Abstract 185: Cancer associated fibroblasts stimulates cancer cell invasion through CXCL12-CXCR4 signaling in gastric cancer

Abstract

Abstract Objectives: Gastric cancer is one of the most threatening malignancies with a high incidence and metastasis rate. Many patients are diagnosed in an advanced stage sometimes with multi-organ metastasis, which leads a poor prognosis of gastric tumors. Chemokine and their receptors have been originally demonstrated as essential mediators of leukocyte directional migration, particularly during infection and inflammation, and have further emerged as crucial players in all stages of tumor development. It has been reported that an important CXCL12-CXCR4 signaling is involved in tumor development and metastasis in several types of cancer including gastric cancer. Cancer associated fibroblasts (CAF) are reported to communicate microenvironment-derived signals through chemokine/chemokine receptor interaction such as CXCL12-CXCR4 signaling. The aim of our study was to evaluate the role of CXCL12-CXCR4 signaling in crosstalk between gastric cancer and CAF. Methods and Results: We evaluated CXCL12 and CXCR4 expression status by immunohistochemistry using a nonbiased database of 89 curatively resected gastric cancers. As a result, CXCL12/ CXCR4 expression are significant correlation with metastasis. Furthermore, we performed Western blotting analysis for CXCL12 and CXCR4 in human gastric cancer cell lines. CXCR4 expression was detectable in all gastric cancer cell lines. We isolated CAF from human gastric cancer tissue resected in our institute. We performed Western blotting analysis for alpha-SMA and CXCL12 in CAF, and confirmed higher expression in CAF than normal fibroblast (NF) isolated from normal gastric mucosa of same patients. Then we established stable AGS gastric cancer cell line expressing GFP. Invasion assay revealed that AGS (gastric cancer cell line) cells with CAF showed more invasive phenotype than that without CAF. We also found the motility of GFP-expressing AGS was elevated during direct co-culture of GFP-expressing AGS cells and CAF compared with NF. Conclusions: These findings revealed that cancer associated fibroblasts were implicated in cancer cell invasion and metastasis through CXCL12-CXCR4 signaling in gastric cancer. The therapeutic blockade of this pathway with CXCR4 antagonist might abrogate gastric cancer cell invasion and metastasis. Citation Format: Daisuke Izumi, Takatsugu Ishimoto, Hietaka Sugihara, Hiroshi Sawayama, Ryuichi Karashima, Satoshi Ida, Yu Imamura, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Cancer associated fibroblasts stimulates cancer cell invasion through CXCL12-CXCR4 signaling in gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 185. doi:10.1158/1538-7445.AM2014-185