Role of Tumor Stromal Interactions and Proteases in Oral Cancer Metastasis

Abstract

To metastasize, tumor cells must migrate through the surrounding stroma which is composed of extracellular matrix (ECM) components, fibroblasts, inflammatory cells, and endothelial cells. Tumor-associated matrix permeability to tumor cells is thought to result from complex interactions between the tumor cell and the cellular and acellular components of the stroma. These interactions result in tumor cell changes in substrate adhesion, cell migration, and focused proteolysis of ECM components. Although the process of ECM degradation has been associated with multiple types of proteases including cathepsins, and serine proteases (such as plasmin), it is the matrix metalloproteinases (MMPs) that are most commonly upregulated and associated with the invasive process. Although tumor cells were originally thought to be the primary source of MMPs within the tumor, it was recently recognized that MMPs are expressed primarily by stromal cells when stimulated by tumor cell derived factors. One mechanism that tumor cells employ to stimulate MMPs from tumor-associated stroma is the expression of ECM metalloproteinase inducer (EMMPRIN). EMMPRIN is a tumor cell expressed protein known to induce growth factors and proteases in the surrounding fibroblasts and endothelial cells. In addition to an analysis of EMMPRIN as a paradigm for tumor–stromal interactions, this chapter will characterize the presence of stromal tissue in head and neck cancer on the basis of histological analysis, the role of proteases in tumor–stromal interactions, and the specific role of membrane type-1 MMP (MT1-MMP) in tumor invasion and metastasis. Furthermore, the clinical trials associated with MMP inhibitors in cancer have been disappointing, and some possible explanations for their failure and future directions are suggested.