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

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

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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.

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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.

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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).

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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

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  1. G Comito
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Correspondence to P Chiarugi.

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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

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