Abstract 4054: Significance of CXCR4/SDF-1 axis expression in gastric cancer under hypoxic enviroment.
Authors: Kinoshita Haruhito , Yashiro Masakazu , Morisaki Tamami , Fukuoka Tatsunari , Hasegawa Tsuyoshi , Hirakawa Toshiki , Aomatsu Naoki , Sakurai Katsunobu , Kimura Kenjiro , Nagahara Hisashi , Toyokawa Takahiro , Amano Ryosuke , Noda Eiji , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Otani Hiroshi , Maeda Kiyoshi , Ohira Masaichi , Hirakawa Kosei 
Published: August 2014

Background: Various types of solid tumors, including gastric cancer, have a heterogeneously hypoxic environment which has been currently considered to be associated with aggressive tumor phenotypes cancer. Stromal cell-derived factor (SDF)-1 and C-X-C chemokine receptor type 4 (CXCR-4) form an important chemokine/receptor pair, and are supposed to be up-regulated by hypoxia inducible factor-1 (HIF-1). Although the chemokine signaling is associated with malignant potential of various carcinomas, few studies have addressed the expression and function of CXCR4 and SDF-1 under hypoxia in gastric cancer. The aim of our study was to clarify the significance of CXCR4 and SDF-1 under hypoxia in gastric carcinoma by evaluating the expression of a hypoxic marker, a carbonic anhydrase 9 (CA-9).

Experimental Design: A total of 297 patients who had undergone a resection of the primary tumor and were confirmed histologically to have sporadic gastric cancer were enrolled in this study. Expressions of CXCR4, SDF-1, and CA-9, were assessed by immunohistochemistry. We examined the association between the expression levels of CXCR4, SDF-1, and CA-9 and clinicopathologic variables of patients with gastric cancers. Furthermore, using three diffuse-type gastric cancer cell lines, OCUM-2M, OCUM-2MD3, and OCUM-12, expression level of CXCR4 and SDF-1 in hypoxia (1% O2) were examined by RT-PCR.

Results: CA-9 expression was found in 48% (143/297) of gastric cancers, CXCR4 was 47% (141/297), and SDF-1 was 41% (122/297). The CA9 expression was significantly correlated with CXCR4 expression and SDF-1. The CA9 expression level was significantly high in cases diffuse-type carcinoma (p=0.028). The prognosis for CA-9-positive patients was significantly poorer than that of CA-9-negative patients (p&lt;0.001,log-rank). The CXCR4 expression level was significantly correlated with lymph node metastasis (p&lt;0.001), and with higher stages (p&lt;0.001). The SDF-1 expression level was significantly higher with lymph node metastasis(p&lt;0.001), and with higher stages (p&lt;0.001). The prognosis for CXCR4-positive patients was significantly poorer than that of CXCR4-negative patients (p&lt;0.001, log-rank). The prognosis for SDF-1-positive patients was significantly poorer than that of SDF-1-negative patients (p=0.008, log-rank). The expression level of CXCR4 mRNA was significantly increased by hypoxia, in comparison with that in normoxia in all of gastric cancer cells.

Conclusion: CXCR4/SDF-1 expression of gastric cancer cells might be regulated with by hypoxic condition. CXCR4/SDF-1 axis might play an important role for the progression of diffuse-type gastric carcinoma with hypoxic environment.

Citation Format: Haruhito Kinoshita, Masakazu Yashiro, Tamami Morisaki, Tatsunari Fukuoka, Tsuyoshi Hasegawa, Toshiki Hirakawa, Naoki Aomatsu, Katsunobu Sakurai, Kenjiro Kimura, Hisashi Nagahara, Takahiro Toyokawa, Ryosuke Amano, Eiji Noda, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Hiroshi Otani, Kiyoshi Maeda, Masaichi Ohira, Kosei Hirakawa. Significance of CXCR4/SDF-1 axis expression in gastric cancer under hypoxic enviroment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4054. doi:10.1158/1538-7445.AM2013-4054