The major cause of death from colorectal cancer (CRC) is liver metastasis and understanding its mechanisms is necessary for early diagnosis and development of new therapies. Interleukin-33 (IL-33) is an IL-1 cytokine that functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or early danger signal. Its role in invoking type 2 immune response is firmly established; however, its role in tumor development and metastasis in only beginning to be elucidated. We identified IL-33 as a potently upregulated cytokine in highly metastatic CRC cells and examined its role in tumor growth and metastasis to the liver. We expressed IL-33 in murine and human CRC cell lines and their growth and spontaneous metastasis to the liver was assessed in orthotopic models of CRC in wild type and IL33 knockout mice. The results suggest that tumor- rather than host- derived IL-33 promoted growth and metastasis by inducing expression of cytokines that stimulated mobilization of CD11b+ GR1+ and CD11b+F4/80+ myeloid cells to remodel the tumor microenvironment, and increase tumor angiogenesis, potentially by activating endothelial cells. Conversely, pro-tumorigenic cytokines derived from the microenvironment induced IL-33 expression in tumor cells to create a sustained pro-tumorigenic loop that promotes tumor growth and metastasis. Our findings underscore the potential of IL-33 as a novel and viable therapeutic target for CRC and liver metastasis.

Citation Format: Maria Marjorette O. Pena, Yu Zhang, Celestia Davis, James C. Ryan, Diego Altomare, Sapana Shah, Daniel Titus Hughes. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C21.