MP92-09 COMBINATION THERAPY USING MOLECULAR-TARGETED DRUGS INHIBITING PLATELET-DERIVED GROWTH FACTOR RECEPTORS IN THE TUMOR MICROENVIRONMENT OF RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2016MP92-09 COMBINATION THERAPY USING MOLECULAR-TARGETED DRUGS INHIBITING PLATELET-DERIVED GROWTH FACTOR RECEPTORS IN THE TUMOR MICROENVIRONMENT OF RENAL CELL CARCINOMA Hiroyuki Kitano, Jun Teishima, Ryo Yuge, Syunsuke Shinmei, Hirotaka Nagamatsu, Keisuke Goto, Kouichi Shoji, Syogo Inoue, Tetsutaro Hayashi, Kazuhiro Sentani, Yasuhiko Kitadai, Wataru Yasui, and Akio Matsubara Hiroyuki KitanoHiroyuki Kitano More articles by this author , Jun TeishimaJun Teishima More articles by this author , Ryo YugeRyo Yuge More articles by this author , Syunsuke ShinmeiSyunsuke Shinmei More articles by this author , Hirotaka NagamatsuHirotaka Nagamatsu More articles by this author , Keisuke GotoKeisuke Goto More articles by this author , Kouichi ShojiKouichi Shoji More articles by this author , Syogo InoueSyogo Inoue More articles by this author , Tetsutaro HayashiTetsutaro Hayashi More articles by this author , Kazuhiro SentaniKazuhiro Sentani More articles by this author , Yasuhiko KitadaiYasuhiko Kitadai More articles by this author , Wataru YasuiWataru Yasui More articles by this author , and Akio MatsubaraAkio Matsubara More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2642AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent studies have shown that the tumor microenvironment, which is comprised of cancer cells and stroma, is involved in cancer progression and platelet-derived growth factor (PDGF) plays a major role in stromal activation. However, the impacts of molecular-targeted drugs on the stroma of renal cell carcinoma (RCC) remain unclear. Therefore, in this study, we used a tyrosine kinase inhibitor (TKI) and a mammalian target of rapamycin inhibitor (mTORI) targeting PDGF receptors with the aim of elucidating their effects on the RCC stroma and analyzing the treatment outcomes obtained with TKI/mTORI combination therapy. METHODS Orthotopic mouse models, created using Caki-1, a luciferase-expressing human RCC cell line, were divided into four groups: control (C), everolimus (E), sunitinib (S) and everolimus/sunitinib (ES). After four-week everolimus at 1 mg/kg/day and sunitinib at 10 mg/kg/day, tumors were removed. Cell viability was measured every 2 weeks by in vivo imaging. Cell proliferation was analyzed in extracted tissues by the Ki67 labeling index (Ki67-LI). Recruitment of cancer-associated fibroblasts (CAFs) and extracellular matrix growth were analyzed by immunostaining for a-smooth muscle actin and type 1 collagen, respectively, angiogenesis and lymphangiogenesis by immunofluorescence staining for CD31 and LYVE-1, respectively, and pericyte recruitment by double-immunofluorescence staining with antibodies against endothelial cell (CD31) and pericyte (desmin) markers. RESULTS Cell viability and Ki67-LI were significantly decreased in the E and ES groups as compared to the S group. We first confirmed expressions of PDGF receptors on CAFs and pericytes by double-immunofluorescence staining. Neither recruitment of CAFs nor growth of type 1 collagen was inhibited in the E group but both were significantly inhibited in the S and ES groups. Compared to the E group, angiogenesis and lymphangiogenesis were significantly inhibited in the S and ES groups. The C and E groups showed pericyte recruitment around blood vessels, but these cells were relatively sparse in the S and ES groups. CONCLUSIONS The comparison between TKI and mTORI revealed mTORI to have significantly greater inhibitory effects on cancer cells, while TKI exerted inhibitory effects on the stroma. Our findings suggest that combining these two molecular-targeted drugs, with the aim of targeting the tumor microenvironment, would be an effective treatment for RCC. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1165 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Hiroyuki Kitano More articles by this author Jun Teishima More articles by this author Ryo Yuge More articles by this author Syunsuke Shinmei More articles by this author Hirotaka Nagamatsu More articles by this author Keisuke Goto More articles by this author Kouichi Shoji More articles by this author Syogo Inoue More articles by this author Tetsutaro Hayashi More articles by this author Kazuhiro Sentani More articles by this author Yasuhiko Kitadai More articles by this author Wataru Yasui More articles by this author Akio Matsubara More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...