Targeting the Stat6 pathway in tumor‐associated macrophages reduces tumor growth and metastatic niche formation in breast cancer

The FASEB JournalVolume 32, Issue 2 p. 969-978 ResearchFree to Read Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer Karin Binnemars-Postma, Karin Binnemars-Postma Targeted Therapeutics, Biomaterials Science and Technology, Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, Enschede, The NetherlandsSearch for more papers by this authorRuchi Bansal, Ruchi Bansal Targeted Therapeutics, Biomaterials Science and Technology, Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, Enschede, The NetherlandsSearch for more papers by this authorGert Storm, Gert Storm Department of Pharmaceutics, Utrecht University, Utrecht, The NetherlandsSearch for more papers by this authorJai Prakash, Corresponding Author Jai Prakash j.prakash@utwente.nl Targeted Therapeutics, Biomaterials Science and Technology, Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, Enschede, The NetherlandsCorrespondence: University of Twente, Drienerlolaan 5, 7522 NB Enschede, The Netherlands. E-mail: j.prakash@utwente.nlSearch for more papers by this author Karin Binnemars-Postma, Karin Binnemars-Postma Targeted Therapeutics, Biomaterials Science and Technology, Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, Enschede, The NetherlandsSearch for more papers by this authorRuchi Bansal, Ruchi Bansal Targeted Therapeutics, Biomaterials Science and Technology, Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, Enschede, The NetherlandsSearch for more papers by this authorGert Storm, Gert Storm Department of Pharmaceutics, Utrecht University, Utrecht, The NetherlandsSearch for more papers by this authorJai Prakash, Corresponding Author Jai Prakash j.prakash@utwente.nl Targeted Therapeutics, Biomaterials Science and Technology, Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, Enschede, The NetherlandsCorrespondence: University of Twente, Drienerlolaan 5, 7522 NB Enschede, The Netherlands. E-mail: j.prakash@utwente.nlSearch for more papers by this author First published: 03 January 2018 https://doi.org/10.1096/fj.201700629RCitations: 40Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Tumor-associated macrophages (TAMs) are the key effector cells in the tumor microenvironment and induce neoangiogenesis, matrix remodeling, and metastasis while suppressing the tumor immune system. These protumoral macrophages display an M2 phenotype induced by IL-4 and IL-13 cytokines. In this study, we hypothesized that the inhibition of the signal transducer and activator of transcription 6 (Stat6) pathway, a common downstream signaling pathway of IL-4 and IL-13, may be an interesting strategy by which to inhibit TAM differentiation and, thus, their protumorigenic activities. In vitro inhibition of the Stat6 pathway by using small interfering RNA or the pharmacologic inhibitor, AS1517499, inhibited the differentiation of mouse RAW264.7 macrophages into the M2 phenotype, as demonstrated by the reduction of Arg-1 (arginase-1) and Mrc-1 (mannose receptor 1) expression and arginase activity. In vivo, AS1517499 significantly attenuated tumor growth and early liver metastasis in an orthotopic 4T1 mammary carcinoma mouse model. Furthermore, in another experiment, we observed an increase in the intrahepatic mRNA expression of F4/80 (EGF-like module-containing mucin-like hormone receptor-like 1; total macrophages) and M2 macrophage markers [Ym-1 (chitinase 3–like protein 3) and Mrc-1] and metastatic niche markers [Mmp-2 (matrix metalloproteinase-2), Postn (periostin), and Cd34] in mice with increasing growth of primary tumors. Of interest, these markers were found to be reduced after treatment with AS1517499. In summary, inhibition of the Stat6 pathway in TAMs is a vital therapeutic approach to attenuate tumor growth and metastasis by inhibiting TAM-induced protumorigenic and prometastatic activities.—Binnemars-Postma, K., Bansal, R., Storm, G., Prakash, J. Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. FASEB J. 32, 969–978 (2018). www.fasebj.org Citing Literature Supporting Information Filename Description fsb2fj201700629r-sup-0001.pdfPDF document, 16.9 MB supplementary material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume32, Issue2February 2018Pages 969-978 RelatedInformation