The expression and biological role of IL-33 in colon cancer is poorly understood. In this study, we show that IL-33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL-33 and overexpression of murine IL-33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL-33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL-33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N-terminal kinase activation (JNK), and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL-33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL-33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL-33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promotes carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL-33 signaling pathway may offer an opportunity to treat patients with metastatic cancer.
- Received June 14, 2016.
- Revision received January 7, 2017.
- Accepted February 22, 2017.
- Copyright ©2017, American Association for Cancer Research.