Studies in rat prostate and liver have suggested that C-CAM1 is involved in the formation and maintenance of histotypic associations in tissues and possibly tumors. Most recently, C-CAM1 has been shown to suppress tumorigenicity of prostate and colon carcinoma cells. However, the mechanisms whereby C-CAM1 suppresses growth and the relationship of this activity to its proposed role in histotypic interactions remain largely unknown. In the present study, we have analysed the growth, phenotypic, morphological and ultrastructural characteristics of four human PC-3 prostate carcinoma cell lines transduced with C-CAM1 retrovirus. We report that three of four lines regained their tumorigenic phenotype in vivo while maintaining high levels of C-CAM1 expression and a growth retarded phenotype in vitro. These findings suggested that high levels of C-CAM1 expression were negatively influencing recovery during reconstitution after freezing or during the latency period after subcutaneous injection and that loss of suppression resulted from changes in expression of other molecules required for full disclosure of C-CAM1 mediated growth inhibition. Results from Northern blot and immunofluorescence analyses of tumor nodules demonstrated that C-CAM1 decreased rather than enhanced phenotypic differentiation and induced ultrastructural and morphological changes that occurred independently of tumor suppression.