Abstract 5903: Interaction with extracellular matrix enhance the chemoresistance via CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts in gastric cancers
Authors: Keisuke Miyake, Takatsugu Ishimoto, Daisuke Izumi, Kota Arima, Tsugio Eto, Daisuke Kuroda, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2017)

Abstract Purpose: Gastric cancers (GCs) 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 cancer environment, especially cancer-associated fibroblasts (CAFs) play an important role in tumor development. Previously, we reported that CXCL12-CXCR4 and integrin beta 1 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 GCs as well. The aim of current study is to elucidate the significance of cancer microenvironment with CAFs mediating signal activation for chemoresistance in GCs. Experimental Design: We first performed reactive oxygen spices (ROS)-sensitive assay and 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 beta 1 in GC cells. Results: ROS-sensitive assay and chemo-sensitive assays revealed that GC cells cultured with CAF-CM showed more resistant to ROS and cisplatin 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 beta 1 silencing. Conclusions: These results suggest that interaction with ECM is important for enhance chemoresitance mediated CXCL12/CXCR4 and integrin beta 1 signal activation by CAFs in GCs. This mechanism underlying the chemoresistance may provide a novel therapeutic target in advanced GCs. Citation Format: Keisuke Miyake, Takatsugu Ishimoto, Daisuke Izumi, Kota Arima, Tsugio Eto, Daisuke Kuroda, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. Interaction with extracellular matrix enhance the chemoresistance via CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts in gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5903. doi:10.1158/1538-7445.AM2017-5903