Involvement of fibronectin in the regulation of urokinase production and binding in murine mammary tumor cells

ALEJANDRO J. URTREGER; JULIO AGUIRRE-GHISO; LYDIA I. PURICELLI; SANTIAGO E. WERBAJH; ANDRES MURO; ELISA D. BAL DE KIER JOFFE

INTERNATIONAL JOURNAL OF CANCER. JOURNAL INTERNATIONAL DU CANCER.

JOHN WILEY & SONS INC

Año: 1999 vol. 82 p. 748 - 753

0020-7136

Tumor invasion and metastasis development is a multistep process involving adhesion molecules as well as tumor proteases. It has been reported that tumor cells lacking fibronectin (FN) expression and engineered to re-express FN showed a marked reduction in metastatic ability. Besides its effects on cell adhesion and migration, FN could be modulating other cellular events associated with the metastatic cascade. To test this hypothesis, we analyzed the production of urokinasetype plasminogen activator (uPA), and its receptor (uPAR), 2 molecules involved in the invasive phenotype, in cells overexpressing RGD wild-type FN (FNwt clones) or RGDmutated FN (FN RGD-minus clones). Secreted uPA activity and antigen were significantly up-regulated in FN-expressing clones, although RGD-minus cells secreted approximately 50% less uPA than the FNwt ones. Interestingly, while control and FN RGD-minus clones were able to readily bind uPA to their surface, FNwt clones exhibited impaired uPA binding. Furthermore, treatment of the parental cell line as well as the control and FN-expressing clones with exogenous purified FN or RGD peptides induced up-regulation of uPA production and the reduction of uPA membrane binding, which was associated with lower expression of uPAR. This modulation by FN was found to be dependent on RGD sequence and b1 integrin. These results strongly suggest a novel activity for the multifunctional glycoprotein FN regarding the regulation of uPA production as well as the capacity of tumor cells to bind uPA.