Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis
Open accessAbstract
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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Several cytokines produced by inflammatory cells, including TNF, IL-6, and IL-8, have angiogenic effects.
“Additionally, several cytokines produced by inflammatory cells have angiogenic effects, including TNF, IL-6, and IL-8 (57, 58).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [58]
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References 69 · Cited by 91
- Authors
- Wagner, M., Bjerkvig, R., Wiig, H., Melero-Martin, J. M., Lin, R.-Z., Klagsbrun, M., & Dudley, A. C.
- Affiliations
- University of Bergen (NO)
- Centre de Recherche Public de la Santé (LU)
- Boston Children's Hospital (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Dudley, Andrew C.
- Venue
- Angiogenesis
- Published
- 2012-05-22
- Volume
- 15
- Issue
- 3
- Pages
- 481-495
- ISSN
- 0969-6970 (ISSN-L)
- 1573-7209
- PMC
- PMC3619408
- OpenAlex
- W1989935936
- Cited by
- 91
- References
- 69
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 8 · 2019: 6 · 2018: 6 · 2017: 8 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 12
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Angiogenesis (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health
- National Cancer Institute (R00CA140708, K99CA140708, CA140708, R01CA177875)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- tumor-associated macrophages, tumor inflammation, tumor angiogenesis, tumor growth, peritumoral adipose tissue, macrophage polarization, vascular endothelial growth factor, MCP-1, interleukin-6, CD11b+ macrophages, melanoma, tumor microenvironment, vascular sprouting
- MeSH terms
- Adipose Tissue, Animals, Flow Cytometry, Fluorescent Antibody Technique, Immunohistochemistry, Inflammation, Macrophages, Male, Mice, Inbred C57BL, Neoplasms, Experimental, Neovascularization, Pathologic, Polymerase Chain Reaction, Culture Media, Conditioned, Mice
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