FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal. J Clin Invest 2016 May 02;126(5):1885-96
Date
04/12/2016Pubmed ID
27064283Pubmed Central ID
PMC4855933DOI
10.1172/JCI85086Scopus ID
2-s2.0-84988489941 (requires institutional sign-in at Scopus site) 92 CitationsAbstract
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 In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.
Author List
Haemmerle M, Bottsford-Miller J, Pradeep S, Taylor ML, Choi HJ, Hansen JM, Dalton HJ, Stone RL, Cho MS, Nick AM, Nagaraja AS, Gutschner T, Gharpure KM, Mangala LS, Rupaimoole R, Han HD, Zand B, Armaiz-Pena GN, Wu SY, Pecot CV, Burns AR, Lopez-Berestein G, Afshar-Kharghan V, Sood AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine DiphosphateAnimals
Antibodies, Neoplasm
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Blood Platelets
Cell Hypoxia
Cell Line, Tumor
Female
Focal Adhesion Kinase 1
Humans
Indazoles
Mice
Mice, Knockout
Neoplasm Proteins
Neovascularization, Pathologic
Ovarian Neoplasms
Pyrimidines
Sulfonamides
Tumor Microenvironment
Xenograft Model Antitumor Assays