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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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Presentation Transcript
hepatocellular carcinoma

Hepatocellular Carcinoma

Overview of Hepatocellular Carcinoma

Epidemiology

signaling pathways for angiogenesis vegfr and pdgfr in the vasculature

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

signaling pathways for cell proliferation and survival pi3k

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

signaling pathways for cell proliferation and survival raf mek erk

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

sorafenib targets both tumor cell proliferation and angiogenesis in vitro

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