BACKGROUND: The solid tumor microvasculature is characterized by structural and functional abnormality and mediates several deleterious aspects of tumor behavior. Here we determine the role of vascular endothelial protein tyrosine phosphatase (VE-PTP), which deactivates endothelial cell (EC) Tie-2 receptor tyrosine kinase, thereby impairing maturation of tumor vessels. METHODS: AKB-9778 is a first-in-class VE-PTP inhibitor. We examined its effects on ECs in vitro and on embryonic angiogenesis in vivo using zebrafish assays. We studied the impact of AKB-9778 therapy on the tumor vasculature, tumor growth, and metastatic progression using orthotopic models of murine mammary carcinoma as well as spontaneous and experimental metastasis models. Finally, we used endothelial nitric oxide synthase (eNOS)-deficient mice to establish the role of eNOS in mediating the effects of VE-PTP inhibition. All statistical tests were two-sided. RESULTS: AKB-9778 induced ligand-independent Tie-2 activation in ECs and impaired embryonic zebrafish angiogenesis. AKB-9778 delayed the early phase of mammary tumor growth by maintaining vascular maturity (P < .01, t test); slowed growth of micrometastases (P < .01, χ(2) test) by preventing extravasation of tumor cells (P < 0.01, Fisher exact test), resulting in a trend toward prolonged survival (27.0 vs 36.5 days; hazard ratio of death = 0.33, 95% confidence interval = 0.11 to 1.03; P = .05, Mantel-Cox test); and stabilized established primary tumor blood vessels, enhancing tumor perfusion (P = .03 for 4T1 tumor model and 0.05 for E0771 tumor model, by two-sided t tests) and, hence, radiation response (P < .01, analysis of variance; n = 7 mice per group). The effects of AKB-9778 on tumor vessels were mediated in part by endothelial nitric oxide synthase activation. CONCLUSIONS: Our results demonstrate that pharmacological VE-PTP inhibition can normalize the structure and function of tumor vessels through Tie-2 activation, which delays tumor growth, slows metastatic progression, and enhances response to concomitant cytotoxic treatments.
BACKGROUND: The solid tumor microvasculature is characterized by structural and functional abnormality and mediates several deleterious aspects of tumor behavior. Here we determine the role of vascular endothelial protein tyrosine phosphatase (VE-PTP), which deactivates endothelial cell (EC) Tie-2 receptor tyrosine kinase, thereby impairing maturation of tumor vessels. METHODS:AKB-9778 is a first-in-class VE-PTP inhibitor. We examined its effects on ECs in vitro and on embryonic angiogenesis in vivo using zebrafish assays. We studied the impact of AKB-9778 therapy on the tumor vasculature, tumor growth, and metastatic progression using orthotopic models of murine mammary carcinoma as well as spontaneous and experimental metastasis models. Finally, we used endothelial nitric oxide synthase (eNOS)-deficient mice to establish the role of eNOS in mediating the effects of VE-PTP inhibition. All statistical tests were two-sided. RESULTS:AKB-9778 induced ligand-independent Tie-2 activation in ECs and impaired embryonic zebrafish angiogenesis. AKB-9778 delayed the early phase of mammary tumor growth by maintaining vascular maturity (P < .01, t test); slowed growth of micrometastases (P < .01, χ(2) test) by preventing extravasation of tumor cells (P < 0.01, Fisher exact test), resulting in a trend toward prolonged survival (27.0 vs 36.5 days; hazard ratio of death = 0.33, 95% confidence interval = 0.11 to 1.03; P = .05, Mantel-Cox test); and stabilized established primary tumor blood vessels, enhancing tumor perfusion (P = .03 for 4T1 tumor model and 0.05 for E0771 tumor model, by two-sided t tests) and, hence, radiation response (P < .01, analysis of variance; n = 7 mice per group). The effects of AKB-9778 on tumor vessels were mediated in part by endothelial nitric oxide synthase activation. CONCLUSIONS: Our results demonstrate that pharmacological VE-PTP inhibition can normalize the structure and function of tumor vessels through Tie-2 activation, which delays tumor growth, slows metastatic progression, and enhances response to concomitant cytotoxic treatments.
Authors: Satoshi Kashiwagi; Yotaro Izumi; Takeshi Gohongi; Zoe N Demou; Lei Xu; Paul L Huang; Donald G Buerk; Lance L Munn; Rakesh K Jain; Dai Fukumura Journal: J Clin Invest Date: 2005-06-09 Impact factor: 14.808
Authors: H Kojima; K Sakurai; K Kikuchi; S Kawahara; Y Kirino; H Nagoshi; Y Hirata; T Nagano Journal: Chem Pharm Bull (Tokyo) Date: 1998-02 Impact factor: 1.645
Authors: C Suri; J McClain; G Thurston; D M McDonald; H Zhou; E H Oldmixon; T N Sato; G D Yancopoulos Journal: Science Date: 1998-10-16 Impact factor: 47.728
Authors: M S O'Reilly; L Holmgren; Y Shing; C Chen; R A Rosenthal; M Moses; W S Lane; Y Cao; E H Sage; J Folkman Journal: Cell Date: 1994-10-21 Impact factor: 41.582
Authors: Daniel Dubinski; Elke Hattingen; Christian Senft; Volker Seifert; Kevin G Peters; Yvonne Reiss; Kavi Devraj; Karl H Plate Journal: J Cereb Blood Flow Metab Date: 2019-06-25 Impact factor: 6.200
Authors: Hannes C A Drexler; Matthias Vockel; Christian Polaschegg; Maike Frye; Kevin Peters; Dietmar Vestweber Journal: Mol Cell Proteomics Date: 2019-08-19 Impact factor: 5.911
Authors: Cristina T Kesler; Ethel R Pereira; Cheryl H Cui; Gregory M Nelson; David J Masuck; James W Baish; Timothy P Padera Journal: FASEB J Date: 2015-05-14 Impact factor: 5.191
Authors: John D Martin; Dai Fukumura; Dan G Duda; Yves Boucher; Rakesh K Jain Journal: Cold Spring Harb Perspect Med Date: 2016-12-01 Impact factor: 6.915
Authors: Sara M Tolaney; Yves Boucher; Dan G Duda; John D Martin; Giorgio Seano; Marek Ancukiewicz; William T Barry; Shom Goel; Johanna Lahdenrata; Steven J Isakoff; Eren D Yeh; Saloni R Jain; Mehra Golshan; Jane Brock; Matija Snuderl; Eric P Winer; Ian E Krop; Rakesh K Jain Journal: Proc Natl Acad Sci U S A Date: 2015-11-02 Impact factor: 11.205