Abstract
Abstract Purpose: Lysyl oxidase families are involved in a variety of pathological processes, including cancer progression. Lysyl oxidase-like 2 (LOXL2) in the tumor stroma was mainly expressed in fibroblasts, which are a major stromal compartment of gastric cancer. Significance of LOXL2 remains unclear in gastric carcinoma. The aim of this study was to clarify the role of fibroblast-derived LOXL2 in the development of gastric cancer. Methods: Two gastric cancer cell lines, OCUM-12 and NUGC-3, and cancer-associated fibroblasts (CAF) were used in this in vitro study. The effect of fibroblast-derived LOXL2 on the motility of gastric cancer cells was analyzed by wound-healing assay, double-chamber invasion assay, and western blot. The correlation between LOXL2 expression and the clinicopathological features of 548 primary gastric carcinomas was examined by immunohistochemistry. Results: LOXL2 mRNA expression of CAF, was significantly higher than that of normal fibroblasts. CAF significantly stimulated the migration and invasion of OCUM-12 and NUGC-3 cells. This motility-stimulating ability of CAF was inhibited by LOXL2 siRNA. Western blot analysis indicated that phosphorylation of focal adhesion kinase (FAK) in cancer cells was increased by the conditioned medium from CAF, and was not affected by the conditioned medium from LOXL2 siRNA-treated CAF. Immunohistochemical study indicated that LOXL2 expression in stromal cells was significantly associated with tumor invasion depth, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal dissemination. The overall survival of all patients with LOXL2-positive stromal cells was significantly poorer than those with LOXL2-negative stromal cells. Multivariable logistic regression analysis revealed that LOXL2 expression in stromal cells was an independent predictive parameter for the overall survival of patients with gastric cancer. Conclusion: LOXL2 from CAF may stimulate the motility of gastric cancer cells. LOXL2 expression in stromal cells may be a useful prognostic factor for patients with gastric cancer. Citation Format: Hiroaki Kasashima, Masakazu Yashiro, Kisyu Kitayama, Go Masuda, Haruhito Kinoshita, Katsunobu Sakurai, Takahiro Toyokawa, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. Lysyl oxidase-like 2 (LOXL2) from cancer-associated fibroblasts stimulates the progression of gastric carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5063. doi:10.1158/1538-7445.AM2015-5063
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