Researchers have also focused on the effects of alcohol on other molecular mechanisms impacting cancer. In 2009, Christopher Forsyth, Ph.D., assistant professor of medicine and biochemistry at Rush University Medical Center, and colleagues reported that alcohol stimulates epithelial-to-mesenchymal (EMT) transition, which is associated with the progression of cancer cells into a more aggressive form.
Dr. Forsyth told GEN that his idea for looking at alcohol’s effect on Snail proteins came from observations that these factors are critical to the process of embryogenesis. “If you block Snail when the nervous system is forming, you don’t get a nervous system because epithelial cells can’t migrate to form one.”
He credited Angela Nieto, Ph.D., currently professor and head of the developmental neurobiology unit at the Instituto de Neurociencias, with the original insight on Snail proteins. It has been shown that when the Snail gene is overexpressed in mice, it induces formation of multiple tumors.
To assess the effects of alcohol exposure on biochemical markers for EMT, Dr. Forsyth’s research group compared the in vitro effects of alcohol on colon and breast cancer cell lines, a normal intestinal epithelial cell line, and colonic mucosal biopsy samples from alcoholics.
The study results indicated that alcohol upregulated the signature EMT phenotypic marker vimentin as well as matrix metalloprotease (MMP)-2, MMP-7, and MMP-9. It also increased cell migration in colon and breast cancer cells, another characteristic of EMT.
Additionally, alcohol stimulated the expression and activity of Snail. In vivo, Snail expression was significantly elevated in colonic mucosal biopsies from alcoholics. Furthermore, Snail siRNA knockdown was shown to prevent alcohol-stimulated vimentin expression.
The investigators also found that alcohol stimulated activation of epidermal growth factor receptor (EGFR) signaling, and an EGFR inhibitor blocked alcohol-induced cell migration and Snail mRNA expression.
Dr. Forsyth said that this data was the first to show that alcohol turns on certain intracellular signals involved in EMT via an EGFR-Snail mediated pathway. “Our hope,” Dr. Forsyth told GEN, “is that we understand signaling pathways affected by alcohol in human cells so we can also understand how alcohol promotes disease.”