IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis

Abstract

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b+ GR1+ and CD11b+F4/80+ myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target.

Interleukin‐33‐nuclear factor‐κB‐CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by directing regulatory T cells

“…Interleukin‐33 could recruit IL‐1R‐associated kinase 1 and 4 to the receptor complex in cytoplasmic region of ST2 by binding to the IL‐33 receptor, which triggers numerous signaling downstream, including NF‐κB, that might lead to inflammation . Activated NF‐κB enhances the expression of various proteins that could promote metastasis . In our results, after knockdown of IL‐33, the level of CCL2 was decreased when the NF‐κB pathway was inhibited.…”

“…It was reported that IL‐33 could be secreted by necrotic epithelial cells, and then bind to its cognate ST2 receptor, thus activating mitogen‐related protein kinase and NF‐κB . Results from previous studies indicated that IL‐33 has a proinflammatory function and is considered as a “danger” signal .…”

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

“…Similarly, IL33 transcript levels were found to be higher in stage I–III CRC compared to adjacent normal colonic tissue. However, IL33 expression was lower in stage IV CRC than in stage I–III intestinal tumors (84). In contrast, another study reports progressively increasing levels of IL33 and IL1RL1 transcript from low to high grade and stage of human CRC (85).…”

“…Experiments using bone marrow (BM) chimeric mice indicated that IL-33/ST2 signaling was engaged on both the radio-resistant and the radio-sensitive compartment (83). In a different model of CRC, syngeneic MC-38 colon carcinoma cells injected into the cecum of recipient mice showed enhanced growth and liver metastasis when overexpressing IL-33 (84). …”

“…IL-33 also stimulates the secretion of S100A8/9 (a DAMP) and VEGF from these cell populations to support tumor angiogenesis and metastasis (84). …”