Abstract 199: Clinicopathological significance of stromal enzymes lysyl oxidase like 1, 3, and 4 in gastric cancer
Authors: Hiroaki Kasashima, Yasuhiro Fukui, Iguru Omori, Zizhou Wang, Shintaro Ozawa, Takemi Ishidate, Ken Yonemitsu, Yuki Seki, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Shigeru Lee, Masakazu Yashiro, Maeda Kiyoshi
Journal: Cancer Research (2025)

Abstract Background and Objective: The Lysyl oxidase (LOX) family comprises enzymes that physiologically participate in the cross-linking of extracellular matrix components such as collagen and elastin, thereby playing roles in cell differentiation and tissue formation. In the tumor microenvironment, LOX is known to contribute to the remodeling of the cancer stroma and to influence cancer cell metastasis and differentiation. Our previous studies have reported associations between LOX, LOX-like (LOXL)2, and prognosis in gastric cancer. In this study, we investigated the clinicopathological significance of LOXL1, 3, and 4 in gastric cancer through immunohistochemical staining. Methods: Immunohistochemical staining was performed to analyze the relationship between LOXL1, LOXL3, LOXL4 expression and the clinicopathological characteristics of 597 gastric cancer patients. Additionally, the influence of TGF-β on the expression of LOXL1, LOXL3, and LOXL4 was examined in vitro using diffuse-type gastric cancer cell lines (OCUM-2M, OCUM-12, KATO-III), gastric cancer lymph node metastatic cell lines (OCUM-2MLN), and gastric cancer peritoneal dissemination cell lines (OCUM-2MD3). Results: LOXL1, LOXL3, and LOXL4 expression was significantly associated with T-factor, lymph node metastasis, lymphatic invasion, and venous invasion. LOXL1 expression was more common in the intestinal-type histological subtype (p &amp;lt; 0.001). Gastric cancer patients positive for LOXL1, LOXL3, or LOXL4 had a lower overall survival rate compared to negative patients (p &amp;lt; 0.001 for each). In vitro analysis revealed that LOXL1 mRNA expression was significantly higher in gastric cancer cell lines compared to lymph node metastatic and peritoneal dissemination cell lines, while LOXL3 and LOXL4 were significantly more expressed in metastatic and peritoneal dissemination cell lines. Western blot analysis showed similar results. When TGF-β was added to the gastric cancer cell lines, LOXL1 expression decreased, while LOXL3 and LOXL4 expression increased. Discussion: The expression of LOXL1, LOXL3, and LOXL4 in gastric cancer is suggested to be associated with distant metastasis and poorer prognosis. TGF-β may influence the expression of LOXL1, LOXL3, and LOXL4 and potentially correlate with histological subtypes of gastric cancer. Citation Format: Hiroaki Kasashima, Yasuhiro Fukui, Iguru Omori, Zizhou Wang, Shintaro Ozawa, Takemi Ishidate, Ken Yonemitsu, Yuki Seki, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Shigeru Lee, Masakazu Yashiro, Kiyoshi Maeda. Clinicopathological significance of stromal enzymes lysyl oxidase like 1, 3, and 4 in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 199.