Abstract 407: FTY720 suppressed CT26 murine colon cancer peritoneal carcinomatosis progression by decreasing tumor associated macrophages and TNF-alpha

Abstract

Abstract Introduction: The median survival of colon cancer peritoneal carcinomatosis (PC), the dissemination of cancer cells throughout the abdominal cavity, is only 5-9 months, which is a reflection of lack of effective treatment. The tumor microenvironment of solid cancers is characterized by a reactive stroma with an abundance of inflammatory mediators. Tumor associated macrophages (TAM), one of major players in the connection between inflammation and cancer, control a number of functions of the tumor microenvironment. including development and progression of PC, since they produce TNF-alpha that promotes adhesion of cancer cells to the peritoneum. In advanced cancer, TNF-alpha increases the metabolic rate and reduces body weight, known as cachexia. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator that is produced by sphingosine kinase 1 (SphK1) plays important roles in cancer progression through S1P receptor-1 (S1PR1). The aim of this study was to elucidate the role of S1P signaling in TAMs and TNF-alpha production in murine colon cancer PC model using FTY720, a pro-drug that is converted in vivo to a functional antagonist of S1PR1 that disrupts S1P signaling. Methods: A murine colon cancer PC model was generated by IP injection of CT26-luc cells in immune intact BALB/c mice. FTY720 was given by gavage 1mg/kg oral daily. Mice were sacrificed 13 days after CT26-luc-cells injection. Expression of TNF-alpha, F4/80, CD86, and CD206 were determined by qPCR. TNF-alpha expression was determined by immunohistochemistry. Results: FTY720 completely suppressed the progression of CT26 PC, which is evaluated by the number and total weight of PC nodules, and it preserved body weight loss in the statement of cachexia. Also FTY720 significantly decreased F4/80 mRNA levels in the PC nodules. However there were no significant differences in the CD86/CD206 ratios in the tumors of the both FTY720 treated group and no treated group, which suggests that there are no changes in M1/M2 composition of the macrophage population. TNF-alpha mRNA in the tumors was also significantly decreased by FTY720 treated group and FTY720 significantly decreased expression of TNF-alpha. Conclusion: Our results suggest that FTY720 significantly decreased numbers of TAMs and production of TNF-alpha in PC tumors, which resulted in suppression of PC progression. Given its additional favorable effect against cachexia, FTY720 may provide better quality of life in advanced colon cancer PC patients. Citation Format: Tomoyoshi Aoyagi, Dorit Avini, Masayuki Nagahashi, Akimitsu Yamada, Krista P. Terracina, Wei-Ching Huang, Kazunori Aoki, Yasunori Matsumoto, Sarah Spiegel, Hisahiro Matsubara, Kazuaki Takabe. FTY720 suppressed CT26 murine colon cancer peritoneal carcinomatosis progression by decreasing tumor associated macrophages and TNF-alpha. [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 407. doi:10.1158/1538-7445.AM2015-407