title: 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 In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.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.forename: Monika
authors.initials: M
authors.lastname: Haemmerle
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Taylor
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Choi
authors.forename: Jean M
authors.initials: JM
authors.lastname: Hansen
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Min Soon
authors.initials: MS
authors.lastname: Cho
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Archana S
authors.initials: AS
authors.lastname: Nagaraja
authors.forename: Tony
authors.initials: T
authors.lastname: Gutschner
authors.forename: Kshipra M
authors.initials: KM
authors.lastname: Gharpure
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zand
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.forename: Sherry Y
authors.initials: SY
authors.lastname: Wu
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.forename: Alan R
authors.initials: AR
authors.lastname: Burns
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Vahid
authors.initials: V
authors.lastname: Afshar-Kharghan
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068258:Bevacizumab / Q000494:pharmacology; D001792:Blood Platelets / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007191:Indazoles; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000912:Antibodies, Neoplasm; D007191:Indazoles; D009363:Neoplasm Proteins; D011743:Pyrimidines; D013449:Sulfonamides; D000068258:Bevacizumab; D000244:Adenosine Diphosphate; C516667:pazopanib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse