiapoptotic proteins  transporter proteins  antigen

Strategies  Prinncipally, there are therefore two strategies to be considered for CSC cancer therapies: exposure of CSCs to sufficiently high levels  Drug delivery  Inhibition of drug pump the development of novel therapeutic agents that are targeted to CSCs.  Wnt  Pten  Her1/Her2  Differentiation induction Niche as the targets  Anti-angiogenesis

Thank You o( ∩ _ ∩ )o