title: Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Kentucky College of Medicine, 130 Health Sciences Research Building, 1095 Veterans Drive, Lexington, KY 40536, USA. sywang@ahmu.edu.cn
authors.forename: Siying
authors.initials: S
authors.lastname: Wang
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Feifei
authors.initials: F
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bower
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Lu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zunji
authors.initials: Z
authors.lastname: Ke
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D018932:Chemokine CCL2; D054390:Receptors, CCR2; D000431:Ethanol