Alcohol promotes mammary tumor growth through activation of VEGF-dependent tumor angiogenesis

Abstract

Alcohol consumption has been recognized as a risk factor for breast cancer. Experimental studies demonstrate that alcohol exposure promotes the progression of existing mammary tumors. However, the mechanisms underlying this effect remain unclear. In the present study, the role of vascular endothelial growth factor (VEGF) in alcohol promotion of breast cancer development was investigated using a mouse xenograft model of mammary tumors and a three-dimensional (3D) tumor/endothelial cell co-culture system. For the mouse xenograft model, mouse E0771 breast cancer cells were implanted into the mammary fat pad of C57BL6 mice. These mice were exposed to alcohol in their drinking water. For the 3D co-culture system, E0771 cells and MDA-MB231 breast cancer cells were co-cultured with SVEC4-10EE2 and human umbilical vein endothelial cells, respectively. The results demonstrated that alcohol increased tumor angiogenesis and accelerated tumor growth. Furthermore, it appeared that alcohol induced VEGF expression in breast cancer cells in vitro and in vivo. Blocking VEGF signaling by SU5416 inhibited tumor angiogenesis in the 3D tumor/endothelial cell co-culture system. Furthermore, injection of SU5416 into mice inhibited alcohol-promoted mammary tumor growth in vivo. These results indicate that alcohol may promote mammary tumor growth by stimulating VEGF-dependent angiogenesis.

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

“…Alcohol-induced increase in the growth of breast cancer cells may result from either enhanced cell proliferation or promotion of survival. Animal studies confirm that alcohol consumption not only promotes the growth but also the metastasis of breast cancer cells to the lung and colon in mice [32, 33, 43, 44]. MMTV-neu transgenic mice are extensively used for the study of the tumorigenesis and progression of breast cancer.…”

“…Several studies consistently show that alcohol promotes tumor angiogenesis [39, 43, 44, 50, 51]. A number of mechanisms have been proposed for alcohol-induced angiogenesis; these include enhanced endothelial cell proliferation and migration, promotion of cancer/endothelial cell interaction and alterations of tumor microenvironment.…”

“…An in vitro study shows that alcohol can directly target endothelial cells and cause actin filament reorganization, resulting in enhanced migration and tube formation of endothelial cells [39]. Using a 3-D endothelial cell/breast cancer cell co-culture system, we show that alcohol significantly increases the angiogenesis in the presence of cancer cells [43, 44]. The effect of alcohol is likely mediated by the stimulation of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) signaling.…”

“…VEGF is a key regulator of angiogenesis. Alcohol upregulates the expression of VEGF and its receptor Flt-1 in mice; inhibiting VEGF-mediated signaling partially blocks alcohol-stimulated angiogenesis and tumor growth [44, 51]. MCP-1, also called chemokine (CC motif) ligand 2 (CCL2), is a pro-inflammatory chemokine, acting as a potent chemoattractant for monocytes and macrophages.…”

The contribution of natural selection to present-day susceptibility to chronic inflammatory and autoimmune disease

“…Alcohol dehydrogenase ( ADH ) alleles that enhance alcohol metabolism are thought to have been under positive selection starting at the dawn of the Mesolithic [79–81]. Increased consumption or metabolism of alcohol, however, alters immune traits by changing innate immune modulation, triggering liver inflammation and promoting tumor development [82–88]. Similar arguments can be made about the indirect impact of other putative dietary adaptations such as the rise of multiple alleles upstream of the transcription start site for the gene that expresses Lactase/Lactase-Phlorizin Hydrolase ( LCT ) alleles in European populations approximately 2000–20 000 years ago [89,90].…”