Abstract 5113: CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts enhances the chemoresistance in gastric cancer

Abstract

Abstract Purpose: Gastric cancer (GC) is an aggressive cancer metastasizing with a high propensity for peritoneal dissemination and liver metastasis. Some studies have been shown that not only cancer cells but also their surrounding stroma, especially cancer-associated fibroblasts (CAFs) play an important role in tumor development. Previously, we reported that CXCL12-CXCR4 and integrin β1 signal activation by CAFs co-operates for promoting FAK phosphorylation and enhances the invasiveness of GC cells in extracellular matrix (ECM).On the other hand, a previous study presented that CXCR4 and integrin signaling co-operates in mediating adhesion and chemoresistance in small cell lung cancer cells. Therefore, we hypothesized that CXCL12-CXCR4 and integrin signal activation by CAFs enhances the chemoresistance in GC as well. The aim of current study is to elucidate the significance of CAFs mediating signal activation for chemoresistance in GCs. Experimental Design: We first performed chemo-sensitive assays using GC cells cultured with fresh medium or with CAF-conditioned-medium (CM), and these experiments were conducted on non-coated and Matrigel-coated plates. Next, we examined the CXCL12-CXCR4 and integrin related signaling by western blotting analysis. Furthermore, we investigated the critical molecule for chemoresistance using silencing CXCR4 or integrin β1 in GC cells. Results: Chemo-sensitive assays revealed that GC cells cultured with CAF-CM showed more resistant to cisplatin and reactive oxygen spices (ROS) than those cultured with fresh medium. Moreover, GC cells with CAF-CM on Matrigel-coated plates exhibited remarkable resistance in these assays. On the other hand, western blotting analysis showed that Akt activity in GC cells cultured with CAF-CM was up-regulated in concurrence with FAK phosphorylation. Finally, the chemoresitance induced by CAFs was significantly suppressed by CXCR4 or integrin β1 silencing. Conclusions: These results suggest that CXCL12/CXCR4 and integrinβ1 signal activation by CAFs promoted the chemoresistance through enhancing their interaction with ECM in GC. This mechanism underlying the chemoresistance may provide a novel therapeutic target in advanced GCs. Citation Format: Yuka Tamaoki, Takatsugu Ishimoto, Keisuke Miyake, Daisuke Izumi, Daisuke Kuroda, Tsugio Eto, Kota Arima, Hironobu Shigaki, Junji Kurashige, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts enhances the chemoresistance in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5113.