| First Author | Linde N | Year | 2012 |
| Journal | J Pathol | Volume | 227 |
| Issue | 1 | Pages | 17-28 |
| PubMed ID | 22262122 | Mgi Jnum | J:183427 |
| Mgi Id | MGI:5318654 | Doi | 10.1002/path.3989 |
| Citation | Linde N, et al. (2012) Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages. J Pathol 227(1):17-28 |
| abstractText | 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. |
