Cancer cell-derived interleukin-33 decoy receptor sST2 enhances orthotopic tumor growth in a murine pancreatic cancer model Keizo Takenaga Miho Akimoto Nobuko Koshikawa Hiroki Nagase 10.1371/journal.pone.0232230 https://plos.figshare.com/articles/dataset/Cancer_cell-derived_interleukin-33_decoy_receptor_sST2_enhances_orthotopic_tumor_growth_in_a_murine_pancreatic_cancer_model/12201560 <div><p>Background</p><p>Proinflammatory interleukin-33 (IL-33) binds to its receptor ST2L and is involved in inflammation and the malignant behavior of cancer cells. However, the role of IL-33-ST2L and the IL-33 decoy receptor sST2 in the tumor microenvironment of pancreatic cancer is unclear. Because we previously reported that sST2 derived from colon cancer cells profoundly influences malignant tumor growth, we hypothesized that sST2 released from pancreatic cancer cells also modulates IL-33-ST2L signaling in the tumor microenvironment, thereby influencing tumor growth.</p><p>Methods</p><p>ST2 (ST2L and sST2) expression in mouse pancreatic cancer Panc02 cells was downregulated by shRNAs. mRNA expression levels of IL-33, ST2, cytokines and chemokines in the cells and tumor tissues were examined using real-time PCR. sST2 secretion and the amount of CXCL3 in tumor tissues were measured using ELISA. Tumor growth was investigated after injection of the cells into the pancreas of C57BL/6 mice. MPO<sup>+</sup>, F4/80<sup>+</sup> and CD20<sup>+</sup> cells in tumor tissues were detected using immunohistochemistry.</p><p>Results</p><p>Some but not all human and mouse pancreatic cancer cell lines preferentially expressed sST2. Then, we investigated the role of sST2 in orthotopic tumor growth of sST2-expressing mouse pancreatic cancer Panc02 cells in immunocompetent mice. shRNA-mediated knockdown of sST2 expression in the cells suppressed orthotopic tumor growth, which was partially recovered by overexpression of shRNA-resistant sST2 mRNA but was not evident in IL-33 knockout mice. This was associated with decreases in <i>Cxcl3</i> expression, vessel density and accumulation of cancer-associated neutrophils but not cancer-associated macrophages. Administration of SB225002, an inhibitor of the CXCL3 receptor CXCR2, induced similar effects.</p><p>Conclusions</p><p>Cancer cell-derived sST2 enhances tumor growth through upregulation of CXCL3 via inhibition of IL-33-ST2L signaling in the tumor microenvironment of pancreatic cancer. These results suggest that the sST2 and the CXCL3-CXCR2 axis could be therapeutic targets.</p></div> 2020-04-27 17:29:56 modulates IL -33-ST mouse pancreatic cancer cell lines mouse pancreatic cancer Panc 02 cells receptor ST 2L pancreatic cancer cells Cxcl 3 expression colon cancer cells CXCL 3 mRNA expression levels CXCL 3-CXCR axis PCR pancreatic cancer sST 2-expressing mouse pancreatic cancer Panc 02 cells tumor microenvironment Conclusions Cancer cell-derived sST 2 Methods ST 2 cancer cell-derived interleukin -33 decoy receptor sST 2 IL -33 decoy receptor sST 2 orthotopic tumor growth sST 2 secretion MPO tumor growth shRNA-resistant sST 2 mRNA sST 2 sST 2 expression ELISA IL -33 knockout mice SB C 57BL mice murine pancreatic cancer model Background Proinflammatory interleukin -33 tumor tissues IL -33-ST