Department of Internal Medicine, University of Kentucky College of Medicine, 130 Health Sciences Research Building, 1095 Veterans Drive, Lexington, KY 40536, USA.
Breast Cancer Res Treat. 2012 Jun;133(3):1037-48. doi: 10.1007/s10549-011-1902-7. Epub 2011 Dec 9.
Alcohol consumption is a risk factor for breast cancer in humans. Experimental studies indicate that alcohol exposure promotes malignant progression of mammary tumors. However, the underlying cellular and molecular mechanisms remain unclear. Alcohol induces a pro-inflammatory response by modulating the expression of cytokines and chemokines. Monocyte chemoattractant protein-1 (MCP-1), also known as chemokine (C-C motif) ligand 2, is a pro-inflammatory chemokine implicated in breast cancer development/malignancy. We investigated the role of MCP-1 in alcohol-promoted mammary tumor progression. Using a xenograft model, we demonstrated that alcohol increased tumor angiogenesis and promoted growth/metastasis of breast cancer cells in C57BL/6 mice. Alcohol up-regulated the expression of MCP-1 and its receptor CCR2 in breast cancer cells in vitro and in vivo. Using a three-dimensional tumor/endothelial cell co-culture system, we demonstrated MCP-1 regulated tumor/endothelial cell interaction and promoted tumor angiogenesis. More importantly, MCP-1 mediated alcohol-promoted angiogenesis; an antagonist of the MCP-1 receptor CCR2 significantly inhibited alcohol-stimulated tumor angiogenesis. The CCR2 antagonist abolished ethanol-stimulated growth of mammary tumors in mice. We further demonstrated that MCP-1 enhanced the migration, but not the proliferation of endothelial cells as well as breast cancer cells. These results suggest that MCP-1 plays an important role in ethanol-stimulated tumor angiogenesis and tumor progression.
饮酒是人类罹患乳腺癌的一个风险因素。实验研究表明，酒精暴露会促进乳腺肿瘤的恶性进展。然而，其潜在的细胞和分子机制尚不清楚。酒精通过调节细胞因子和趋化因子的表达来诱导促炎反应。单核细胞趋化蛋白-1（MCP-1），也称为趋化因子（C-C 基序）配体 2，是一种促炎趋化因子，与乳腺癌的发生/恶性有关。我们研究了 MCP-1 在酒精促进乳腺肿瘤进展中的作用。使用异种移植模型，我们证明酒精增加了肿瘤血管生成，并促进了 C57BL/6 小鼠中乳腺癌细胞的生长/转移。酒精在体外和体内上调了乳腺癌细胞中 MCP-1 及其受体 CCR2 的表达。使用三维肿瘤/内皮细胞共培养系统，我们证明 MCP-1 调节肿瘤/内皮细胞相互作用并促进肿瘤血管生成。更重要的是，MCP-1 介导了酒精促进的血管生成；MCP-1 受体 CCR2 的拮抗剂显著抑制了酒精刺激的肿瘤血管生成。该 CCR2 拮抗剂消除了乙醇刺激的小鼠乳腺肿瘤生长。我们进一步证明 MCP-1 增强了内皮细胞和乳腺癌细胞的迁移，但不增强其增殖。这些结果表明，MCP-1 在乙醇刺激的肿瘤血管生成和肿瘤进展中起重要作用。
