Endostatin gene therapy inhibits intratumoral macrophage M2 polarization

Endostatin gene therapy inhibits intratumoral macrophage M2 polarization

Author Foguer, Karen Autor UNIFESP Google Scholar
Braga, Marina de Souza Autor UNIFESP Google Scholar
Schatzmann Peron, Jean Pierre Google Scholar
Bortoluci, Karina Ramalho Autor UNIFESP Google Scholar
Bellini, Maria Helena Autor UNIFESP Google Scholar
Abstract Background: Renal cell carcinoma (RCC) is a highly vascularized cancer resistant to chemotherapy and radiotherapy. RCC is frequently infiltrated with immune cells, with macrophages being the most abundant cell type. Alternatively activated M2 macrophages are known to contribute to tumor progression. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we investigated the impact of ES gene therapy on the polarization of tumor-associated macrophages (TAMs) in lung metastases from tumor-bearing mice. Methods: BALB/c mice divided into three groups: Normal, Control and ES-treated. Tumor-bearing mice were treated with ES-transduced cells or control cells over ten days. At the end of the study, plasma was collected, and pulmonary macrophages were isolated and used for FACS or RT-PCR. ELISA tests were used to analyze plasma and cell culture supernatant cytokines. Results: ES treatment significantly reduced the levels of anti-inflammatory and pro-angiogenic cytokines, including IL4, IL-10, IL-13 and VEGF. Gene expression of M2 markers, such as IL-10, Arg-1, VEGF and YM-1, declined significantly. Flow cytometry showed a reduction in the number of M2 F4/80 + CD36 + CD206 + CD209+ macrophages and in IL-10 secretion by these cells. Reduced levels of IL-10 were also found in the culture supernatants of the ES-treated group. Conclusions: Our research corroborates previous observations that ES has an important anti-tumoral role. However, aside from promoting interferon-g secretion and an effective T cell response, we show here that this switch is extended to TAMs, complicating the maintenance of pro-tumorigenic M2 macrophages and thus favoring tumor elimination. (C) 2016 Elsevier Masson SAS. All rights reserved.
Keywords Renal cell carcinoma
Endostatin
Tumor-associated macrophages
xmlui.dri2xhtml.METS-1.0.item-coverage Paris
Language English
Sponsor FAPESP
CNPq
CAPES/PNPD
Grant number FAPESP: 2011/18703-2
CNPq: 473102/2012-9
Date 2016
Published in Biomedicine & Pharmacotherapy. Paris, v. 79, p. 102-111, 2016.
ISSN 0753-3322 (Sherpa/Romeo, impact factor)
Publisher Elsevier France-Editions Scientifiques Medicales Elsevier
Extent 102-111
Origin http://dx.doi.org/10.1016/j.biopha.2016.01.035
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000373527100014
URI https://repositorio.unifesp.br/handle/11600/56147

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