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Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter Of

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Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter Of Published OnlineFirst June 30, 2016; DOI: 10.1158/0008-5472.CAN-16-1071 Cancer Molecular and Cellular Pathobiology Research Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter of Vascular Permeability, Angiogenesis, and Tumor Progression Patrick Fournier1,2, Sylvie Dussault1, Alfredo Fusco3, Alain Rivard1,4, and Isabelle Royal1,2,4 Abstract The protein tyrosine phosphatase PTPRJ/DEP-1 has been gel plugs infused with VEGF. In the absence of DEP-1, angio- implicated in negative growth regulation in endothelial cells, genesis triggered by ischemia or during tumor formation was where its expression varies at transitions between proliferation defective, which in the latter case was associated with reduced and contact inhibition. However, in the same cells, DEP-1 has tumor cell proliferation and increased apoptosis. Macrophage also been implicated in VEGF-dependent Src activation, per- infiltration was also impaired, reflecting reduced vascular per- meability, and capillary formation, suggesting a positive role in meability in the tumors or a possible cell autonomous effect of regulating these functions. To resolve this dichotomy in vivo,we DEP-1. Consequently, the formation of spontaneous and investigated postnatal angiogenesis and vascular permeability experimental lung metastases was strongly decreased in in a DEP-1–deficient mouse. In this study, we report that DEP-1 DEP-1–deficient mice. In clinical specimens of cancer, less is required for Src activation and phosphorylation of its endo- vascularized tumors exhibited lower microvascular expression thelial cell–specific substrate, VE-cadherin, after systemic injec- of DEP-1. Altogether, our results established DEP-1 as an tion of VEGF. Accordingly, VEGF-induced vascular leakage was essential driver of VEGF-dependent permeability, angiogenesis, abrogated in the DEP-1–deficient mice. Furthermore, capillary and metastasis, suggesting a novel therapeutic route to cancer formation was impaired in murine aortic tissue rings or Matri- treatment. Cancer Res; 76(17); 1–12. Ó2016 AACR. Introduction ated growth inhibition (2, 3). Similarly, overexpression of DEP-1 in many tumor cells is associated with inhibition of cell prolif- Angiogenesis and increased vessel permeability play key roles eration and migration (2, 4–7). Consistent with this role, some of during the development of a number of pathologies including its known substrates include growth factor receptors such as the tumor growth and cancer progression (1). Therefore, much effort PDGFR, EGFR, MET, and ERK1/2 (8–11). aims at understanding the molecular mechanisms underlying the In confluent and quiescent endothelial cells, DEP-1 colocalizes formation and remodeling of blood vessels as a way to identify at cell–cell junctions with VEGFR2 and VE-cadherin, and nega- new approaches to harness these processes. The receptor-like tively regulates VEGFR2 phosphorylation and cell proliferation protein tyrosine phosphatase DEP-1, also named PTPRJ or (3, 12, 13). However, in addition to its role as an attenuator of CD148, is expressed in various cell types including epithelial, VEGFR2 activity, DEP-1 is also a positive regulator of Src activa- hematopoietic, and endothelial cells. It encompasses an extracel- tion and of important Src kinase–dependent biological functions lular domain containing eight fibronectin-type III-like motifs, a in VEGF-stimulated cells, including cell survival, permeability, transmembrane domain, a single intracellular catalytic domain, invasion, and capillary formation (14–19). This is induced and a short C-terminal tail (2). DEP-1 expression is found to through the VEGF-mediated tyrosine-phosphorylation of the increase with cell density, and contributes to cell contact–medi- C-terminal tail of DEP-1 on Y1311 and Y1320, which allows DEP-1 to associate with Src and dephosphorylate its inhibitory Y529 (15). Interestingly, inactivation of DEP-1 in mice, via the 1 CRCHUM - Centre de recherche du Centre Hospitalier de l'Universite swapping of its catalytic domain with GFP, resulted in mid- de Montreal, Montreal, Quebec, Canada. 2Institut du cancer de Mon- treal, Montreal, Quebec,Canada. 