title: Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages.
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.
authors.affiliation: Tumour and Microenvironment Group, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Linde
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Lederle
authors.forename: Sofia
authors.initials: S
authors.lastname: Depner
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Gutschalk
authors.forename: Margareta M
authors.initials: MM
authors.lastname: Mueller
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002461:Cell Line, Transformed; D002465:Cell Movement; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D015603:Keratinocytes; D008262:Macrophage Activation; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016753:Interleukin-10; D015847:Interleukin-4