Regulation of tumor cell invasion by extracellular matrix

The ability of malignant tumor cells to invade normal surrounding tissue contributes in large part to the significant morbidity and mortality of these cancers. The process of invasion involves adherence of the tumor cells to the extracellular matrix (ECM), degradation of matrix components, and movement of the cell body. Attachment-to ECM molecules is mediated by the integrin family of extracellular matrix receptors. Integrins are a large family of heterodimeric proteins which transduce a variety of signals from the ECM. Ligand occupancy is critical for activation of integrin signaling. This signaling may occur via several different pathways. One of the best characterized of these pathways is the mitogen activated protein kinase (MAPK) cascade. This serial phosphorylation of substrate proteins terminates in activation of transcription factors which regulate expression of target genes. Many of these genes are critical for extracellular matrix degradation or cell migration. Among these are the matrix metalloproteinases (MMPs), a large family of ECM-degrading enzymes. Regulatory elements in the promoters of MMPs have been characterized, providing insight into how MMP expression is controlled. This review focuses on mechanisms by which the ECM regulates tumor cell invasion through integrin signaling via the MAPK pathway using MMP expression as the model.