title: Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter of Vascular Permeability, Angiogenesis, and Tumor Progression.
abstract: The protein tyrosine phosphatase PTPRJ/DEP-1 has been implicated in negative growth regulation in endothelial cells, where its expression varies at transitions between proliferation and contact inhibition. However, in the same cells, DEP-1 has also been implicated in VEGF-dependent Src activation, permeability, and capillary formation, suggesting a positive role in regulating these functions. To resolve this dichotomy in vivo, we investigated postnatal angiogenesis and vascular permeability in a DEP-1-deficient mouse. In this study, we report that DEP-1 is required for Src activation and phosphorylation of its endothelial cell-specific substrate, VE-cadherin, after systemic injection of VEGF. Accordingly, VEGF-induced vascular leakage was abrogated in the DEP-1-deficient mice. Furthermore, capillary formation was impaired in murine aortic tissue rings or Matrigel plugs infused with VEGF. In the absence of DEP-1, angiogenesis triggered by ischemia or during tumor formation was defective, which in the latter case was associated with reduced tumor cell proliferation and increased apoptosis. Macrophage infiltration was also impaired, reflecting reduced vascular permeability in the tumors or a possible cell autonomous effect of DEP-1. Consequently, the formation of spontaneous and experimental lung metastases was strongly decreased in DEP-1-deficient mice. In clinical specimens of cancer, less vascularized tumors exhibited lower microvascular expression of DEP-1. Altogether, our results established DEP-1 as an essential driver of VEGF-dependent permeability, angiogenesis, and metastasis, suggesting a novel therapeutic route to cancer treatment. Cancer Res; 76(17); 5080-91. ©2016 AACR.
authors.affiliation: CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada. Institut du cancer de Montréal, Montréal, Quebec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fournier
authors.affiliation: CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dussault
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli "Federico II", Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.affiliation: CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada. Département de Médecine, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Rivard
authors.affiliation: CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada. Institut du cancer de Montréal, Montréal, Quebec, Canada. Département de Médecine, Université de Montréal, Montréal, Quebec, Canada. Isabelle.royal@umontreal.ca.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Royal
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D018450:Disease Progression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3