Abstract
Curative therapies for patients with hepatocellular carcinoma (HCC) are mainly invasive, and with the exception of sorafenib, no medical treatments are available for advanced or metastatic stages of HCC. We investigated the antitumoral effect of blocking the transforming growth factor beta (TGF-beta) signaling pathway in HCC with LY2109761, a kinase inhibitor of TGF-beta receptor I kinase. The antitumor activity of LY2109761 was associated with inhibition of molecular pathways involved in neo-angiogenesis and tumor growth of HCC. This anti-angiogenic effect is more effective than that of bevacizumab, which specifically targets vascular endothelial growth factor (VEGF). We found that the paracrine cross-talk between HCC and endothelial cells is blocked by LY210976, inhibiting blood vessel formation. This effect was mediated by SMAD2/3 and affected the secretion of VEGF. Finally, LY2109761 does not show significant effects on physiological angiogenetic development.
Conclusion:
These data support the rationale for targeting TGF-beta signaling in patients with HCC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Humanized
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Bevacizumab
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Carcinoma, Hepatocellular / blood supply*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology*
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Cell Line, Tumor
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Cell Proliferation* / drug effects
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Chick Embryo
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Embryonic Development / drug effects
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Humans
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Liver Neoplasms / blood supply*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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Neovascularization, Pathologic / metabolism*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Pyrazoles / pharmacology
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Pyrroles / pharmacology
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / drug effects
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / physiology
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Smad Proteins / metabolism
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Transforming Growth Factor beta1 / metabolism
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Angiogenesis Inhibitors
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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LY2109761
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Pyrazoles
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Pyrroles
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta1
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Vascular Endothelial Growth Factor A
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Bevacizumab
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I