Inhibition of Transforming Growth Factor β Receptor I... : Hepatology (original) (raw)
Hepatobiliary Malignancies
Inhibition of Transforming Growth Factor β Receptor I Kinase Blocks Hepatocellular Carcinoma Growth Through Neo-angiogenesis Regulation†
Mazzocca, Antonio1; Fransvea, Emilia1; Lavezzari, Gabriela2; Antonaci, Salvatore1; Giannelli, Gianluigi1,*,‡
1 Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy
2 Theranostics Health, Rockville, MD
*Address reprint requests to: Dipartimento di Clinica Medica, Immunologia e Malattie Infettive, Sezione di Medicina Interna, Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy
E-mail:[email protected]
Received 13 April 2009; Accepted 7 June 2009.
Published online in Wiley InterScience (www.interscience.wiley.com)..
Grant sponsor: University of Bari; Grant sponsor: Regione Puglia.
†Potential conflict of interest: Nothing to report.
‡fax: 39-080-5478-126.
Additional Supporting Information may be found in the online version of this article.
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 β (TGF-β) signaling pathway in HCC with LY2109761, a kinase inhibitor of TGF-β 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 phsyiological angiogenetic development.
Conclusion:
These data support the rationale for targeting TGF-β signaling in patients with HCC. (Hepatology 2009.)
Copyright © 2009 American Association for the Study of Liver Diseases.