Angiogenesis

, 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. Dudley
Original Paper

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.

Keywords

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

Notes

Acknowledgments

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

Conflict of interest

None.

References

  1. 1.
    Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849PubMedCrossRefGoogle Scholar
  2. 2.
    Schafer M, Werner S (2008) Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 9:628–638PubMedCrossRefGoogle Scholar
  3. 3.
    Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217PubMedCrossRefGoogle Scholar
  4. 4.
    McAllister SS, Weinberg RA (2010) Tumor-host interactions: a far-reaching relationship. J Clin Oncol 28:4022–4028PubMedCrossRefGoogle Scholar
  5. 5.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555PubMedCrossRefGoogle Scholar
  6. 6.
    Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612PubMedCrossRefGoogle Scholar
  7. 7.
    Nucera S, Biziato D, De Palma M (2011) The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int J Dev Biol 55:495–503PubMedCrossRefGoogle Scholar
  8. 8.
    Murdoch C, Giannoudis A, Lewis CE (2004) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104:2224–2234PubMedCrossRefGoogle Scholar
  9. 9.
    Guleng B, Tateishi K, Ohta M, Kanai F, Jazag A, Ijichi H, Tanaka Y, Washida M, Morikane K, Fukushima Y, Yamori T, Tsuruo T, Kawabe T, Miyagishi M, Taira K, Sata M, Omata M (2005) Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res 65:5864–5871PubMedCrossRefGoogle Scholar
  10. 10.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631PubMedCrossRefGoogle Scholar
  11. 11.
    Murdoch C, Muthana M, Lewis CE (2005) Hypoxia regulates macrophage functions in inflammation. J Immunol 175:6257–6263PubMedGoogle Scholar
  12. 12.
    Grimshaw MJ, Balkwill FR (2001) Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation–a potential mechanism. Eur J Immunol 31:480–489PubMedCrossRefGoogle Scholar
  13. 13.
    Tan J, Buache E, Chenard MP, Dali-Youcef N, Rio MC (2011) Adipocyte is a non-trivial, dynamic partner of breast cancer cells. Int J Dev Biol 55:851–859PubMedCrossRefGoogle Scholar
  14. 14.
    Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, Wang YY, Meulle A, Salles B, Le Gonidec S, Garrido I, Escourrou G, Valet P, Muller C (2011) Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71:2455–2465PubMedCrossRefGoogle Scholar
  15. 15.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969PubMedCrossRefGoogle Scholar
  16. 16.
    Montovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686CrossRefGoogle Scholar
  17. 17.
    Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51PubMedCrossRefGoogle Scholar
  18. 18.
    Biswas SK, Sica A, Lewis CE (2008) Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 180:2011–2017PubMedGoogle Scholar
  19. 19.
    Kusmartsev S, Gabrilovich DI (2005) STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174:4880–4891PubMedGoogle Scholar
  20. 20.
    Tsai CS, Chen FH, Wang CC, Huang HL, Jung SM, Wu CJ, Lee CC, McBride WH, Chiang CS, Hong JH (2007) Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys 68:499–507PubMedCrossRefGoogle Scholar
  21. 21.
    Hursting SD, Nunez NP, Varticovski L, Vinson C (2007) The obesity-cancer link: lessons learned from a fatless mouse. Cancer Res 67:2391–2393PubMedCrossRefGoogle Scholar
  22. 22.
    Vona-Davis L, Rose DP (2007) Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14:189–206PubMedCrossRefGoogle Scholar
  23. 23.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184PubMedCrossRefGoogle Scholar
  24. 24.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808PubMedGoogle Scholar
  25. 25.
