Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression

Oncogene volume 33, pages 2423–2431 (2014)Cite this article

Subjects

Abstract

Inflammation is now acknowledged as an hallmark of cancer. Cancer-associated fibroblasts (CAFs) force a malignant cross talk with cancer cells, culminating in their epithelial–mesenchymal transition and achievement of stemness traits. Herein, we demonstrate that stromal tumor-associated cells cooperate to favor malignancy of prostate carcinoma (PCa). Indeed, prostate CAFs are active factors of monocyte recruitment toward tumor cells, mainly acting through stromal-derived growth factor-1 delivery and promote their trans-differentiation toward the M2 macrophage phenotype. The relationship between M2 macrophages and CAFs is reciprocal, as M2 macrophages are able to affect mesenchymal–mesenchymal transition of fibroblasts, leading to their enhanced reactivity. On the other side, PCa cells themselves participate in this cross talk through secretion of monocyte chemotactic protein-1, facilitating monocyte recruitment and again macrophage differentiation and M2 polarization. Finally, this complex interplay among cancer cells, CAFs and M2 macrophages, cooperates in increasing tumor cell motility, ultimately fostering cancer cells escaping from primary tumor and metastatic spread, as well as in activation of endothelial cells and their bone marrow-derived precursors to drive de novo angiogenesis. In keeping with our data obtained in vitro, the analysis of patients affected by prostate cancers at different clinical stages revealed a clear increase in the M2/M1 ratio in correlation with clinical values. These data, coupled with the role of CAFs in carcinoma malignancy to elicit expression of stem-like traits, should focus great interest for innovative strategies aimed at the co-targeting of inflammatory cells and fibroblasts to improve therapeutic efficacy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

CAFs:

cancer-associated fibroblasts

CAMs:

cancer-associated macrophages

CM:

conditioned media

COX-2:

cycloxigenase-2

EMT:

epithelial–mesenchymal transition

EPCs:

endothelial progenitor cells

HPFs:

human prostate fibroblasts

HUVEC:

human umbilical vein endothelial cells

IFN-γ:

interferon gamma

IL:

interleukin

LPS:

lipopolysaccharides

MCP-1:

monocyte chemotactic protein-1

M-CSF:

macrophage colony-stimulating factor

PCa:

prostate carcinoma

ROS:

reactive oxygen species

SDF-1:

stromal-derived growth factor-1

SMA:

α-smooth muscle actin

TGF-β:

transforming growth factor-β.

References

  1. Cirri P, Chiarugi P . Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev 2012; 31: 195–208.

    Article  PubMed  Google Scholar 

  2. Kalluri R, Zeisberg M . Fibroblasts in cancer. Nat Rev Cancer 2006; 6: 392–401.

    Article  CAS  PubMed  Google Scholar 

  3. Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De DA et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res 2012; 72: 5130–5140.

    Article  CAS  PubMed  Google Scholar 

  4. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res 2010; 70: 6945–6956.

    Article  CAS  PubMed  Google Scholar 

  5. Giannoni E, Bianchini F, Calorini L, Chiarugi P . Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal 2011; 14: 2361–2371.

    Article  CAS  PubMed  Google Scholar 

  6. Friedl P, Hegerfeldt Y, Tusch M . Collective cell migration in morphogenesis and cancer. Int J Dev Biol 2004; 48: 441–449.

    Article  CAS  PubMed  Google Scholar 

  7. Kalluri R . EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009; 119: 1417–1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mantovani A, Sica A, Locati M . New vistas on macrophage differentiation and activation. Eur J Immunol 2007; 37: 14–16.

    Article  CAS  PubMed  Google Scholar 

  9. Martinez FO, Helming L, Gordon S . Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 2009; 27: 451–483.

    Article  CAS  PubMed  Google Scholar 

  10. Allavena P, Sica A, Solinas G, Porta C, Mantovani A . The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 2008; 66: 1–9.

