Soluble IL-33 receptor sST2 inhibits colorectal cancer malignant growth by modifying the tumour microenvironment.

Miho Akimoto,Takahiro Ochiya,Hiroyuki Takamaru,Riruke Maruyama,Keizo Takenaga

doi:10.1038/ncomms13589

Abstract

Interleukin-33 (IL-33) was recently shown to be involved in the inflammatory tumour microenvironment and the progression of colorectal cancer (CRC). We report here that the expression level of sST2, a soluble form of the IL-33 receptor (ST2L), is inversely associated with the malignant growth of CRC. sST2 is downregulated in high-metastatic cells compared with low-metastatic human and mouse CRC cells. Knockdown of sST2 in low-metastatic cells enhances tumour growth, metastasis and tumour angiogenesis, whereas its overexpression in high-metastatic cells suppresses these processes. Circulating and intratumourally administered sST2-Fc fusion protein reduce tumour growth, metastatic spread and tumour angiogenesis in mice bearing high-metastatic CRC. Mechanistically, sST2 suppresses IL-33-induced angiogenesis, Th1- and Th2-responses, macrophage infiltration and macrophage M2a polarization. In conclusion, we show that sST2 negatively regulates tumour growth and the metastatic spread of CRC through modification of the tumour microenvironment. Thus, the IL-33/ST2L axis may be a potential therapeutic target in CRC.

Highlights

Interleukin-33 (IL-33) was recently shown to be involved in the inflammatory tumour microenvironment and the progression of colorectal cancer (CRC)
Based on the observations that IL-33 exhibited a pro-angiogenic effect in human umbilical vein endothelial cells (HUVECs) via Akt signalling[29] and that sST2 expression in human and mouse CRC cells resulted in decreased tumour vessel density (Figs 1–4), we investigated the involvement of sST2 in the inhibition of IL-33-mediated angiogenic responses of HUVECs
The present results show that mouse CRC tissues contain much higher levels of IL-33 than normal tissues, such as the colon

Summary

Results

The results showed that NM11-shsST2 and LuM1-VC tumours grew more rapidly, metastasized to the liver more efficiently and had a greater number of tumour vessels than NM11-shCont and LuM1-sST2 tumours (Fig. 3l–n) Together, these data provide evidence that sST2 can inhibit the malignant growth of CRC cells in vivo. Based on the observations that IL-33 exhibited a pro-angiogenic effect in human umbilical vein endothelial cells (HUVECs) via Akt signalling[29] and that sST2 expression in human and mouse CRC cells resulted in decreased tumour vessel density (Figs 1–4), we investigated the involvement of sST2 in the inhibition of IL-33-mediated angiogenic responses of HUVECs. The expression of ST2L and IL-1RAP was confirmed in HUVECs at the mRNA and protein levels (Supplementary Fig. 7), which was consistent with a previous report[30].

D NM11-shsST2

Discussion

Methods