Background: Recurrences often happen in patients with intrahepatic cholangiocarcinoma (ICC) after radical hepatectomies. In addition, ICC has a poor sensitivity for chemotherapy. Most of the recurrence in ICC is liver metastasis, and how to control liver metastasis should be important to improve patients' prognosis.

Purpose and Methods: Samples of ICC (primary and metastatic lesions) were collected as a multicenter study of the Kyushu Liver Surgery Study Group. cDNA microarray was performed using five frozen samples of ICC primary and metastatic sites; primary A - liver metastasis A1, re-liver metastasis A2, and primary B - liver metastasis B. Protein expression of the five high or low expression genes was evaluated by immunohistochemical staining using 25 primary ICC and 33 metastatic lesions; 22 cases of liver, 7 cases of lymph node, 2 cases of lung, 1 case of bone, and 1 case of adrenal gland. In in vitro experiments, ICC cell lines of the epithelial type (HuCCT-1, RBE) and the spindle type (SSP-25, HuH-28) were used.

Results: Using cDNA microarray, genes of high expression (KRT83, CXCL12) and low expression (REG3G, OLFM4) were extracted in the metastatic site as compared with the primary tumor, evaluated by the sum of three pairs: primary A - liver metastasis A1, primary A - liver metastasis A2, and primary B - liver metastasis B. In addition, as a result of analyzing the results of the cDNA microarray with gene set enrichment analysis (GSEA), it was associated with a gene group related to the cell cycle, and CD168 was identified to be strongly correlated among them. In immunohistochemical staining, CXCL12 was significantly increased in liver metastasis compared to primary tumor (p = 0.0329), but there was no significant difference in the other 4 genes. Furthermore, in immunohistochemical staining, CXCR7, a receptor for CXCL12, was significantly increased in liver metastatic sites (p=0.0011). Next, in vitro experiments showed that gene expression of CXCL12 -CXCR4/CXCR7 differed depending on morphology: high in the spindle type cells (SSP25, HuH28) and low in the epithelial type cells (HuCCT-1, RBE). There was no significant difference in proliferative capacity between the two types of morphology, but the invasive ability was significantly higher in the spindle-shaped cell lines (p <0.05). By suppressing CXCL12, invasive ability was suppressed in both SSP-25 and HuH28 cells.

Conclusions: CXCL12 may be involved in hepatic metastasis of ICC with organ specificity. Currently, the possibility of therapeutic application against CXCL12 in vivo is under consideration.

Citation Format: Tatsunori Miyata, Yo-ichi Yamashita, Tomoharu Yoshizumi, Masayuki Shiraishi, Masayuki Ota, Susumu Eguchi, Shinichi Aishima, Hideo Baba, Hikaru Fujioka. Cxcl12 is involved in liver metastasis of intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1069.