Regulation of endothelial Fas expression as a mechanism of promotion of vascular integrity by mural cells in tumors

• Published in: Cancer science 2017-05, Vol.108 (5), p.1080-1088
• Main Authors: Kamei, Ryosuke, Tanaka, Hiroyoshi Y., Kawano, Takao, Morii, Chiharu, Tanaka, Sayaka, Nishihara, Hiroshi, Iwata, Caname, Kano, Mitsunobu R.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis; Cancer; Carcinoma - metabolism; Carcinoma - pathology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell culture; Cell Line, Tumor; Cloning; Coculture Techniques - methods; Colon; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Drug delivery; endothelial cells; Endothelial Cells - metabolism; Endothelium; Fas; fas Receptor - metabolism; Gene expression; Hemorrhage; Humans; Ligands; Male; Medical research; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; mural cells; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Original; Pancreas; Signal Transduction - physiology; Smooth muscle; Studies; Tumors; vascular integrity
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13216

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. Mural cells are essential in the promotion of vascular integrity, but whether the regulation of death signaling is involved was hitherto unknown. We show in vitro and in vivo that mural cells promote vascular integrity in tumors via down‐regulation of the death receptor Fas in endothelial cells.