A new anti-cancer strategy by control ling crosstalk of oral carcinoma cells with extracellular matrix molecules

对于肿瘤间质中细胞外基质(ECM)分子的产生，人们对肿瘤细胞或基质细胞的类型知之甚少。为了探讨每种细胞类型在ECM分子产生中的作用，作为本研究项目的一个初步实验，研究了鳞癌细胞系和间质成纤维细胞系直接接触和间接接触两种共培养体系中四种ECM分子在蛋白质和mRNA水平的表达。在单细胞培养条件下，SCC细胞和成纤维细胞之间Perlecan和其他ECM分子的蛋白和mRNA表达水平相似，而成纤维细胞的ECM表达水平升高，而SCC细胞与SCC细胞接触时ECM表达水平下降。鳞状细胞癌细胞和成纤维细胞之间的水平差异在直接接触中明显比间接接触中明显。这些结果表明，口腔鳞癌细胞在没有间质成纤维细胞的情况下产生ECM分子，这相当于原位癌，而在成纤维细胞存在的情况下，它们停止产生ECM，这对应于侵袭性鳞癌。这些现象在口腔癌手术标本的组织切片中也得到了免疫组织化学和原位杂交的证实。在其他实验中，ECM的产生及其代谢被证明是由实质细胞和基质细胞共同控制的。因此，与侵袭性鳞状细胞癌细胞直接接触后的间质成纤维细胞比鳞状细胞癌细胞对肿瘤间质的形成更负责，鳞状细胞癌的组织学侵袭可定义为间质诱导的存在。基于这些发现，我们提出了“实质-间质转换以产生细胞外基质”的肿瘤生物学概念。

It was poorly understood which cell types, tumor cells or stromal cells, were responsible for the production of extracellular matrix (ECM) molecules in the neoplastic stroma. To investigate the role of each cell type's participation in the production of ECM molecules, as a primary experiment of this research project, the expression of four ECM molecules at the protein and the mRNA levels was studied in two kinds of co-culture systems in direct and indirect contacts between squamous cell carcinoma (SCC) cell systems and stromal fibroblast cell systems. While similar protein and mRNA expression levels for perlecan and other ECM molecules between SCC cells and fibroblasts in a monocellular culture condition, these ECM expression levels of fibroblasts were elevated, and instead those of SCC cells dropped when they were in contact with SCC cells. The differences in the levels between SCC cells and fibroblasts were significantly more evident in direct contact than in indirect contact. These results indicated that oral SCC cells produce ECM molecules in the absence of stromal fibroblasts, which correspond to carcinomas in-situ, and that they stop producing ECM in the presence of fibroblasts, which correspond to invasive SCC. These phenomena were also confirmed in tissue sections from oral carcinoma surgical specimens by immunohistochemistry and in-situ hybridization. In other experiments, ECM production and its metabolism were shown to be controlled by both parenchymal and stromal cells. It is thus suggested that stromal fibroblasts after direct contact with invading SCC cells are more responsible than SCC cells for the formation of neoplastic stroma, and that histological invasion of SCC can be defined as the presence of stromal induction. Based on the findings, we have proposed a tumor biological concept of "parenchymal-stromal switching for ECM production."