INVASION BY CULTURED HUMAN FOLLICULAR THYROID-CANCER CORRELATES WITH INCREASED BETA(1) INTEGRINS AND PRODUCTION OF PROTEASES

A recognized model of tumor invasion requires cells to adhere to epithelial basement membrane and extracellular matrix components triggering release of proteases thus allowing cancer cells to invade the substrate. This adhesion is mediated by beta(1) integrins, a family of receptors to substrates such as collagen, laminin, and fibronectin. In order to study tumor invasion in follicular thyroid cancer (FTC), we used cell lines derived from a single patient's FTC primary tumor (FTC-133), neck lymph node metastases (FTC-236), and lung metastases (FTC-238). In vitro invasion as determined by the ability of the tumor cells to penetrate Matrigel(R) was assessed by scanning electron microscopy. FTC-133 did not invade, FTC-236 was moderately invasive, and FTC-238 was highly invasive. Immunoprecipation with a monoclonal antibody to beta(1) integrin subunits and SDS-PAGE showed increased synthesis and flow cytometry showed increased expression of this subunit in FTC-236 and FTC-238 compared to FTC-133. Proteolytic activity was assessed by gelatin zymography. FTC-238 cell extract and conditioned media exhibited a more complex array of proteases consistent with activated type I collagenase and stromelysin compared to the less invasive clones, however 72 and 92 kd gelatinases consistent with type IV collagenases were present in the conditioned media from all three lines. In conclusion, in vitro invasion parallels in vivo metastasis by the source cells in the FTC-133/236/238 cell-lines. The ability to invade basement membrane preparation correlates with increased synthesis and expression of beta(1) integrins and activation of tumor proteases.