Biasi Fiorella, Mascia Cinzia, Poli Giuseppe
Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy.
Carcinogenesis. 2008 May;29(5):890-4. doi: 10.1093/carcin/bgn106. Epub 2008 May 2.
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.
目前已达成共识，肿瘤细胞往往对转化生长因子-β1（TGF-β1）的生长调节作用变得不那么敏感，主要原因是TGF-β1特异性受体的表达和/或活性降低，许多人类癌症（包括结肠癌）均有此报道。因此，肠道黏膜中TGF-β1的持续增加，如炎症过程和/或高动物脂肪饮食摄入所导致的增加，可能对肿瘤克隆的进展至关重要。事实上，这种促凋亡和促分化细胞因子可以消除仍对TGF-β1的抗增殖作用敏感的肿瘤细胞（TGF-β1受体阳性细胞），间接促进对TGF-β1耐药的细胞（TGF-β1受体缺陷或阴性细胞）的扩增。肿瘤转化的结肠黏膜中TGF-β1的实际浓度仍存在争议，且对这种抗增殖分子敏感性降低首次出现的相关致癌过程阶段尚未精确确定。然而，毫无疑问，动物脂肪氧化产物（如氧化甾醇和醛类）可使巨噬细胞系细胞中的TGF-β1水平和活性上调，本文对此进行了综述。但吞噬细胞和成纤维细胞组成性表达TGF-β1，并在肿瘤相关基质中积聚。因此，至少在消化道肿瘤病变中，过量饮食摄入胆固醇和n-6多不饱和脂肪酸导致结肠肿瘤相关基质中这种细胞因子系统上调似乎是癌症进展的主要机制。
