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Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis

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Abstract

Tumor-associated stroma is typified by a persistent, non-resolving inflammatory response that enhances tumor angiogenesis, growth and metastasis. Inflammation in tumors is instigated by heterotypic interactions between malignant tumor cells, vascular endothelium, fibroblasts, immune and inflammatory cells. We found that tumor-associated adipocytes also contribute to inflammation. We have analyzed peritumoral adipose tissue in a syngeneic mouse melanoma model. Compared to control adipose tissue, adipose tissue juxtaposed to implanted tumors exhibited reduced adipocyte size, extensive fibrosis, increased angiogenesis and a dense macrophage infiltrate. A mouse cytokine protein array revealed up-regulation of inflammatory mediators including IL-6, CXCL1, MCP-1, MIP-2 and TIMP-1 in peritumoral versus counterpart adipose tissues. CD11b+ macrophages contributed strongly to the inflammatory activity. These macrophages were isolated from peritumoral adipose tissue and found to over-express ARG1, NOS2, CD301, CD163, MCP-1 and VEGF, which are indicative of both M1 and M2 polarization. Tumors implanted at a site distant from subcutaneous, anterior adipose tissue were strongly growth-delayed, had fewer blood vessels and were less populated by CD11b+ macrophages. In contrast to normal adipose tissue, micro-dissected peritumoral adipose tissue explants launched numerous vascular sprouts when cultured in an ex vivo model. Thus, inflamed tumor-associated adipose tissue fuels the growth of malignant cells by acting as a proximate source for vascular endothelium and activated pro-inflammatory cells, in particular macrophages.

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Acknowledgments

ACD is supported by a K99/ROO award (CA140708) from the National Cancer Institute and National Institutes of Health.

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Authors and Affiliations

  1. Department of Biomedicine, University of Bergen, Bergen, Norway

    Marek Wagner, Rolf Bjerkvig & Helge Wiig

  2. Centre de Recherché Public de la Santé, Luxembourg, Luxembourg

    Rolf Bjerkvig

  3. Department of Cardiac Surgery, Children’s Hospital Boston and Harvard Medical School, Boston, MA, USA

    Juan M. Melero-Martin & Ruei-Zeng Lin

  4. Vascular Biology Program, Children’s Hospital Boston and Harvard Medical School, Boston, MA, USA

    Michael Klagsbrun

  5. Department of Surgery, Children’s Hospital Boston and Harvard Medical School, Boston, MA, USA

    Michael Klagsbrun

  6. Department of Cell and Molecular Physiology, Lineberger Comprehensive Cancer Center and McAllister Heart Institute, University of North Carolina at Chapel Hill, 8340 Medical Biomolecular Research Bldg., Chapel Hill, NC, 27599, USA

    Andrew C. Dudley

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  1. Marek Wagner
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Correspondence to Andrew C. Dudley.

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Wagner, M., Bjerkvig, R., Wiig, H. et al. Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis. Angiogenesis 15, 481–495 (2012). https://doi.org/10.1007/s10456-012-9276-y

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  • DOI: https://doi.org/10.1007/s10456-012-9276-y

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