Matrix metalloproteases in head and neck cancer

Abstract

Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.

FIGURE 1

Head and neck cancer is composed of multiple cell types, each with different patterns of matrix metalloprotease (MMP) expression. The biologic complexity of MMPs in vivo was not appreciated during initial clinical trials of MMP inhibitors. Multiple cell types express MMPs.

FIGURE 2

Tumor cell invasion of surrounding tissues requires multiple invasion programs. Migration of tumor cells occurs through the dense extracellular matrix (blue arrow); the tumor cells intravasate into the nearby vasculature (red arrow), followed by extravasation from the circulation into other organs. ECM, extracellular matrix.