The contributions of interleukin (IL)-17 to cancer remain unclear and somewhat controversial. We took a genetic approach to explore its role in prostate cancers by interbreeding IL-17 receptor C (IL-17RC)-deficient mice with mice that are conditionally mutant for PTEN, one established preclinical model for prostate cancer. Mice that were IL-17RC-deficient (IL-17RC À ) displayed prostates that were smaller than mice that. In addition, IL-17RC À mice developed a reduced number of invasive prostate adenocarcinomas with lower rates of cellular proliferation and higher apoptosis than IL-17RC þ mice. Moreover, the fibromuscular stroma surrounding prostatic glands was relatively thicker in IL-17RC À mice and was associated with decreased matrix metalloproteinase (Mmp)7 expression and increased Timp1, 2, and 4 expression, whereas administration of recombinant mouse IL-17 induced prostatic expression of Mmp7. Taken together, our results suggested that IL-17 promotes the formation and growth of prostate adenocarcinoma, and that an IL-17-MMP7 signaling axis is required for the transition of prostatic intraepithelial neoplasia to frank adenocarcinoma. Cancer Res; 72(10); 2589-99. Ó2012 AACR.

Introduction Tumor-associated macrophages (TAMs) are divided into M1 and M2 macrophages. M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth and metastasis. The aim of this study was to study the possible causes leading to formation of an M2 macrophage-dominant tumor microenvironment in non-small cell lung cancer. Methods Forty-eight archived lung tumor samples were examined for expression of interleukin-17 (IL-17) receptors IL-17RA and IL-17RC and the number of TAMs using immunohistochemical staining. Twenty fresh lung tumors and matched normal lung tissues were examined for expression of IL-17, cyclooxygenase-2, and prostaglandin E2, using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Macrophage migration assays were performed using fresh lung tumor tissues and IL-17 as chemoattractants. Induction of M2 macrophage differentiation was analyzed using real-time quantitative polymerase chain reaction. Results TAMs expressed IL-17RA and IL-17RC. Lung tumors expressed higher levels of IL-17, cyclooxygenase-2, and prostaglandin E2, compared to normal lung tissues. Lung tumor tissues attracted migration of mouse RAW264.7 macrophages and primary peritoneal macrophages through IL-17, which was mediated by IL-17RA and IL-17RC. IL-17 did not induce either M1 or M2 macrophage differentiation. However, human lung cancer A549 cells strongly induced M2 macrophage differentiation of RAW264.7 macrophages when the two cell lines were co-cultured. The inductive factor secreted by A549 cells was identified to be prostaglandin E2. Conclusions IL-17 recruits macrophages and prostaglandin E2 induces M2 macrophage differentiation, hence the increased levels of IL-17 and prostaglandin E2 in lung cancer contribute to formation of an M2 macrophage-dominant tumor microenvironment.