Abstract 424: Chemokine CXCL14 is a multistep tumor suppressor

PURPOSE: The multistep nature of tumor formation has been well established and each step depends on the mutation or abnormal regulation of various genes. In order to elucidate the in vivo function of CXCL14, we used CXCL14 transgenic (Tg) mice and investigated the effects of this chemokine at multiple stages during cancer development, in addition to the effects on the overall survival rate. Furthermore, we also sought to determine the role of CXCL14 in the action of natural killer (NK) and natural killer T (NKT) cells. EXPERIMENTAL PROCEDURES: Carcinogenic rate was determined in mice undergoing AOM/DSS-induced colorectal carcinogenesis. The growth rate of implanted tumor cells was determined by injecting Lewis lung carcinoma (LLC) cells or B16 melanoma cells subcutaneously into the dorsolateral region of Tg or isogenic wild type C57BL/6 (Wt) mice. Tumor cells were also injected intravenously via a tail vein into Wt, T-cell and B-cell deficient SCID mice or T-cell, B-cell and NK cell-deficient NOG mice to investigate colonization to the lungs. Tg or Wt mice were also pre-injected with NK cell function inhibitory anti-asialo GM1 antibodies to see the role of NK cells in CXCL14-dependent tumor suppression in vivo. Melanoma cells that had been engineered to express the CXCL14 gene under the control of doxycycline (B16-LMT3-Tet/OnBRAK) were also used. RESULTS: The rate of AOM/DSS-induced colorectal carcinogenesis in these mice was significantly lower compared with that in Wt mice. When tumor cells were injected into these mice, the size of the tumors that developed and the number of metastatic nodules in the lungs of the animals were always significantly lower in the Tg mice than in the Wt ones. Injection of anti-asialo-GM1 antibodies to the mice before and after injection of tumor cells attenuated the suppressing effects of CXCL14 on the tumor growth and metastasis, suggesting that NK cell activity plays an important role during CXCL14-mediated suppression of tumor growth and metastasis. The importance of NK cells on the metastasis was also supported when CXCL14 was expressed on the B16-LMT3-Tet/OnBRAK melanoma cells. The injection of alpha-galactosylceramide, an activator of NKT cells appeared to decrease the degree of melanoma cell metastasis in both the Wt and Tg mice, but the effect was much stronger in the Tg mice than in the Wt mice, indicating that the presence of both CXCL14 and alpha-galactosylceramide resulted in a synergistic effect and even greater tumor suppression. Finally, the survival rates after tumor cell injection were significantly increased for the Tg mice. CONCLUSION: High expression of the CXCL14 gene either in host cells, or tumor cells resulted in suppression of growth and metastasis of tumor cells. As these Tg mice showed no obvious signs of abnormality, we propose CXCL14 to be a promising molecular target for cancer suppression/prevention. Citation Format: Ryu-Ichiro Hata, Kazuhito Izukuri, Yasumasa Kato, Soichiro Sasaki, Chihiro Miyamoto, Tetsu Akasaka, Xiaoyan Yang, Yojiro Maehata, Yoji Nagashima, Kazuyoshi Takeda, Tohru Kiyono, Naofumi Mukaida, Masaru Taniguchi. Chemokine CXCL14 is a multistep tumor suppressor. [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 424. doi:10.1158/1538-7445.AM2015-424