Lipolysis-stimulated lipoprotein receptor overexpression is a novel predictor of poor clinical prognosis and a potential therapeutic target in gastric cancer

// Takahito Sugase 1, 2, 3 , Tsuyoshi Takahashi 1 , Satoshi Serada 2 , Minoru Fujimoto 2 , Tomoharu Ohkawara 2 , Kosuke Hiramatsu 2 , Masahiro Koh 1 , Yurina Saito 1 , Koji Tanaka 1 , Yasuhiro Miyazaki 1 , Tomoki Makino 1 , Yukinori Kurokawa 1 , Makoto Yamasaki 1 , Kiyokazu Nakajima 1 , Kazuhiro Hanazaki 3 , Masaki Mori 1 , Yuichiro Doki 1 and Tetsuji Naka 2 1 Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan 2 Center for Intractable Immune Disease, Kochi University, Nankoku, Japan 3 Department of Surgery, Kochi University, Nankoku, Japan Correspondence to: Tsuyoshi Takahashi, email: ttakahashi2@gesurg.med.osaka-u.ac.jp Tetsuji Naka, email: naka@kochi-u.ac.jp Keywords: gastric cancer; LSR; lipid metabolism; antibody therapy; mouse model Received: April 30, 2018      Accepted: July 28, 2018      Published: August 31, 2018 ABSTRACT The prognosis of patients with advanced gastric cancer (GC) remains poor despite the recent advances in molecular targeted therapies, and the search for biomarkers that can predict prognosis and additional new agents with acceptable toxicity profiles are needed. Lipolysis-stimulated lipoprotein receptor (LSR) is a lipoprotein receptor that binds to triglyceride-rich lipoproteins and related to some malignancies. Herein, we examined the association between LSR expression and the prognosis of patients with GC, and investigated the antitumor effect of a previously developed anti-human LSR monoclonal antibody (#1–25). We first performed immunohistochemical analysis of LSR protein expression in GC and normal tissues, and then examined its association with the prognosis of 110 patients with GC. LSR was overexpressed in most of primary GC and metastatic tumors, but not in normal tissues. Patients with strong LSR expression ( N = 80, 72.7%) had significantly poorer overall survival (OS) than those with weak expression ( P = 0.017). Multivariate analysis identified strong LSR (as well as pT) as independent and significant prognostic factors for OS. Next, we demonstrated that very low density lipoprotein (VLDL) treatment increases cell proliferation in LSR-expressing GC cell lines in vitro ; LSR inhibition using #1–25 inhibited VLDL-induced proliferation by suppressing JAK/STAT and PI3K signaling. In vivo , we demonstrated a marked antitumor effect of #1–25 in 2 distinct GC cell line xenograft mice models. Our findings suggest that LSR plays a key functional role in GC development, and that this antigen can be therapeutically targeted to improve GC treatment.