FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal
Monika Haemmerle, … , Vahid Afshar-Kharghan, Anil K. Sood
Monika Haemmerle, … , Vahid Afshar-Kharghan, Anil K. Sood
Published April 11, 2016
Citation Information: J Clin Invest. 2016;126(5):1885-1896. https://doi.org/10.1172/JCI85086.
View: Text | PDF
Research Article Oncology

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

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 In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.

Authors

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. Pecot, Alan R. Burns, Gabriel Lopez-Berestein, Vahid Afshar-Kharghan, Anil K. Sood

×

Figure 4

Role of platelet FAK on tumor growth.

Options: View larger image (or click on image) Download as PowerPoint
Role of platelet FAK on tumor growth. (A) Mean aggregate tumor weight an...
(A) Mean aggregate tumor weight and (B) representative images of necropsy in WT or platelet-specific FAK-deficient mice that carried tumors induced by i.p. injection of ID8-VEGF murine ovarian cancer cells and were exposed to long-term treatment or withdrawal of anti-VEGF antibody (B20). (C) Quantification of extravasated platelets in ID8-VEGF tumors in WT or platelet-specific FAK-deficient mice. (D) Mean aggregate tumor weight and (E) number of tumor nodules of orthotopic SKOV3ip1 tumors after treatment with pazopanib, the FAK inhibitor GSK2256098 (FAKi), or a combination of the two. (F) Mean aggregate weight of orthotopic SKOV3ip1 tumors after withdrawal or long-term antiangiogenic therapy alone or in combination with FAK inhibitor GSK2256098. (A and D–F) n = 8–10 mice per group. (B and C) Quantification and representative images of tumors from at least 5 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001 (1-way ANOVA followed by a Tukey’s multiple comparison post-hoc test in A and C–F). Averaged data are presented as the mean ± SEM.