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Hepatocellular Carcinoma

Hepatocellular Carcinoma. Overview of Hepatocellular Carcinoma Epidemiology. Cell Interactions During HCC Angiogenesis. Agents that Target the EGFR Signaling Pathway . Agents that Target Angiogenic Signaling. Cell membrane. GEF. GrB2. x. x. x. SHC. x. x. x. x. x. x.

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Hepatocellular Carcinoma

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  1. Hepatocellular Carcinoma Overview of Hepatocellular Carcinoma Epidemiology

  2. Cell Interactions During HCC Angiogenesis

  3. Agents that Target the EGFR Signaling Pathway

  4. Agents that Target Angiogenic Signaling

  5. Cell membrane GEF GrB2 x x x SHC x x x x x x Signaling Pathways for Angiogenesis: VEGFR and PDGFR in the Vasculature RTK: VEGFR-1 VEGFR-2 VEGFR-3 PDGFR x x Ras PI3K PLC Raf HBx PTEN Akt PKC MEK1/2 CediranibBevacizumabBMS-582664SorafenibSunitinibThalidomideTSU-68 mTOR BAD Site of action ERK1/2 NF-ҚB BcL-XL NF-ҚB c-MYC c-JUN p53 Angiogenesis Semela D, et al. J Hepatol 2004;41:864–80 Clauss M. Semin Thromb Hemost 2000;26:561–69

  6. Cell membrane x GEF GrB2 x x SHC x x x x x x Signaling Pathways for Cell Proliferation and Survival: PI3K RTK: FGFREGFRIGF-IRc-MET wnt Receptor Receptor Ras HBx DSH PI3K PTEN PLC Raf GBP Akt PKC MEK1/2 GSK3 mTOR BAD ERK1/2 Site of actionErlotinibGefitinibLapatinibRAD001SorafenibSunitinib NF-ҚB -catenin BcL-XL c-MYC c-JUN NF-ҚB -catenin p53 Survival Transcription/translation 1. Horie Y, et al. J Clin Invest 2004; 113:1774–83; 2. Hu T-H, et al. Cancer 2003; 97:1929–40. 3. Anzola M. J Viral Hepat 2004;11:383–93

  7. RTK: FGFREGFRIGF-IRc-MET Cell Membrane x Receptor GEF GrB2 x x x SHC x x x x x x Signaling Pathways for Cell Proliferation and Survival: Raf/MEK/ERK Wnt Receptor Ras PI3K DSH PLC Raf HBx PTEN GBP Akt PKC MEK1/2 mTOR GSK3 BAD ERK1/2 Site of actionErlotinibGefitinibLapatinibRAD001SorafenibSunitinib NF-ҚB -catenin BcL-XL NF-ҚB c-MYC c-JUN -catenin p53 Survival Transcription/Translation 1. Feitelson MA, et al. Surg Clin N Am 2004;84:339–54 2. Thorgeirsson S, Grisham JW. Nat Genet 2002;31:339–46 3. Wiesenauer CA, et al. J Am Coll Surg 2004;198:410–21 4. Hwang YH, et al. Hepatol Res 2004;29:113–21

  8. Paracrine stimulation VEGF PDGF-β Ras Ras Apoptosis Raf Raf MEK X X X X X X X X Apoptosis EGF MEK PDGF VEGF Angiogenesis Proliferation Survival Nucleus Nucleus Sorafenib ERK ERK Sorafenib Targets both Tumor-cell Proliferation and Angiogenesis In Vitro Tumor cell Endothelial cell or pericyte VEGFR-2 PDGFR-β KIT/Flt-3/RET Wilhelm SM, et al. Cancer Res 2004;64:7099–109

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