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01.3 klampfer pc

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01.3 klampfer pc

  1. 1. Tumor stroma: an active player in cancer<br />
  2. 2. Soluble factors produced by stromal cells alter signaling pathways in tumor cells<br />HCT116-<br />NFkB-LUC<br />HCT116-<br />Hes1/5-LUC<br />Macrophages<br />0.4µm<br />HCT116-<br />TOP-LUC<br />HCT116-<br />STAT1-LUC<br />HCT116-<br />STAT3-LUC<br />HCT116-<br />AP1-LUC<br />Tumor cells <br />
  3. 3. Colon cancer cells stimulate macrophages to release IL1b;<br />the role of pSTAT1<br />( siRNA)<br />STAT1<br />NSP<br />pSTAT1<br />STAT3<br />-actin<br />(IL-1b)<br /> 0 8h 24h 48h<br />pGSK3<br />c-myc<br />tGSK3b<br />
  4. 4. Vitamin D3 inhibits the protumorigenic activity of macrophages<br />THP1/IL1 -/-<br />THP1/D3<br />CTRL<br />THP1<br />pGSK3<br />c-myc<br />tGSK3b<br />
  5. 5. Vitamin D3: an inhibitor of IL1b release from macrophages<br />24h<br />48h<br />1, 25(OH)2D3 (nM)<br />50<br />50<br />0<br />0<br />25<br />25<br />pSTAT1<br />STAT1<br />-actin<br />CTRL <br />1, 25(OH)2D3 (nM)<br />
  6. 6. IL1b mediates the crosstalk between tumor cells <br />and macrophages<br />??<br />Wnt targets<br />b-catenin<br />TCF<br />STAT1<br />pSTAT1<br />GSK3b<br />NFkB<br />AKT<br />PDK1<br />IL-1b<br />Proliferation<br />
  7. 7. Macrophages interfere with TRAIL-induced apoptosis <br />Hke3<br />HCT116<br />Trail-Mo <br />Trail –IL1<br />Trail -Mo<br />Trail-Mo <br />CTRL<br />Trail <br />CTRL<br />Trail<br />Cl caspase 8 (41,43 kDa)<br />Cl caspase 8 (18 kDa)<br />Cl caspase 9<br />bactin<br />
  8. 8. IL1 is sufficient/required to inhibit TRAIL-induced apoptosis <br />
  9. 9. Vitamin D3 restores TRAIL induced apoptosis in VDR <br />dependent manner<br />A<br />C<br />Trail-THP1-VDR-/--D3<br />Trail-THP1-D3-IL1<br />Trail-THP1-VDR-/-<br />Trail-THP1-D3<br />Trail-THP1<br />CTRL<br />Trail<br />Cl caspase 8 (41,43 kDa)<br />Cl caspase 8 (18 kDa)<br />B<br />Cleaved caspase 9<br />PARP (FL)<br />PARP (Cleaved)<br />Total -catenin (LE)<br />Total -catenin (HE)<br />actin<br />
  10. 10. CTRL<br />TRAIL<br />Trail/THP1<br />Trail/IL1<br />neo<br />dnIkB<br />dnAKT<br />dnTCF4<br />Macrophage/IL1 inhibit TRAIL-induced apoptosis through NFkB/Wnt signaling<br />
  11. 11. b catenin, an important target of TRAIL signaling<br />Neo<br />dnIB<br />dnAKT<br />dnTCF4<br />Trail-THP1<br />Trail–THP1<br />Trail-THP1<br />Trail-THP1<br />Trail–IL1<br />Trail-IL1<br />Trail-IL1<br />Trail-IL1<br />CTRL<br />CTRL<br />CTRL<br />CTRL<br />Trail<br />Trail<br />Trail<br />Trail<br />Cleaved caspase 8<br />Cleaved caspase-9<br />-catenin<br />PARP (FL)<br />PARP (Cleaved)<br />bactin<br />
  12. 12. Neo<br />dnAKT<br />dnIkB<br />dnTCF4<br />CTRL<br />CTRL<br />THP1<br />THP1<br />CTRL<br />CTRL<br />TNF<br />THP1<br />THP1<br />TNF<br />TNF<br />IL1<br />IL1<br />TNF<br />IL1<br />IL1<br />Snail<br />c-Jun<br />bactin<br />Macrophages stabilize Snail in tumor cells <br />THP1-STAT1 siRNA<br />THP1-IL1 siRNA<br />THP1-D3<br />CTRL<br />THP1<br />THP1<br />CTRL<br />Snail<br />Snail<br />bactin<br />bactin<br />
  13. 13. IL1b mediates the crosstalk between tumor cells <br />and macrophages<br />??<br />Snail<br />Wnt targets<br />b-catenin<br />TCF<br />STAT1<br />pSTAT1<br />GSK3b<br />NFkB<br />AKT<br />IL-1b<br />Proliferation<br />Survival<br />
  14. 14. Versican<br />Normal (71) Breast, colon, esophageal, hepatocellular, lung (235) Thyroid (35)<br />Yu et al, PloS Genet 2008<br />Rectal cancer Colon cancer <br />
  15. 15. VCAN stimulates macrophages to release IL1b<br />A<br />siRNA<br />NSP<br />VERSICAN<br />B<br />Top-Luc<br />
  16. 16. Snail regulates the expression of VCAN <br /> NSP Snail VER (siRNA)<br />VCAN<br />bcatenin<br />(siRNA)<br />
  17. 17. Co-expression of VCAN and Snail in colon cancer patients<br />Lin, Clinical Cancer research, 2007 (55 colon cancer patients, Affymetrics) <br />
  18. 18. IL1b: a messenger that perpetuates the crosstalk between colon cancer cells <br />and macrophages <br />VCAN <br />EMT<br />VCAN<br />Vit D3<br />Growth<br />c-myc<br />??<br />Snail<br />Wnt targets<br />b-catenin<br />TCF<br />pSTAT1<br />GSK3b<br />TRAIL<br />NFkB<br />AKT<br />PDK1<br />IL-1b<br />
  19. 19. Thank you: <br />Pawan Kaler, PhD<br />Malika Godasi, MD<br />Vincent Galea<br />Leonard Augenlicht, PhD<br />

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