The plasmin cascade and matrix metalloproteinases in non-small cell lung cancer

There are several steps involved in the metastatic spread of cancer from the primary tumour to a secondary remote site. Firstly, the cancer cells have to escape from the primary site and then intravasate into the blood or lymphatic circulation. The cells must survive transportation in the circulation before extravasating at a distant site. These cells then need to establish themselves at the new site before growth and replication can occur to form a metastatic colony. During this time the malignant cell has to avoid destruction by the host immune system. Vital to the growth of both the primary and metastatic disease is the capacity of the tumour to induce breakdown of the extracellular matrix (ECM) and the formation of a blood supply through new blood vessel formation, a process known as angiogenesis. The ECM is a framework of proteins and proteoglycans secreted by and surrounding stromal fibroblasts. It gives structural support to cells and plays a central role in cell adhesion, diVerentiation, proliferation, and migration. The ECM is separated from epithelial cells by a basement membrane which is made up of type IV collagen and creates a scaVold upon which heparan sulphate, laminin, and other components are arranged. 1