Domains of Laminin and Basement Membrane Collagen which Play a Role in Metastases

Abstract

Metastasis is a complex multistep process in which interaction of tumor cell surface components with the extracellular matrix may play a role (1–7). An important type of matrix traversed by tumor cells at multiple stages of metastases is the continuous basement membrane. Metastasizing tumor cells traverse endothelial basement membranes during both entrance into and egress from the circulation (8). The initial step of this traversal is thought to be attachment (9), which may be mediated in part through tumor cell surface receptor binding to laminin, a glycoprotein uniquely localized to basement membranes (1–4). We have previously demonstrated that human carcinoma cells and murine BL6 melanoma cells bind laminin with high affinity and that they possess a cell surface plasma membrane laminin receptor with a M_r of approximately 67,000 (1–3). A similar receptor has been identified on murine fibrosarcoma cells (4). Murine melanoma cells can be selected for metastatic propensity based on their ability to use laminin to attach to type IV collagen in vitro (10). Those tumor cells which preferentially utilize laminin for attachment exhibit a ten fold increase in metastatic propensity (10). By electron microscopy the laminin molecule has the structure of a “cross” with one long arm (75 nm) and three short arms (37 nm), each containing globular end regions (1,5,11). The carbohydrate composition of laminin is heterogeneous. Specific sugar moieties are enriched on the globular end regions compared to the rod shaped portions of the molecule (11). Digestion of laminin with alpha thrombin will remove the long arm but leave the short arms intact (12). Cathepsin G or chymotrypsin will produce a laminin fragment devoid of the long arm and the globular end regions of the short arms (12). The C₁ fragment is “T” shaped and contains the disulfide “knot” where the three short arms are joined together.