title: Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression.
abstract: 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.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Shom
authors.initials: S
authors.lastname: Goel
authors.forename: Nisha
authors.initials: N
authors.lastname: Gupta
authors.forename: Brian P
authors.initials: BP
authors.lastname: Walcott
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.forename: Cristina T
authors.initials: CT
authors.lastname: Kesler
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Kirkpatrick
authors.forename: Takahiro
authors.initials: T
authors.lastname: Heishi
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.forename: John D
authors.initials: JD
authors.lastname: Martin
authors.forename: Eleanor
authors.initials: E
authors.lastname: Ager
authors.forename: Rekha
authors.initials: R
authors.lastname: Samuel
authors.forename: Shuhan
authors.initials: S
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Yazbek
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Vakoc
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Padera
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology*; D018450:Disease Progression; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D029961:Zebrafish Proteins; D052250:Nitric Oxide Synthase Type III; D042787:Receptor, TIE-2; C468146:tek protein, zebrafish; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
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