Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Cancer Sci. 2012 Apr;103(4):797-805. doi: 10.1111/j.1349-7006.2012.02209.x. Epub 2012 Feb 15.
Tumor progression has been recognized as the product of evolving crosstalk between cancer cells and the surrounding stromal cells. Cancer-associated orthotopic myofibroblasts may be linked to the progression of gastric carcinomas. To understand the significance of orthotopic myofibroblasts, we examined the effects of cancer-associated orthotopic myofibroblasts on the malignant phenotype of gastric cancer cells. Three human gastric cancer cell lines (OCUM-2MD3, OCUM-12, MKN-45) and four human gastric fibroblast cell lines (cancer-associated orthotopic fibroblast [CaF]-29, CaF-33, normal orthotopic fibroblast [NF]-29, NF-33) were used. The cancer-associated orthotopic fibroblast cell lines CaF-29 and CaF-33 were established from a tumoral gastric wall, and normal orthotopic fibroblast NF-29 and NF-33 were established from a non-tumoral gastric wall. Fibroblasts that were α-smooth muscle actin-positive were defined as myofibroblasts. We examined the effects of cancer-associated orthotopic myofibroblasts on the aggressiveness of gastric cancer cells by wound-healing assay, invasion assay, and RT-PCR. The ratios of myofibroblasts in CaF-29 (33%) and CaF-33 (46%) were significantly (P < 0.001) greater than those in NF-29 (11%) or NF-33 (13%). Although all four orthotopic fibroblast lines increased the motility of gastric cancer cells, including migration and invasion ability, the motility-stimulating activity of cancer-associated fibroblasts (CaF-29 and CaF-33) was significantly higher than that of normal fibroblasts (NF-29 and NF-33). These motility-stimulating activities of cancer-associated orthotopic fibroblasts were downregulated by Smad2 siRNA treatment and anti-transforming growth factor-β neutralizing antibody. These findings suggest that cancer-associated orthotopic myofibroblasts may play an important role in the progression of gastric cancers and that transforming growth factor-β produced by myofibroblasts may be one of the factors associated with the aggressiveness of gastric carcinoma cells.
肿瘤的进展已被认为是癌细胞与周围基质细胞之间不断相互作用的结果。癌相关的原位肌成纤维细胞可能与胃癌的进展有关。为了了解原位肌成纤维细胞的意义，我们研究了癌相关的原位肌成纤维细胞对胃癌细胞恶性表型的影响。使用了三个人胃癌细胞系（OCUM-2MD3、OCUM-12、MKN-45）和四个人胃成纤维细胞系（癌相关的原位成纤维细胞[CaF]-29、CaF-33、正常原位成纤维细胞[NF]-29、NF-33）。CaF-29 和 CaF-33 源自肿瘤胃壁，NF-29 和 NF-33 源自非肿瘤胃壁。α-平滑肌肌动蛋白阳性的成纤维细胞被定义为肌成纤维细胞。我们通过划痕愈合试验、侵袭试验和 RT-PCR 研究了癌相关的原位肌成纤维细胞对胃癌细胞侵袭性的影响。CaF-29（33%）和 CaF-33（46%）中的肌成纤维细胞比例显著高于 NF-29（11%）或 NF-33（13%）（P < 0.001）。虽然所有四种原位成纤维细胞系都增加了胃癌细胞的运动性，包括迁移和侵袭能力，但癌相关成纤维细胞（CaF-29 和 CaF-33）的运动刺激活性明显高于正常成纤维细胞（NF-29 和 NF-33）。Smad2 siRNA 处理和抗转化生长因子-β中和抗体可下调癌相关原位成纤维细胞的这些运动刺激活性。这些发现表明，癌相关的原位肌成纤维细胞可能在胃癌的进展中发挥重要作用，肌成纤维细胞产生的转化生长因子-β可能是与胃癌细胞侵袭性相关的因素之一。
