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.
Highlights
Gastric cancer (GC) is the fifth most common cancer worldwide, with an estimated 952,000 new cases (7% of the total cancer incidence) and 723,000 gastric cancer (GC)-associated deaths (9% of the total cancer mortality) recorded in 2012
We analysed the association between lipolysis-stimulated lipoprotein receptor (LSR) expression and prognosis in patients with GC, and evaluated the anti-tumor effects of anti-human LSR (hLSR) monoclonal antibody (mAb) (#1–25) in vitro and in vivo
We detected higher LSR expression in metastatic sites including the lymph nodes, peritoneum, and liver, as well as in the primary GCs compared to normal tissues
Summary
Gastric cancer (GC) is the fifth most common cancer worldwide, with an estimated 952,000 new cases (7% of the total cancer incidence) and 723,000 GC-associated deaths (9% of the total cancer mortality) recorded in 2012. Almost three-quarters of the new-diagnosed cases occurred in Asia [1]. Most patients present with inoperable advanced www.oncotarget.com or metastatic disease and only receive palliative treatment, even though early detection is more common in Asia than in other regions [4]. Molecular targeted therapy in cancer inhibits the target molecule with less severe adverse events than that of cytotoxic agents [9]. Despite the recently reported benefits of combination therapies [5, 6, 10, 11], the prognoses of patients with advanced GC remain poor [4, 12]. The search for biomarkers that can predict prognosis is increasingly important, and additional new agents with acceptable toxicity profiles are needed
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