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MON 2011 - Slide 16 - M.R. Alison - Joint medics and nurses spotlight session Recent developments in the field of cancer stem cells and implications in the clinical setting
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MON 2011 - Slide 16 - M.R. Alison - Joint medics and nurses spotlight session Recent developments in the field of cancer stem cells and implications in the clinical setting

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MON 2011 - Slide 16 - M.R. Alison - Joint medics and nurses spotlight session Recent developments in the field of cancer stem cells and implications in the clinical setting MON 2011 - Slide 16 - M.R. Alison - Joint medics and nurses spotlight session Recent developments in the field of cancer stem cells and implications in the clinical setting Presentation Transcript

  • Cancer stem cells: implications in the clinical setting Malcolm Alison; m.alison@qmul.ac.uk 4 th April 2011
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  • Time Initiator Promoter Initiators & promoters * Tumours Tumours No tumours DMBA TPA
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  • SVZ astrocytic ribbon
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  • Cancer Stem Cells The idea is not new
  • Hamburger and Salmon 1977, Science The plating efficiency of most 1 0 tumours is <1% PE = macroscopic colonies formed number of tumour cells plated
  • The tumour battleground
  • Markers Cancer stem cells
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  • Flow Cytometry
  • Fluorescence Activation Process (or Immunofluorescence) FITC FITC Antibodies recognize specific molecules in the surface of some cells But not others When the cells are analyzed by flow cytometry the cells expressing the marker for which the antibody is specific will manifest fluorescence. Cells who lack the marker will not manifest fluorescence Antibodies are artificially conjugated to fluorochromes Antibodies FITC FITC FITC FITC
  • Fluorescence intensity 10 1 10 4 10 3 10 2 Relative fluorescence intensity Number of Events FITC FITC FITC FITC FITC FITC FITC FITC FITC FITC
  • Y X Z Y Z X Cells are presented to the laser using principles of hydrodynamic focusing Laser optics Laser Beam Flow chamber Sheath Sample
  • 2 Parameter Histogram FITC FL PE FL Negative Population Single Positive FITC Population Single Positive PI Population Double Positive Population
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  • Xenografting
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  • The pre-eminence of ALDH as a cancer stem cell marker Responsible for the oxidation (detoxification) of cytotoxic aldehydes to carboxylic acids RCHO + NAD + + H 2 0 RCOOH + NADH + H + : a major cellular defence mechanism
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  • Vitamin A Differentiation
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  • Charafe-Jauffret et al.
  • Only 21 of 203 cases were ALDH1 +
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  • Victoria L Bautch
  • How do you increase CSC numbers
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  • p53 MDM2 =
  • The cancer stem cells bandwagon
  • Malignant melanoma
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  • In Ptc +/- mice, Math1 + /CD15 + (SSEA1) selects for TPCs
  • E-Cadherin
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  • Options for therapy •  Irradiation • Self-renewal pathways (Wnts, Notch, Hedgehog, PTEN-Akt) • Aldehyde dehydrogenase activity •  EMT •  ABC transporters •  miRNAS and HDACi • Targeting the niche
  • Cancer stem cells are very chemoresistant and radioresistant
  • Front line treatment of pancreatic cancer enriches for CSCs In vitro In vivo
  • Colorectal xenograft treated with cyclophosphamide but Dylla et al.
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  • Time Selection pressures: nutrition/oxygen/immunity/therapy Clonal co-existence Clone 1 Clone 3 Clone 2
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  • A more complex subclonal architecture in ALL Does genetic diversity affect the nature of tumour propagating cells? Yes, the potency, but not the phenotype (CD34 + CD38 -/low CD19 + )
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  • Enrich Less apoptosis Enhanced DDR
  • Targeting L1CAM with shRNA sensitises GSCs to irradiation
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  • Induce differentiation = reduced sphere formation Inhibit ALDH = increased sphere formation
  • Dissociated CK20 colonosphere cells treated in vitro for 6 days
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  • Hedgehog signalling
  • Keeping things stem-like Mdm2
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  • Hedgehog inhibitor: Cyclopamine Corn Lilly Cyclopia Poor oral bioavailability; short half-life
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  • Reduces Gli expression Reduces ALDH bri % * Blocked metastasis
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  • GFs PI3K PIP3 Akt PTEN ABCG2
  • Knock-down of PTEN increases efficiency of mammosphere formation
  • Combination therapy works
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  • Sulforaphane
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  • Related to a large reduction in ALDEFLUOR+ cells
  • also inhibits xenograft growth
  • • Cancer is a stem cell disease • Tumours have stem cells: ‘cancer stem cells’ • Therapy should target cancer stem cells
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