Abstract 436: SDF1α / CXCR4 axis might be associated with growth-interaction between cancer-associated fibroblasts and gastric cancer cells in hypoxic tumor microenvironment
Authors: Kinoshita Haruhito , Yashiro Masakazu , Kasashima Hiroaki , Masuda Go , Morisaki Tamami , Fukuoka Tatsunari , Sakurai Katsunobu , Toyokawa Takahiro , Kimura Kenjiro , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Ohira Masaichi , Hirakawa Kosei 
Published: August 2015

Background: Cancer-associated fibroblasts (CAF) have been suggested to be associated with the progression of gastric cancer cells. Hypoxic region was frequently found in cancer microenvironment of gastric cancer. The aim of our study was to clarify the interaction between CAF and gastric cancer cells under hypoxia. We found that hypoxia up-regulated the growth and interaction between the CAF and gastric cancer cells through SDF1α/CXCR4 dependent mechanism.

Materials and Methods: Six gastric cancer cell lines and three fibroblasts cell lines were used. The expression level of CXCR4 under hypoxia was examined by RT-PCR, Western blot. SDF1 production from CAF under hypoxia wad examined by ELISA. The proliferation of diffuse type gastric cancer cells that were co-culture with CAF was examined under hypoxia, in comparison with that under normoxia. Proliferation activity of diffuse type gasitrc cancer cells was examined in the presence of CAF, CXCR4 inhibitor, FGFR2 inhibitor, HIF1α siRNA or CXCR4 siRNA under hypoxia, in comparison with that under normoxia.

Results: The proliferation of diffuse type gastric cancer cells was significantly increased in the presence of CAF. The proliferation - stimulating effects by CAF were evident in hypoxia, in compared with normoxia. CXCR4 expression of diffuse type gastric cancer cells was significantly increased under hypoxia, but decreased FGFR2 expression under hypoxia. HIF1α siRNA significantly down-regulated CXCR4 expression level in hypoxia. SDF1 from CAF was increased under hypoxia, and was also decreased by HIF1α knockdown. FGFR2 inhibitor significantly decreased he proliferation-stimulating activity of CAF under normoxia, but not under hypoxia. Although, CXCR4 inhibitor significantly decreased the proliferation-stimulating activity of CAF under hypoxia, but not under normoxia. These findings suggested that the key signaling associated with the growth-interaction between CAF and gastric cancer cells in hypoxic condition might be different from those in normoxic condition.

Conclusion: Hypoxic microenvironment switch the driver signaling from FGF7/FGFR2 to SDF-1/CXCR4 in diffuse type of gastric cancer. CXCR4/SDF1 axis might play an important role for the proliferation of gastric cancer in hypoxic tumor microenvironment.

Citation Format: Haruhito Kinoshita, Masakazu Yashiro, Hiroaki Kasashima, Go Masuda, Tamami Morisaki, Tatsunari Fukuoka, Katsunobu Sakurai, Takahiro Toyokawa, Kenjiro Kimura, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. SDF1α / CXCR4 axis might be associated with growth-interaction between cancer-associated fibroblasts and gastric cancer cells in hypoxic tumor microenvironment. [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 436. doi:10.1158/1538-7445.AM2015-436