    Red Eagle A, Chawla A (2010) In obesity and weight loss, all roads lead to the mighty macrophage. J Clin Invest. 120(10):3437–3440PubMedCrossRefGoogle Scholar
  26. 26.
    Gordon S (2007) Macrophage heterogeneity and tissue lipids. J Clin Invest 117:89–93PubMedCrossRefGoogle Scholar
  27. 27.
    Janderová L, McNeil M, Murrell AN, Mynatt RL, Smith SR (2003) Human mesenchymal stem cells as an in vitro model for human adipogenesis. Obes Res 11:65–74PubMedCrossRefGoogle Scholar
  28. 28.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830PubMedGoogle Scholar
  29. 29.
    Cao Y (2010) Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat Rev Drug Discov 9:107–115PubMedCrossRefGoogle Scholar
  30. 30.
    Gealekman O, Guseva N, Hartigan C, Apotheker S, Gorgoglione M, Gurav K, Tran KV, Straubhaar J, Nicoloro S, Czech MP, Thompson M, Perugini RA, Corvera S (2011) Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation 123:186–194PubMedCrossRefGoogle Scholar
  31. 31.
    Bissell MJ, Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17:320–329PubMedCrossRefGoogle Scholar
  32. 32.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410PubMedCrossRefGoogle Scholar
  33. 33.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRefGoogle Scholar
  34. 34.
    Gimbrone MA Jr, Leapman SB, Cotran RS, Folkman J (1972) Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 136:261–276PubMedCrossRefGoogle Scholar
  35. 35.
    Folkman J, Cole P, Zimmerman S (1966) Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg 164:491–502PubMedCrossRefGoogle Scholar
  36. 36.
    Folkman J, Kalluri R (2004) Cancer without disease. Nature 427:787PubMedCrossRefGoogle Scholar
  37. 37.
    Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337PubMedCrossRefGoogle Scholar
  38. 38.
    Bissell MJ, Labarge MA (2005) Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 7:17–23PubMedGoogle Scholar
  39. 39.
    Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695PubMedCrossRefGoogle Scholar
  40. 40.
    Boucher Y, Jain RK (1992) Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res 52:5110–5114PubMedGoogle Scholar
  41. 41.
    Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498–1503PubMedCrossRefGoogle Scholar
  42. 42.
    Andarawewa KL, Motrescu ER, Chenard MP, Gansmuller A, Stoll I, Tomasetto C, Rio MC (2005) Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front. Cancer Res 65:10862–10871PubMedCrossRefGoogle Scholar
  43. 43.
    Motrescu ER, Rio MC (2008) Cancer cells, adipocytes and matrix metalloproteinase 11: a vicious tumor progression cycle. Biol Chem 389:1037–1041PubMedCrossRefGoogle Scholar
  44. 44.
    Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13:952–961PubMedCrossRefGoogle Scholar
  45. 45.
    Rieder F, Kessler SP, West GA, Bhilocha S, de la Motte C, Sadler TM, Gopalan B, Stylianou E, Fiocchi C (2011) Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis. Am J Pathol 179:2660–2673PubMedCrossRefGoogle Scholar
  46. 46.
    Lee SB, Kalluri R (2010) Mechanistic connection between inflammation and fibrosis. Kidney Int Suppl S22–S6Google Scholar
  47. 47.
    Lebleu VS, Sugimoto H, Miller CA, Gattone VH 2nd, Kalluri R (2008) Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease. Lab Invest 88:284–292PubMedCrossRefGoogle Scholar
  48. 48.
    Elkabets M, Gifford AM, Scheel C, Nilsson B, Reinhardt F, Bray MA, Carpenter AE, Jirström K, Magnusson K, Ebert BL, Pontén F, Weinberg RA, McAllister SS (2011) Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J Clin Invest 121:784–799PubMedCrossRefGoogle Scholar
  49. 49.
    Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP (2005) Selective depletion of macropahges reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115:56–65PubMedGoogle Scholar
  50. 50.
    Martin P, Leibovich SJ (2005) Inflammatory cells during wound repair: the goo, the bad and the ugly. Trends Cell Biol 15:599–607PubMedCrossRefGoogle Scholar
