The contribution of animal fat oxidation products to colon carcinogenesis, through modulation of TGF-beta1 signaling.
It is now unanimously accepted that neoplastic cells tend to become less susceptible to the growth regulatory effects of transforming growth factor-beta1 (TGF-beta1), mainly because of reduced expression and/or activity of TGF-beta1-specific receptors, as reported for many human cancers including colon cancer. Consequently, a sustained increase of TGF-beta1 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-beta1's antiproliferative action (TGF-beta1 receptor-positive cells), indirectly favoring the expansion of TGF-beta1 resistant ones (TGF-beta1 receptors deficient or negative cells). The actual concentration of TGF-beta1 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-beta1 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-beta1 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.
Biasi
Fiorella
F
Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy.
Mascia
Cinzia
C
Poli
Giuseppe
G
D000818:Animals; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D003110:Colonic Neoplasms / Q000453:epidemiology*; D015179:Colorectal Neoplasms / Q000453:epidemiology; D004041:Dietary Fats / Q000009:adverse effects*; D043371:Fatty Acids, Omega-6 / Q000009:adverse effects; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000209:etiology; D007413:Intestinal Mucosa / Q000503:physiopathology*; D008019:Life Style; D010084:Oxidation-Reduction; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D004041:Dietary Fats; D043371:Fatty Acids, Omega-6; D053773:Transforming Growth Factor beta1; D001094:Arachidonate 5-Lipoxygenase