FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

Monika Haemmerle, Justin Bottsford-Miller, Sunila Pradeep, Morgan L. Taylor, Hyun Jin Choi, Jean M. Hansen, Heather J. Dalton, Rebecca L. Stone, Min Soon Cho, Alpa M. Nick, Archana S. Nagaraja, Tony Gutschner, Kshipra M. Gharpure, Lingegowda S. Mangala, Rajesha Rupaimoole, Hee Dong Han, Behrouz Zand, Guillermo N. Armaiz-Pena, Sherry Y. Wu, Chad V. PecotAlan R. Burns, Gabriel Lopez-Berestein, Vahid Afshar-Kharghan, Anil K. Sood

Research output: Contribution to journalArticle

Abstract

Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.

Original languageEnglish (US)
Pages (from-to)1885-1896
Number of pages12
JournalJournal of Clinical Investigation
Volume126
Issue number5
DOIs
StatePublished - May 2 2016

ASJC Scopus subject areas

  • Medicine(all)

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    Haemmerle, M., Bottsford-Miller, J., Pradeep, S., Taylor, M. L., Choi, H. J., Hansen, J. M., Dalton, H. J., Stone, R. L., Cho, M. S., Nick, A. M., Nagaraja, A. S., Gutschner, T., Gharpure, K. M., Mangala, L. S., Rupaimoole, R., Han, H. D., Zand, B., Armaiz-Pena, G. N., Wu, S. Y., ... Sood, A. K. (2016). FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal. Journal of Clinical Investigation, 126(5), 1885-1896. https://doi.org/10.1172/JCI85086