Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species
Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species
复制标题
DOI：
10.1242/jcs.03011
复制
发表时间：
2006-07-01
影响因子：
4
通讯作者：
Brenneisen, Peter
中科院分区：
文献类型：
--
作者：
Cat, Bahar;Stuhlmann, Dominik;Brenneisen, Peter
肌成纤维细胞，肿瘤进展的关键，填充反应性基质的微生态系统。使用体外肿瘤间质模型的皮肤癌变，我们在这里报告，肿瘤细胞衍生的转化生长因子β 1（TGF β 1）启动活性氧物种依赖性表达的α-平滑肌肌动蛋白，一个生物标志物的肌纤维母细胞属于一组迟反应基因。此外，蛋白激酶C（PKC）参与脂质过氧化氢触发的成纤维细胞向肌成纤维细胞转分化（间充质-间充质转化，MMT）的分子事件。与成纤维细胞相反，肌成纤维细胞分泌大量的肝细胞生长因子（HGF）、血管内皮生长因子（VEGF）和白细胞介素-6（IL-6），导致肿瘤细胞的侵袭能力显著增加。巯基N-乙酰基-L-半胱氨酸、微量营养素亚硒酸盐以及硒蛋白P和脂质过氧化抑制剂α-生育酚和丁基化羟基甲苯显著降低TGF β 1启动的肌成纤维细胞的数量以及HGF、VEGF和IL-6的分泌，这与肿瘤细胞的侵袭能力降低相关。基质治疗的新概念，即通过抗氧化剂和微量营养素保护基质细胞免受肿瘤细胞在肿瘤-基质相互作用中的主导影响，可能构成预防MMT在肿瘤侵袭的化学预防策略中的基础。
Myofibroblasts, pivotal for tumor progression, populate the microecosystem of reactive stroma. Using an in vitro tumor-stroma model of skin carcinogenesis, we report here that tumor-cell-derived transforming growth factor beta 1 (TGF beta 1) initiates reactive oxygen species-dependent expression of alpha-smooth muscle actin, a biomarker for myofibroblastic cells belonging to a group of late-responsive genes. Moreover, protein kinase C (PKC) is involved in lipid hydroperoxide-triggered molecular events underlying transdifferentiation of fibroblasts to myofibroblasts (mesenchymal-mesenchymal transition, MMT). In contrast to fibroblasts, myofibroblasts secrete large amounts of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), resulting in a significant increase in the invasive capacity of tumor cells. The thiol N-acetyl-L-cysteine, the micronutrient selenite as well as selenoprotein P and the lipid peroxidation inhibitors alpha-tocopherol and butylated hydroxytoluene significantly lower both the number of TGF beta 1-initiated myofibroblasts and the secretion of HGF, VEGF and IL-6, correlating with a diminished invasive capacity of tumor cells. This novel concept of stromal therapy, namely the protection of stromal cells against the dominating influence of tumor cells in tumor-stroma interaction by antioxidants and micronutrients, may form the basis for prevention of MMT in strategies for chemoprevention of tumor invasion.