Reduction of integrin β4 and enhanced migration on laminin in association with intraepithelial spreading of urinary bladder carcinomas

Purpose: The aim of the present study was to investigate the biological and molecular basis of intraepithelial spreading (IES) of carcinomas in situ (CIS) of the urinary bladder, which were considered to be precursors of nodular invasive carcinomas. Materials and Methods: The propensity for IES of human transitional carcinoma cells was examined by inoculation into murine renal pelvis and urinary bladder, and the biological character of the cells with a high propensity for IES was explored in vitro. Results: Three of 6 cell lines exhibited a high propensity for IES. When cultured on laminin, these IES cells scattered, whereas 3 non-IES cells and 2 immortalized transitional epithelial cells did not. IES cells showed strong adhesiveness, haptotaxis and enhanced migration on laminin compared with both non-IES and immortalized transitional epithelial cells. In IES cells, expression of the integrin β₄ subunit was markedly reduced and the integrin α₆β₁ complex was predominant compared with the integrin α₆β₄ complex. Transfection of IES cells with integrin β₄ subunit cDNA inhibited their ability to migrate on laminin and their propensity for IES. In addition, expression of the integrin β₄ subunit was reduced in surgically resected specimens of CIS of the urinary bladder. Conclusion: The results indicate that a reduction in integrin β₄ plays a role in IES of CIS of the urinary bladder through enhanced migration on laminin.