USE OF RECONSTITUTED BASEMENT MEMBRANE EXTRACTS TO STUDY OF THE MECHANISMS OF THE INVASION OF MALIGNANT TUMORS THROUGH BASEMENT MEMBRANES

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Basement membrane are thin extracellular structures surrounding most epithelial tissues, nerves and muscles as well as the lining of most blood and lymph vessels. Tumor invasion of basement membrane is a crucial step in the multistage process which leads to the formation of metastasis. Tumor cells cross basement membranes as they initially invade the lymphatic or vascular beds during dissemination, and they penetrate into their target tissue. It is likely that the invasion of tumor cells through basement membranes involves distinct events, including: a) attachment of tumor cells to laminin in the basement membranes through cell surface receptors; b) secretion of enzymes by tumor cells that cause the degradation of basement membrane barrier, and c) migration of tumor cells into the target tissue. we have used the reconstituted basement membrane molecules formed into barriers in order to investigate the invasiveness of malignant bone and soft tissue tumor cells in vitro. Results obtained from our study were as follows: 1) HT1080 human fibrosarcoma cells attach to the basement membrane via four attachment sites of laminin (YIGSR,PDSGR,RGD,IKVAV) and type IV collagen.2) The binding of tumor cells to laminin in the basement membranes were found to induce the secretion of collagenase IV and motility both of which are crucial factors for the invasion.3) Cyclic AMP analogues and a synthetic peptide, Tyr-Ile-Gly-Ser-Arg (YIGSR), from the B1 chain of laminin were able to suppress the invasiveness of HT1080 human fibrosarcoma cells. These agents were also found to reduce the lung colonization in vivo.4) Not only the cell lines but also the primary cultures of malignant bone and soft tissue tumors showed invasiveness in vitro while non-metastatic cells failed to do so.5) Co-injection of basement membrane extracts facilitated the transplantability of human malignant bone and soft tissue tumors obtained at surgery into nude mice.