TY - JOUR
T1 - FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal
AU - Haemmerle, Monika
AU - Bottsford-Miller, Justin
AU - Pradeep, Sunila
AU - Taylor, Morgan L.
AU - Choi, Hyun Jin
AU - Hansen, Jean M.
AU - Dalton, Heather J.
AU - Stone, Rebecca L.
AU - Cho, Min Soon
AU - Nick, Alpa M.
AU - Nagaraja, Archana S.
AU - Gutschner, Tony
AU - Gharpure, Kshipra M.
AU - Mangala, Lingegowda S.
AU - Rupaimoole, Rajesha
AU - Han, Hee Dong
AU - Zand, Behrouz
AU - Armaiz-Pena, Guillermo N.
AU - Wu, Sherry Y.
AU - Pecot, Chad V.
AU - Burns, Alan R.
AU - Lopez-Berestein, Gabriel
AU - Afshar-Kharghan, Vahid
AU - Sood, Anil K.
N1 - Funding Information:
Portions of this work were supported by the NIH (CA177909, CA016672, CA109298, UH2TR000943, P50 CA083639, and P50 CA098258), the Cancer Prevention and Research Institute of Texas (RP110595 and RP120214), the Ovarian Cancer Research Fund Inc. (Program Project Development Grant), the RGK Foundation, the Gilder Foundation, the Judi A. Rees Ovarian Cancer Research Fund, Mr. and Mrs. Daniel P. Gordon, the Blanton-Davis Ovarian Cancer Research Program, and the Betty Anne Asche Murray Distinguished Professorship (to A.K. Sood and V. Afshar-Kharghan). M. Haemmerle is supported by a fellowship from the Deutsche Forschungsgemeinschaft. J. Bottsford-Miller, H.J. Dalton, B. Zand, R.L. Stone, and J.M. Hansen were supported by the National Cancer Institute-Department of Health and Human Services-NIH T32 training grant (T32 CA101642). T. Gutschner is supported by the Odyssey Fellowship Program at The University of Texas MD Anderson Cancer Center. S.Y. Wu is supported by the Ovarian Cancer Research Fund Inc., the Foundation for Women's Cancer, and Cancer Prevention Research Institute of Texas training grants (RP101502 and RP101489). R. Rupaimoole was supported in part by the Russell and Diana Hawkins Family Foundation Discovery Fellowship. K.M. Gharpure is supported by the Altman-Goldstein Discovery Fellowship. We thank all members of the MD Anderson Flow Cytometry and Cellular Imaging Core Facility for excellent technical assistance. The core facility is funded by the National Cancer Institute Cancer Center support grant P30CA16672.
PY - 2016/5/2
Y1 - 2016/5/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI85086
DO - 10.1172/JCI85086
M3 - Article
C2 - 27064283
AN - SCOPUS:84988489941
SN - 0021-9738
VL - 126
SP - 1885
EP - 1896
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -