In vitro effects of fenretinide on cell-matrix interactions

Background: Understanding the molecular basis of the metastatic spread of c ancer and the underlying mechanisms is crucial for the development and appr opriate clinical use of novel therapeutic agents directed at prevention of metastasis. Retinoids have been reported to inhibit cell proliferation, mod ulate cell differentiation, enhance apoptosis and to prevent the conversion of in situ cancer to locally invasive malignancy by suppressing the invasi ve process as well as by inhibiting angiogenesis. Fenretinide (4-HPR), a sy nthetic derivative of retinoic acid, is less toxic than natural retinoids a nd is active in the prevention and treatment of a variety of tumours in ani mal models. Its efficacy in cancer chemoprevention and therapy has been inv estigated in clinical trials. Materials and Methods: In order to evaluate t he effects of I-HPR on the late stages of tumour progression, chemically tr ansformed BALB/c 3T3 cells, showing a fully malignant phenotype, were expos ed to 4-HPR (0.25-10 muM; 72 hours pre-treatment) and then analysed for in vitro invasive ability. The possible mechanisms of action responsible for t he anti-invasive activity of 4-HPR were investigated, analysing cellular ad hesion, motility, and proteolytic capability. Results: Data showed that 4-H PR significantly inhibited the invasive phenotype of chemically transformed cells; the reduction in Matrigel invasion was dose-dependent and seemed no r to be related to cytotoxic effects or reduction in cell proliferation rat es induced by 4-HPR assayed doses. The 4-HPR-induced decrease in chemotacti c motility of transformed cells correlated well with the invasion inhibitio n. 4-HPR, at active concentrations, differently affected cell adhesion to t he extracellular matrix, depending on the coating substrate used (laminin, collagen IV, fibronectin and vitronectin). 4-HPR treatment significantly en hanced cell adhesion to laminin, while reducing cell-vitronectin attachment . It did not modify the attachment of the cells to fibronectin and collagen IV.