Participation of Stromal component in Cancer Progression

癌细胞的侵袭和转移被认为是由周围的微环境如基质细胞和细胞外基质蛋白等介导的。我们已经证明成纤维细胞分泌一种趋化因子，增强口腔癌细胞的运动能力。肿瘤的侵袭和转移也是由降解细胞外基质蛋白的蛋白水解酶介导的。基质金属蛋白酶-2(MMP2)降解基底膜的主要成分，如IV型胶原、层粘连蛋白和纤维连接蛋白。在包括鳞状细胞癌(SCC)在内的多种肿瘤中，基质金属蛋白酶-2的表达增加与其侵袭和转移潜能有关。然而，包括MMP2、MMP9和基质分解素在内的MMPs不是由肿瘤细胞本身系统分泌的，而是由瘤周宿主组织中的非恶性间质细胞分泌的。为了探讨基质成分参与SCC细胞的蛋白分解活性，我们研究了成纤维细胞对SCC细胞表面MMP2活化的影响。本研究所检测的鳞癌细胞不表达基质金属蛋白酶-2，鳞癌细胞质膜不能与基质金属蛋白酶-2结合并激活它。然而，用成纤维细胞条件培养液(成纤维细胞-CM)处理SCC细胞后，细胞表面的基质金属蛋白酶-2结合和活化增强。此外，成纤维细胞可诱导SCC细胞膜型基质金属蛋白酶(MT1-MMPs)的表达。这些发现提示成纤维细胞可能通过增加鳞癌细胞表面的蛋白水解酶活性来促进鳞癌细胞的侵袭。

The invasion and metastasis of cancer cells has been proposed to be mediated by the surrounding microenvironment such as stromal cells and extracellular matrix proteins. We have demonstrated that fibroblasts secrete a chemotactic factor and enhance the motility of oral cancer cells. Tumor invasion and metastasis are also mediated by proteolytic enzymes that degrade extracellular matrix proteins. Matrix metalloproteinase-2 (MMP-2) degrades the major components of basement membrane such as type IV collagen, laminin and fibronectin. In various tumors including squamous cell carcinoma (SCC), increased production of MMP-2 has been associated their invasive and metastatic potential. However, MMPs including MMP-2, MMP-9 and stromelysin are not systematically secreted by tumor cells themselves but by nonmalignant stromal cells in the peritumoral host tissues.To assess the participation of stromal components in the proteolytic activity of SCC cells, we investigated the effect of fibroblasts on MMP-2 activation on the surface of SCC cells. SCC cells examined in this study serereted no MMP-2 and the plasma membrane of SCC cells failed to bind MMP-2 and activate it. However, treatment of SCC cells with fibroblast-conditioned medium (fibroblast-CM) led to the enhancement of MMP-2 binding and activation on the cell surface. Moreover, fibroblasts induced the expression of membrane type 1 MMP (MT1-MMP) in SCC cells. These findings suggest that fibroblasts might facilitate the invasion of SCC cells by increasing the proteolytic activity on the surfaces of SCC cells.