    Article  PubMed  Google Scholar 

  11. Geldhof AB, van Ginderachter JA, Liu Y, Noel W, de BP . Ablation of NK cell function during tumor growth favors Type 2-associated macrophages, leading to suppressed CTL generation. Clin Dev Immunol 2003; 10: 71–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Solinas G, Germano G, Mantovani A, Allavena P . Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 2009; 86: 1065–1073.

    Article  CAS  PubMed  Google Scholar 

  13. Mantovani A, Allavena P, Sica A, Balkwill F . Cancer-related inflammation. Nature 2008; 454: 436–444.

    Article  CAS  PubMed  Google Scholar 

  14. Sica A, Schioppa T, Mantovani A, Allavena P . Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006; 42: 717–727.

    Article  CAS  PubMed  Google Scholar 

  15. Talmadge JE, Donkor M, Scholar E . Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev 2007; 26: 373–400.

    Article  PubMed  Google Scholar 

  16. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP . Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 2009; 15: 416–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Erez N, Truitt M, Olson P, Arron ST, Hanahan D . Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 2010; 17: 135–147.

    Article  CAS  PubMed  Google Scholar 

  18. Cat B, Stuhlmann D, Steinbrenner H, Alili L, Holtkotter O, Sies H et al. Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species. J Cell Sci 2006; 119 (Pt 13): 2727–2738.

    Article  CAS  PubMed  Google Scholar 

  19. Comito G, Giannoni E, Di GP, Segura CP, Gerlini G, Chiarugi P . Stromal fibroblasts synergize with hypoxic oxidative stress to enhance melanoma aggressiveness. Cancer Lett 2012; 324: 31–41.

    Article  CAS  PubMed  Google Scholar 

  20. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    Article  CAS  PubMed  Google Scholar 

  21. Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med 2010; 2: 211–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mantovani A, Sica A . Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010; 22: 231–237.

    Article  CAS  PubMed  Google Scholar 

  23. Giannoni E, Taddei ML, Parri M, Bianchini F, Santosuosso M, Grifantini R et al. EphA2-mediated mesenchymal-amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts. J Mol Med 2013; 91: 103–115.

    Article  CAS  PubMed  Google Scholar 

  24. Nolan DJ, Ciarrocchi A, Mellick AS, Jaggi JS, Bambino K, Gupta S et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev 2007; 21: 1546–1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Giannoni E, Parri M, Chiarugi P . EMT and oxidative stress: a bidirectional interplay affecting tumor malignancy. Antioxid Redox Signal 2012; 16: 1248–1263.

    Article  CAS  PubMed  Google Scholar 

  26. Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ, Fukumura D et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci USA 2010; 107: 21677–21682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Muerkoster SS, Werbing V, Koch D, Sipos B, Ammerpohl O, Kalthoff H et al. Role of myofibroblasts in innate chemoresistance of pancreatic carcinoma–;epigenetic downregulation of caspases. Int J Cancer 2008; 123: 1751–1760.

    Article  PubMed  Google Scholar 

  28. Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011; 20: 370–383.

    Article  CAS  PubMed  Google Scholar 

  29. Guido C, Whitaker-Menezes D, Capparelli C, Balliet R, Lin Z, Pestell RG et al. Metabolic reprogramming of cancer-associated fibroblasts by TGF-beta drives tumor growth: connecting TGF-beta signaling with ‘Warburg-like’ cancer metabolism and L-lactate production. Cell Cycle 2012; 11: 3019–3035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Servais C, Erez N . From sentinel cells to inflammatory culprits: cancer-associated fibroblasts in tumour-related inflammation. J Pathol 2013; 229: 198–207.

    Article  CAS  PubMed  Google Scholar 

  31. Hao NB, Lu MH, Fan YH, Cao YL, Zhang ZR, Yang SM . Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol 2012; 2012: 948098.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sica A, Porta C, Morlacchi S, Banfi S, Strauss L, Rimoldi M et al. Origin and functions of tumor-associated myeloid cells (TAMCs). Cancer Microenviron 2012; 5: 133–149.