3Dipartimento di Biologia e Patologia gestation death, characterized by enlarged primitive vessels, Cellulare e Molecolare, Universita degli Studi di Napoli "Federico II", increased endothelial cell proliferation, and defective vascular 4 Naples, Italy. Departement de Medecine, Universite de Montreal, remodeling and branching (20). Surprisingly, DEP-1 knockout Montreal, Quebec, Canada. (KO) mice are viable and fertile, with no apparent phenotype Note: Supplementary data for this article are available at Cancer Research (21–23). However, further characterization of these mice models Online (http://cancerres.aacrjournals.org/). revealed that DEP-1 positively regulates B cell and macrophage Corresponding Author: Isabelle Royal, CRCHUM, 900, rue St-Denis, Montreal, immunoreceptor signaling, platelet activation, and airway Quebec H2X 0A9, Canada. Phone: 514-890-8000, ext. 25497; Fax: 514-412-7591; smooth muscle contractility (22, 24, 25). As the underlying E-mail: [email protected] mechanism, DEP-1 was proposed to promote these biological doi: 10.1158/0008-5472.CAN-16-1071 responses via activation of Src family kinases (SFK), similarly to Ó2016 American Association for Cancer Research. what was observed in endothelial cells in vitro (14). Therefore, to www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst June 30, 2016; DOI: 10.1158/0008-5472.CAN-16-1071 Fournier et al. determine the role of DEP-1 during angiogenesis and permeabil- beads (GE Healthcare). Lung lysates and immunoprecipitated ity in vivo, the biological consequences of its lost expression were proteins were resolved by SDS-PAGE and transferred on nitrocel- investigated in DEP-1 KO mice. We demonstrate here that DEP-1 lulose membranes (0.45 mm; Bio-Rad). Western blotting and ECL is essential for Src activation and the phosphorylation of its detection (Amersham Biosciences/GE Healthcare) were performed substrate VE-cadherin in response to VEGF stimulation in vivo. according to the manufacturer's recommendations. Alternatively, Consequently, impaired vascular permeability, capillary forma- lungs were frozen in OCT and 5-mm cryosections were processed tion, and recovery from hindlimb ischemia are observed in DEP-1 for immunofluorescence. Formalin-fixed sections were incubated KO mice. Also, tumor growth and the formation of spontaneous for 1 hour with CD31 antibody (1/50), washed twice with PBS and experimental metastases were greatly reduced in mice with no 5 minutes, and then incubated 45 minutes with Alexa Fluor 488– expression of DEP-1, consistent with an important reduction in coupled anti-mouse antibody (1/800). After PBS washes, the same tumor-associated microvessel density and defective vascular per- steps were followed with pY418Src (1/100) and Alexa Fluor 594– meability in these mice. These results thus demonstrate for the first coupled anti-rabbit (1/800) antibodies. Slides were next washed time the positive and essential role played by DEP-1 in postnatal twice with PBS and water, and mounted in ProLong Gold antifade and tumor-associated angiogenesis, and identify stroma-derived reagent (Invitrogen/Molecular Probes). Fluorescence was visual- DEP-1 as an important promoter of tumor progression. ized using a Nikon Eclipse E600 microscope and photographed with an Â20 objective lens, using a Photometrics CoolSNAP fi Materials and Methods camera (Roper Scienti c). Images were captured with NIS-Ele- ments AR 3.0 software (Nikon). Antibodies and reagents Y529 Y1175 Antibodies against Src, non-p Src, p VEGFR2, cleaved Permeability assays caspase-3, and horseradish peroxidase (HRP)-conjugated second- Anesthetized WT or DEP-1 KO mice (8/10-week-old) were ary IgGs were purchased from Cell Signaling Technology, New injected with Evans blue (50 mg/kg) via the tail vein. Immediately Y418 England Biolabs. p Src, Alexa Fluor 488–coupled donkey anti- after, mice were injected intradermally on each side of the ventral goat, and Alexa Fluor 594-coupled donkey anti-rabbit antibodies midline with an equal volume of PBS, VEGF (200 ng), or hista- were purchased from Invitrogen. DEP-1 goat antibody was from mine (625 ng). Thirty minutes later, mice were perfused with PBS R&D Systems. CD31 (M-20), Ki67, PY99, and VEGFR2 antibodies and the skin was photographed. For basal permeability assays, were purchased from Santa Cruz Biotechnology. VE-Cadherin mice were perfused with PBS 1 hour after injection of Evans blue. (11D4.1) and F4/80 (A3-1) antibodies were from BD Pharmingen For the quantification of intratumor vascular permeability, mice (BD Biosciences) and Thermo Scientific, respectively. Recombi- were injected with Evans blue 21 days after injection of tumor cells nant human VEGF-A was obtained from the Biological Resources and perfused with PBS after 1 hour. Sites of injection, organs, and Branch Preclinical Repository of the National Cancer Institute - tumors were collected, weighed, and incubated for 48 hours at Frederick Cancer Research and Development Center. Evans blue 56C in formamide to extract Evans blue. Absorbance at 600 nm dye and formamide were purchased from Sigma. was determined in triplicate and normalized on tissue weight, and on the relative concentration of Evans blue present in the blood of Animal model and cell lines the corresponding mice. þ À DEP-1 KOand wild-type
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