Increased canonical NF-kappaB signaling specifically in macrophages is sufficient to limit tumor progression in syngenei
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RESEARCH ARTICLE
Open Access
Increased canonical NF-kappaB signaling specifically in macrophages is sufficient to limit tumor progression in syngeneic murine models of ovarian cancer Alyssa A. Hoover1†, Demetra H. Hufnagel2†, Whitney Harris1, Kennady Bullock1, Evan B. Glass3, Esther Liu1, Whitney Barham1, Marta A. Crispens4,5, Dineo Khabele6, Todd D. Giorgio3,5, Andrew J. Wilson4,5 and Fiona E. Yull1,4,5*
Abstract Background: New treatment options for ovarian cancer are urgently required. Tumor-associated macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic goal. We have previously shown that upregulated NF-kappaB (NF-κB) signaling in macrophages promotes M1 polarization, but effects in the context of ovarian cancer are unknown. Therefore, we aimed to investigate the therapeutic potential of increasing macrophage NF-κB activity in immunocompetent mouse models of ovarian cancer. Methods: We have generated a transgenic mouse model, termed IKFM, which allows doxycycline-inducible overexpression of a constitutively active form of IKK2 (cIKK2) specifically within macrophages. The IKFM model was used to evaluate effects of increasing macrophage NF-κB activity in syngeneic murine TBR5 and ID8-Luc models of ovarian cancer in two temporal windows: 1) in established tumors, and 2) during tumor implantation and early tumor growth. Tumor weight, ascites volume, ascites supernatant and cells, and solid tumor were collected at sacrifice. Populations of macrophages and T cells within solid tumor and/or ascites were analyzed by immunofluorescent staining and qPCR, and soluble factors in ascitic fluid were analyzed by ELISA. Comparisons of control versus IKFM groups were performed by 2-tailed Mann-Whitney test, and a P-value < 0.05 was considered statistically significant. (Continued on next page)
* Correspondence: [email protected] † Alyssa A. Hoover and Demetra H. Hufnagel contributed equally to this work. 1 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA 4 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Vanderbilt University Medical Center, Nashville, TN, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
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