Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies

Dana D. Hu-Lowe, Enhong Chen, Lianglin Zhang, Katherine D. Watson, Patrizia Mancuso, Patrick Lappin, Grant Wickman, Jeffrey H. Chen, Jianying Wang, Xin Jiang, Karin Amundson, Ronald Simon, Andreas Erbersdobler, Simon Bergqvist, Zheng Feng, Terri A. Swanson, Brett H. Simmons, John Lippincott, Gerald F. Casperson, Wendy J. LevinCorrado Gallo Stampino, David R. Shalinsky, Katherine W. Ferrara, Walter Fiedler, Francesco Bertolini

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin+ perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.

Original languageEnglish (US)
Pages (from-to)1362-1373
Number of pages12
JournalCancer Research
Volume71
Issue number4
DOIs
StatePublished - Feb 15 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Hu-Lowe, D. D., Chen, E., Zhang, L., Watson, K. D., Mancuso, P., Lappin, P., Wickman, G., Chen, J. H., Wang, J., Jiang, X., Amundson, K., Simon, R., Erbersdobler, A., Bergqvist, S., Feng, Z., Swanson, T. A., Simmons, B. H., Lippincott, J., Casperson, G. F., ... Bertolini, F. (2011). Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. Cancer Research, 71(4), 1362-1373. https://doi.org/10.1158/0008-5472.CAN-10-1451