Downregulation of sST2, a decoy receptor for interleukin-33, enhances subcutaneous tumor growth in murine pancreatic cancer cells.

Abstract

Despite the recent scientific advancements, pancreatic cancer remains the seventh leading cause of cancer-related mortality. Pancreatic cancer progression is closely associated with inflammation, and we previously showed that short hairpin RNA-mediated knockdown of sST2 expression, a soluble decoy receptor for the proinflammatory molecule interleukin-33 (IL-33), in mouse Panc02 pancreatic cancer cells reduced malignant growth following pancreatic (orthotopic) implantation. Furthermore, this growth suppression was accompanied by decreased tumor angiogenesis, reduced expression of the neutrophil chemoattractant CXCL3, and a lower number of tumor-associated neutrophils (TANs). In contrast to previous results, in this study, we showed that IL-33-dependent tumor growth and pulmonary metastasis occurred following subcutaneous (ectopic) implantation of sST2-knockdown cells. This was associated with a decrease in the levels of the anti-inflammatory molecule adiponectin and the number of GLUT4-positive cancer-associated adipocytes, as well as an increase in IκBα phosphorylation levels, Cxcl3 expression, and the accumulation of infiltrating CD206⁺ protumor N2 TANs. Taken together, these results suggest that Panc02 cell-derived sST2 differentially affects malignant growth in the tumor microenvironment depending on the implantation site.