Carcinogenesis Advance Access originally published online on May 2, 2008
Carcinogenesis 2008 29(5):890-894; doi:10.1093/carcin/bgn106
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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, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy
* To whom correspondence should be addressed. Tel: +39 011 6705422; Fax: +39 011 6705424; Email: giuseppe.poli{at}unito.it
It is now unanimously accepted that neoplastic cells tend to become less susceptible to the growth regulatory effects of transforming growth factor-β1 (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 proapoptotic and prodifferentiating cytokine could eliminate neoplastic cells still susceptible to TGF-β1's antiproliferative action (TGF-β1 receptor-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 upregulated 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, upregulation 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.
Abbreviations: AA, arachidonic acid; HNE, 4-hydroxynonenal; IBD, inflammatory bowel disease; IL, interleukin; 5-LOX, 5-lipoxygenase; PUFA, polyunsaturated fatty acid; TGF-β1, transforming growth factor-β1
Received March 17, 2008; revised April 15, 2008; accepted April 20, 2008.