Cat Bahar, Stuhlmann Dominik, Steinbrenner Holger, Alili Lirija, Holtkötter Olaf, Sies Helmut, Brenneisen Peter
Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
J Cell Sci. 2006 Jul 1;119(Pt 13):2727-38. doi: 10.1242/jcs.03011. Epub 2006 Jun 6.
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 beta1 (TGFbeta1) 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 TGFbeta1-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.
肌成纤维细胞在肿瘤进展中起关键作用，存在于反应性基质的微生态系统中。利用皮肤癌发生的体外肿瘤-基质模型，我们在此报告，肿瘤细胞衍生的转化生长因子β1（TGFβ1）启动了活性氧依赖性的α-平滑肌肌动蛋白表达，α-平滑肌肌动蛋白是属于一组晚期反应基因的肌成纤维细胞的生物标志物。此外，蛋白激酶C（PKC）参与了脂质氢过氧化物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。与成纤维细胞不同，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），导致肿瘤细胞侵袭能力显著增加。硫醇N-乙酰-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均显著降低TGFβ1启动的肌成纤维细胞数量以及HGF、VEGF和IL-6的分泌，这与肿瘤细胞侵袭能力减弱相关。这种新的基质治疗概念，即通过抗氧化剂和微量营养素保护基质细胞免受肿瘤-基质相互作用中肿瘤细胞的主导影响，可能为肿瘤侵袭化学预防策略中预防MMT奠定基础。