    Article  CAS  PubMed  Google Scholar 

  33. Balkwill FR, Mantovani A . Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 2012; 22: 33–40.

    Article  CAS  PubMed  Google Scholar 

  34. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011; 475: 222–225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Teicher BA, Fricker SP . CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010; 16: 2927–2931.

    Article  CAS  PubMed  Google Scholar 

  36. Hembruff SL, Jokar I, Yang L, Cheng N . Loss of transforming growth factor-beta signaling in mammary fibroblasts enhances CCL2 secretion to promote mammary tumor progression through macrophage-dependent and -independent mechanisms. Neoplasia 2010; 12: 425–433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ksiazkiewicz M, Gottfried E, Kreutz M, Mack M, Hofstaedter F, Kunz-Schughart LA . Importance of CCL2-CCR2A/2B signaling for monocyte migration into spheroids of breast cancer-derived fibroblasts. Immunobiology 2010; 215: 737–747.

    Article  CAS  PubMed  Google Scholar 

  38. Silzle T, Kreutz M, Dobler MA, Brockhoff G, Knuechel R, Kunz-Schughart LA . Tumor-associated fibroblasts recruit blood monocytes into tumor tissue. Eur J Immunol 2003; 33: 1311–1320.

    Article  CAS  PubMed  Google Scholar 

  39. Inoue H, Nishimura K, Oka D, Nakai Y, Shiba M, Tokizane T et al. Prostate cancer mediates osteoclastogenesis through two different pathways. Cancer Lett 2005; 223: 121–128.

    Article  CAS  PubMed  Google Scholar 

  40. de WO, Mareel M . Role of tissue stroma in cancer cell invasion. J Pathol 2003; 200: 429–447.

    Article  Google Scholar 

  41. Zumsteg A, Christofori G . Corrupt policemen: inflammatory cells promote tumor angiogenesis. Curr Opin Oncol 2009; 21: 60–70.

    Article  PubMed  Google Scholar 

  42. Whiteside TL . The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008; 27: 5904–5912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jinushi M, Baghdadi M, Chiba S, Yoshiyama H . Regulation of cancer stem cell activities by tumor-associated macrophages. Am J Cancer Res 2012; 2: 529–539.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Margheri F, Chilla A, Laurenzana A, Serrati S, Mazzanti B, Saccardi R et al. Endothelial progenitor cell-dependent angiogenesis requires localization of the full-length form of uPAR in caveolae. Blood 2011; 118: 3743–3755.

    Article  CAS  PubMed  Google Scholar 

  45. Yoder MC . Developing reagents and conditions to induce mesoderm subsets from ES cells. Cell Stem Cell 2007; 1: 603–604.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Associazione Italiana Ricerca sul Cancro (AIRC), by Istituto Toscano Tumori, and by MIUR (PRIN 2008). Pedro Barcellos-de-Souza was supported by postdoctoral fellowship from Capes (Ministério da Educaçao, Brazil).

Author information

Authors and Affiliations

  1. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

    G Comito, E Giannoni, C P Segura, P Barcellos-de-Souza & P Chiarugi

  2. Histology and Molecular Diagnostic University Careggi Hospital, University of Florence, Florence, Italy

    M R Raspollini & G Baroni

  3. Department of Urology Careggi Hospital, University of Florence, Florence, Italy

    M Lanciotti & S Serni

  4. Tuscany Tumor Institute and ‘Center for Research, Transfer and High Education DenoTHE’, Florence, Italy

    P Chiarugi

Authors
  1. G Comito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Giannoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C P Segura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Barcellos-de-Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M R Raspollini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Baroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Lanciotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Serni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Chiarugi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Chiarugi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Comito, G., Giannoni, E., Segura, C. et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene 33, 2423–2431 (2014). https://doi.org/10.1038/onc.2013.191

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.191

Keywords

This article is cited by

Search

Advanced search

Quick links