Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages
Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages
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DOI：
10.1002/path.3989
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发表时间：
2012-05-01
影响因子：
7.3
通讯作者：
Mueller, Margareta M.
中科院分区：
文献类型：
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作者：
Linde, Nina;Lederle, Wiltrud;Mueller, Margareta M.
炎症有助于肿瘤的生长、侵袭和血管生成。在血管内皮生长因子-A诱导的皮肤癌模型中，我们研究了巨噬细胞及其极化在肿瘤进展中的作用。将鼠血管内皮生长因子-A基因导入人非致瘤角质形成细胞系HaCaT体内，可导致肿瘤生长。由此产生的肿瘤的特征是广泛的血管形成、侵袭性生长和大量M2极化的巨噬细胞，这对恶性表型的建立至关重要。相应地，从荷瘤动物身上去除巨噬细胞会导致肿瘤生长减少，侵袭受到抑制，增殖减少，血管生成减少。在体外，血管内皮生长因子-A对巨噬细胞具有化学吸引作用，但不诱导M2极化。我们确定IL-4和IL-10是参与M2极化的因素。这些因子由体内的肿瘤细胞(IL-10)和巨噬细胞(IL-4)产生。在体外加入重组IL-4和IL-10可诱导具有侵袭性的M2巨噬细胞表型，体内抑制IL-4受体可阻断巨噬细胞M2极化，导致肿瘤表型侵袭性降低。因此，我们提供的证据表明，M2巨噬细胞在VEGF-A诱导的皮肤肿瘤的发展中起关键作用，并且VEGF-A不仅通过促进血管生成，而且通过建立抗炎微环境而促进恶性肿瘤的生长。然而，单独的血管内皮生长因子-A不足以创造促进肿瘤的微环境，需要IL-4和IL-10的存在才能诱导巨噬细胞M2极化。版权所有(C)2012年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
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 (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.