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Session 1.3 Klampfer
- 1. Tumor stroma: an active player in cancer
- 2. Soluble factors produced by stromal cells alter signaling pathways in tumor cells HCT116- NFkB-LUC HCT116- Hes1/5-LUC Macrophages 0.4µm HCT116- TOP-LUC HCT116- STAT1-LUC HCT116- STAT3-LUC HCT116- AP1-LUC Tumor cells
- 3. Colon cancer cells stimulate macrophages to release IL1b; the role of pSTAT1 ( siRNA) STAT1 NSP pSTAT1 STAT3 -actin (IL-1b) 0 8h 24h 48h pGSK3 c-myc tGSK3b
- 4. Vitamin D3 inhibits the protumorigenic activity of macrophages THP1/IL1 -/- THP1/D3 CTRL THP1 pGSK3 c-myc tGSK3b
- 5. Vitamin D3: an inhibitor of IL1b release from macrophages 24h 48h 1, 25(OH)2D3 (nM) 50 50 0 0 25 25 pSTAT1 STAT1 -actin CTRL 1, 25(OH)2D3 (nM)
- 6. IL1b mediates the crosstalk between tumor cells and macrophages ?? Wnt targets b-catenin TCF STAT1 pSTAT1 GSK3b NFkB AKT PDK1 IL-1b Proliferation
- 7. Macrophages interfere with TRAIL-induced apoptosis Hke3 HCT116 Trail-Mo Trail –IL1 Trail -Mo Trail-Mo CTRL Trail CTRL Trail Cl caspase 8 (41,43 kDa) Cl caspase 8 (18 kDa) Cl caspase 9 bactin
- 8. IL1 is sufficient/required to inhibit TRAIL-induced apoptosis
- 9. Vitamin D3 restores TRAIL induced apoptosis in VDR dependent manner A C Trail-THP1-VDR-/--D3 Trail-THP1-D3-IL1 Trail-THP1-VDR-/- Trail-THP1-D3 Trail-THP1 CTRL Trail Cl caspase 8 (41,43 kDa) Cl caspase 8 (18 kDa) B Cleaved caspase 9 PARP (FL) PARP (Cleaved) Total -catenin (LE) Total -catenin (HE) actin
- 10. CTRL TRAIL Trail/THP1 Trail/IL1 neo dnIkB dnAKT dnTCF4 Macrophage/IL1 inhibit TRAIL-induced apoptosis through NFkB/Wnt signaling
- 11. b catenin, an important target of TRAIL signaling Neo dnIB dnAKT dnTCF4 Trail-THP1 Trail–THP1 Trail-THP1 Trail-THP1 Trail–IL1 Trail-IL1 Trail-IL1 Trail-IL1 CTRL CTRL CTRL CTRL Trail Trail Trail Trail Cleaved caspase 8 Cleaved caspase-9 -catenin PARP (FL) PARP (Cleaved) bactin
- 12. Neo dnAKT dnIkB dnTCF4 CTRL CTRL THP1 THP1 CTRL CTRL TNF THP1 THP1 TNF TNF IL1 IL1 TNF IL1 IL1 Snail c-Jun bactin Macrophages stabilize Snail in tumor cells THP1-STAT1 siRNA THP1-IL1 siRNA THP1-D3 CTRL THP1 THP1 CTRL Snail Snail bactin bactin
- 13. IL1b mediates the crosstalk between tumor cells and macrophages ?? Snail Wnt targets b-catenin TCF STAT1 pSTAT1 GSK3b NFkB AKT IL-1b Proliferation Survival
- 14. Versican Normal (71) Breast, colon, esophageal, hepatocellular, lung (235) Thyroid (35) Yu et al, PloS Genet 2008 Rectal cancer Colon cancer
- 15. VCAN stimulates macrophages to release IL1b A siRNA NSP VERSICAN B Top-Luc
- 16. Snail regulates the expression of VCAN NSP Snail VER (siRNA) VCAN bcatenin (siRNA)
- 17. Co-expression of VCAN and Snail in colon cancer patients Lin, Clinical Cancer research, 2007 (55 colon cancer patients, Affymetrics)
- 18. IL1b: a messenger that perpetuates the crosstalk between colon cancer cells and macrophages VCAN EMT VCAN Vit D3 Growth c-myc ?? Snail Wnt targets b-catenin TCF pSTAT1 GSK3b TRAIL NFkB AKT PDK1 IL-1b
- 19. Thank you: Pawan Kaler, PhD Malika Godasi, MD Vincent Galea Leonard Augenlicht, PhD