FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

• Published in: The Journal of clinical investigation Vol. 126; no. 5; pp. 1885 - 1896
• Main Authors: Haemmerle, Monika, Bottsford-Miller, Justin, Pradeep, Sunila, Taylor, Morgan L, Choi, Hyun-Jin, Hansen, Jean M, Dalton, Heather J, Stone, Rebecca L, Cho, Min Soon, Nick, Alpa M, Nagaraja, Archana S, Gutschner, Tony, Gharpure, Kshipra M, Mangala, Lingegowda S, Rupaimoole, Rajesha, Han, Hee Dong, Zand, Behrouz, Armaiz-Pena, Guillermo N, Wu, Sherry Y, Pecot, Chad V, Burns, Alan R, Lopez-Berestein, Gabriel, Afshar-Kharghan, Vahid, Sood, Anil K
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2016
• Subjects: Adenosine Diphosphate - metabolism; Analysis; Animals; Antibodies, Neoplasm - pharmacology; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Bevacizumab - pharmacology; Biomedical research; Blood Platelets - pathology; Cancer therapies; Care and treatment; Cell culture; Cell Hypoxia - drug effects; Cell Hypoxia - genetics; Cell Line, Tumor; Clinical trials; Cytokines; Development and progression; Disease prevention; Dosage and administration; Experiments; Female; Focal Adhesion Kinase 1 - antagonists & inhibitors; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Grants; Health aspects; Humans; Hypoxia; Medical research; Metastasis; Mice; Mice, Knockout; Microscopy; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Pyrimidines - pharmacology; Studies; Sulfonamides - pharmacology; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumors; Vascular endothelial growth factor; Xenograft Model Antitumor Assays
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI85086

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.