, Volume 15, Issue 3, pp 481–495 | Cite as

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

  • Marek Wagner
  • Rolf Bjerkvig
  • Helge Wiig
  • Juan M. Melero-Martin
  • Ruei-Zeng Lin
  • Michael Klagsbrun
  • Andrew C. DudleyEmail author
Original Paper


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.


Angiogenesis Adipose tissue Tumor-associated macrophage Fibrosis Tumor microenvironment Tumor stroma Inflammation 



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

Conflict of interest



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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Marek Wagner
    • 1
  • Rolf Bjerkvig
    • 1
    • 2
  • Helge Wiig
    • 1
  • Juan M. Melero-Martin
    • 3
  • Ruei-Zeng Lin
    • 3
  • Michael Klagsbrun
    • 4
    • 5
  • Andrew C. Dudley
    • 6
    Email author
  1. 1.Department of BiomedicineUniversity of BergenBergenNorway
  2. 2.Centre de Recherché Public de la SantéLuxembourgLuxembourg
  3. 3.Department of Cardiac SurgeryChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  4. 4.Vascular Biology ProgramChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  5. 5.Department of SurgeryChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  6. 6.Department of Cell and Molecular Physiology, Lineberger Comprehensive Cancer Center and McAllister Heart InstituteUniversity of North Carolina at Chapel HillChapel HillUSA

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