Carcinogenesis Advance Access published online on May 2, 2008
Carcinogenesis, doi:10.1093/carcin/bgn106
THE CONTRIBUTION OF ANIMAL-FAT OXIDATION PRODUCTS TO COLON CARCINOGENESIS, THROUGH MODULATION OF TGF-β1 SIGNALING
Department of Clinical and Biological Sciences, University of Turin, Italy
To whom correspondence should be addressed: Prof. Giuseppe Poli, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano (Torino, Italy) Phone: 0039-011-6705422, Fax: 0039-011-6705424, e-mail: giuseppe.poli{at}unito.it
It is now unanimously accepted that neoplastic cells tend to become less susceptible to the growth regulatory effects of TGF-β1, mainly because of reduced expression and/or activity of TGF-β1 specific receptors, as reported for many human cancers including colon cancer. Consequently, a sustained increase of TGF-β1 in the intestinal mucosa, like that caused by inflammatory processes and/or high dietary intake of animal fat, might become crucial for the progression of a neoplastic clone. In fact, this pro-apoptotic and pro-differentiating cytokine could eliminate neoplastic cells still susceptible to TGF-β1’s anti-proliferative action (TGF-β1 receptors positive cells), indirectly favoring the expansion of TGF-β1 resistant ones (TGF-β1 receptors deficient or negative cells). The actual concentration of TGF-β1 in the colonic mucosa undergoing neoplastic transformation is still debated, and the phase of the relevant carcinogenetic process in which a reduced susceptibility to this antiproliferative molecule first occurs has not been precisely established yet. However, no doubt that TGF-β1 level and activity may be up-regulated in cells of the macrophage lineage by animal-fat oxidation products, such as oxysterols and aldehydes, as reviewed here. But, phagocytes as well as fibroblasts, constitutively express TGF-β1, and are accumulating in tumor-associated stroma. Thus, up-regulation of this cytokine system within colonic tumor-associated stroma by excess dietary intake of cholesterol and n-6 polyunsaturated fatty acids appears as a primary mechanism of cancer progression at least in neoplastic lesions of the digestive tract.
Received May 17, 2008; revised April 15, 2008; accepted April 20, 2008.