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Vascular endothelial growth factor‐induced skin carcinogenesis depends on recruitment and alternative activation of macrophages
Author(s) -
Linde Nina,
Lederle Wiltrud,
Depner Sofia,
van Rooijen Nico,
Gutschalk Claudia M,
Mueller Margareta M
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.3989
Subject(s) - angiogenesis , cancer research , macrophage polarization , in vivo , hacat , carcinogenesis , vascular endothelial growth factor , macrophage , neovascularization , m2 macrophage , biology , inflammation , cytokine , immunology , in vitro , microbiology and biotechnology , cancer , vegf receptors , biochemistry , genetics
Abstract Inflammation contributes to tumour growth, invasion and angiogenesis. We investigated the contribution of macrophages and their polarization to tumour progression in a model of VEGF‐A‐induced skin carcinogenesis. Transfection of the human non‐tumourigenic keratinocyte cell line HaCaT with murine VEGF‐A leads to malignant tumour growth in vivo . The resulting tumours are characterized by extensive vascularization, invasive growth and high numbers of M2‐polarized macrophages that crucially contribute to the establishment of the malignant phenotype. Accordingly, macrophage depletion from tumour‐bearing animals resulted in reduced tumour growth, inhibition of invasion, decreased proliferation and reduced angiogenesis. In vitro , VEGF‐A exerted a chemo‐attracting effect on macrophages, but did not induce M2 polarization. We identified IL‐4 and IL‐10 as the factors involved in M2 polarization. These factors were produced by tumour cells (IL‐10) and macrophages (IL‐4) in vivo . Addition of recombinant IL‐4 and IL‐10 in vitro induced a pro‐invasive M2 macrophage phenotype and inhibition of the IL‐4 receptor in vivo blocked M2 polarization of macrophages, resulting in a less aggressive tumour phenotype. Thus, we provide evidence that M2 macrophages are crucial for the development of VEGF‐A‐induced skin tumours and that VEGF‐A contributes to malignant tumour growth, not only by enhancing angiogenesis but also by establishing an anti‐inflammatory microenvironment. However, VEGF‐A alone is not sufficient to create a tumour‐promoting microenvironment and requires the presence of IL‐4 and IL‐10 to induce M2 polarization of macrophages. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.