title: Regulation of endothelial Fas expression as a mechanism of promotion of vascular integrity by mural cells in tumors.
abstract: Angiogenesis is a multi-step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide-reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas-dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an in vitro coculture system of MS-1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an in vivo model in which C26 colon carcinoma cells were inoculated together with MS-1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors.
authors.affiliation: Medical Scientist Training Program, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kamei
authors.affiliation: Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Hiroyoshi Y
authors.initials: HY
authors.lastname: Tanaka
authors.affiliation: Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Morii
authors.affiliation: Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Laboratory of Translational Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Caname
authors.initials: C
authors.lastname: Iwata
authors.affiliation: Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Mitsunobu R
authors.identifier: http://orcid.org/0000-0003-1593-1855
authors.initials: MR
authors.lastname: Kano
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques / Q000379:methods; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D019014:fas Receptor
keywords: Apoptosis; Fas; endothelial cells; mural cells; vascular integrity