  51. 51.
    Martin P, D’Souza D, Martin J, Grose R, Cooper L, Maki R, McKercher SR (2003) Wound healing in the PU.1 null mouse-tissue repair is not dependent on inflammatory cells. Curr Biol 13:1122–1128PubMedCrossRefGoogle Scholar
  52. 52.
    Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, Kovacs EJ, DiPietro LA (2001) Wound healing in MIP-1alpha(−/−) and MCP-1(−/−) mice. Am J Pathol 159:457–463PubMedCrossRefGoogle Scholar
  53. 53.
    Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67PubMedCrossRefGoogle Scholar
  54. 54.
    Kalluri R, Sukhatme VP (2000) Fibrosis and angiogenesis. Curr Opin Nephrol Hypertens 9:413–418PubMedCrossRefGoogle Scholar
  55. 55.
    Liu H, Chen B, Lilly B (2008) Fibroblasts potentiate blood vessel formation partially through secreted factor TIMP-1. Angiogenesis 11:223–234PubMedCrossRefGoogle Scholar
  56. 56.
    Hume DA (2006) The mononuclear phagocyte system. Curr Opin Immunol 18:49–53PubMedCrossRefGoogle Scholar
  57. 57.
    Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, MacDonald AS, Allen JE (2011) Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332:1284–1288PubMedCrossRefGoogle Scholar
  58. 58.
    Tanimoto N, Terasawa M, Nakamura M, Kegai D, Aoshima N, Kobayashi Y, Nagata K (2007) Involvement of KC, MIP-2, and MCP-1 in leukocyte infiltration following injection of necrotic cells into the peritoneal cavity. Biochem Biophys Res Commun 361:533–536PubMedCrossRefGoogle Scholar
  59. 59.
    Armstrong DA, Major JA, Chudyk A, Hamilton TA (2004) Neutrophil chemoattractant genes KC and MIP-2 are expressed in different cell populations at sites of surgical injury. J Leukoc Biol 75:641–648PubMedCrossRefGoogle Scholar
  60. 60.
    Albina JE, Mills CD, Henry WL Jr, Caldwell MD (1990) Temporal expression of different pathways of 1-arginine metabolism in healing wounds. J Immunol 144:3877–3880PubMedGoogle Scholar
  61. 61.
    Zunić G, Supić G, Magić Z, Drasković B, Vasiljevska M (2009) Increased nitric oxide formation followed by increased arginase activity induces relative lack of arginine at the wound site and alters whole nutritional status in rats almost within the early healing period. Nitric Oxide 20:253–258PubMedCrossRefGoogle Scholar
  62. 62.
    Aoki Y, Jaffe ES, Chang Y, Jones K, Teruya-Feldstein J, Moore PS, Tosato G (1999) Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93:4034–4043PubMedGoogle Scholar
  63. 63.
    Cahlin C, Körner A, Axelsson H, Wang W, Lundholm K, Svanberg E. Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia. Cancer Res 60:5488–5493Google Scholar
  64. 64.
    Motro B, Itin A, Sachs L, Keshet E (1990) Pattern of interleukin 6 gene expression in vivo suggests a role for this cytokine in angiogenesis. Proc Natl Acad Sci USA 87:3092–3096PubMedCrossRefGoogle Scholar
  65. 65.
    Lin ZQ, Kondo T, Ishida Y, Takayasu T, Mukaida N (2003) Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol 73:713–721PubMedCrossRefGoogle Scholar
  66. 66.
    Hernández-Rodríguez J, Segarra M, Vilardell C, Sánchez M, García-Martínez A, Esteban MJ, Grau JM, Urbano-Márquez A, Colomer D, Kleinman HK, Cid MC (2003) Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism. Circulation 107:2428–2434PubMedCrossRefGoogle Scholar
  67. 67.
    Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266PubMedCrossRefGoogle Scholar
  68. 68.
    Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656PubMedCrossRefGoogle Scholar
  69. 69.
    Pollard JW (2008) Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol 84:623–630PubMedCrossRefGoogle Scholar

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
  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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