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

在肿瘤间质中，究竟是肿瘤细胞还是基质细胞负责细胞外基质（ECM）分子的产生，目前尚不清楚。为了研究每种细胞类型参与ECM分子产生的作用，作为本研究项目的主要实验，研究了在鳞状细胞癌（SCC）细胞系统和间质成纤维细胞系统直接和间接接触的两种共培养系统中，四种ECM分子在蛋白质和mRNA水平上的表达。虽然在单细胞培养条件下，SCC细胞和成纤维细胞之间的perlecan和其他ECM分子的蛋白质和mRNA表达水平相似，但当成纤维细胞与SCC细胞接触时，这些ECM表达水平升高，而SCC细胞的ECM表达水平则下降。SCC细胞和成纤维细胞之间的水平差异在直接接触时比间接接触时更为明显。这些结果表明，口腔SCC细胞在没有基质成纤维细胞（对应于原位癌）的情况下产生ECM分子，并且在存在成纤维细胞（对应于侵袭性SCC）的情况下停止产生ECM。这些现象在口腔癌手术标本的组织切片上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，我们认为，与侵袭的鳞状细胞直接接触后的间质成纤维细胞比鳞状细胞更容易形成肿瘤间质，鳞状细胞的组织学侵袭可以定义为基质诱导的存在。基于这些发现，我们提出了一个肿瘤生物学概念，即“实质-间质转换导致ECM的产生”。

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."