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  • Review Article
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HCC and angiogenesis: possible targets and future directions

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Abstract

Hepatocellular carcinoma (HCC), the most common primary liver tumor, is notoriously resistant to systemic therapies, and often recurs even after aggressive local therapies. HCCs rely on the formation of new blood vessels for growth, and VEGF is critical in this process. A hallmark of new vessel formation in tumors is their structural and functional abnormality. This leads to an abnormal tumor microenvironment characterized by low oxygen tension. The liver is perfused by both arterial and venous blood and the resulting abnormal microenvironment selects for more-aggressive malignancies. Anti-VEGF therapy with sorafenib was the first systemic therapy to demonstrate improved survival in patients with advanced-stage HCC. This important development in the treatment of HCC raises hope as well as critical questions on the future development of targeted agents including other antiangiogenic agents, which hold promise to further increase survival in this aggressive disease.

Key Points

  • Hepatocellular carcinoma (HCC) is a heterogeneous disease with multiple etiologies that is uniformly fatal when unresectable; other malignant liver tumors include cholangiocarcinoma, angiosarcoma, hemangioendothelioma and hepatoblastoma

  • The growth of HCCs depends on their ability to recruit blood vessels by forming new vessels through sprouting (angiogenesis) and potentially by recruiting proangiogenic bone marrow-derived cells

  • Tumor neovasculature is highly abnormal, both structurally and functionally because of overexpression of VEGF; other molecules are also involved and may be important therapeutic targets

  • Sorafenib was developed as a VEGFR2, VEGFR3, PDGFR-β, and Raf/MEK/ERK signaling inhibitor; despite being standard of care in advanced-stage HCC, its mechanism of action remains unknown

  • Antiangiogeneic agents can transiently prune and normalize the tumor vasculature and improve the outcome of other treatments (chemotherapy, radiation) given during the normalization window

  • Circulating and imaging markers may be useful as pharmacodynamic end points, and may hold promise as potential surrogate and predictive markers for antiangiogenic therapy

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Figure 1: Schematic representation of potential escape mechanisms from anti-VEGF therapy.

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Change history

  • 08 April 2011

    In the version of this article initially published online the acknowledgements section was missing. The text should have read: "The authors acknowledge support by the National Institutes of Health (P01CA80124, R01CA115767, R21CA139168, M01RR01066, Federal Share/NCI Proton Beam Program Income Grants); by a Department of Defense Breast Cancer Research Innovator award (W81XWH-10-1-0016) and by an American Cancer Society Research Grant (RSG-11-073-01-TBG)." The error has been corrected for the print, HTML and PDF versions of the article.

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Acknowledgements

The authors acknowledge support by the National Institutes of Health (P01CA80124, R01CA115767, R21CA139168, M01RR01066, Federal Share/NCI Proton Beam Program Income Grants); by a Department of Defense Breast Cancer Research Innovator award (W81XWH-10-1-0016) and by an American Cancer Society Research Grant (RSG-11-073-01-TBG).

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A. X. Zhu and R. K. Jain contributed equally to the preparation of this manuscript. All authors contributed to researching data for the article, discussions of content, writing of the manuscript and to review and editing of the article before submission.

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Correspondence to Andrew X. Zhu.

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Competing interests

A. X. Zhu declares he is a consultant for Novartis, Pfizer and Sanofi-Aventis. He also receives grant/research support from Bayer. R. K. Jain declares he is a consultant for Astellas, AstraZeneca, MedImmune, Dyax, Noxxon, Genzyme, Regeneron, FibroGen, MorphoSys, SynDevRx, Novartis, Bayer and Pfizer. He receives honoraria from Genzyme and grant/research support from AstraZeneca, MedImmune and Dyax. He is a stock holder or Director at SynDevRx. The other authors declare no competing interests.

Supplementary information

Supplementary Table 1

Angiogenesis activators and inhibitors* (DOC 60 kb)

Supplementary Table 2

Phase II studies of sunitinib in advanced-stage hepatocellular carcinoma (DOC 40 kb)

Supplementary Table 3

Phase II studies of bevacizumab in advanced-stage hepatocellular carcinoma (DOC 41 kb)

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Zhu, A., Duda, D., Sahani, D. et al. HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol 8, 292–301 (2011). https://doi.org/10.1038/nrclinonc.2011.30

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