CD44s expression in human colon carcinomas influences growth of liver metastases

CD44 is a family of cell-surface adhesion molecules which exist in several isoforms arising from mRNA alternative. Malignant transformation of colonic mucosa is associated with alterations in CD44 expression, which result in up-regulation of high-molecular-weight CD44 isoforms and down-regulation of CD44s. We have demonstrated that stable transfection of CD44s into colon-carcinoma cell lines reduces their tumorigenicity. To understand the influence of CD44s expression on the metastatic potential of human colon carcinomas, we measured the ability of several different CD44s-transfected colon carcinomas to establish experimental liver metastases following splenic inoculation in mice. We observed that introduction of CD44s into 2 different human colon carcinoma cell lines, HT29 and KM12C6, resulted in reduced growth of liver metastases by as much as 75%. To explore the relationship between hyaluronate adhesion and metastasis, we transfected HT29 cells with cDNA encoding a mutant CD44s that does not bind to hyaluronate. HT29 transfectants expressing this mutant CD44s demonstrate an 84% reduction in growth of liver metastases, despite minimal binding to hyaluronate by the mutant CD44s. In concert, these results indicate that CD44s down-regulation, which occurs with malignant transformation of colonic mucosa, is associated with enhanced growth of experimental liver metastases. Consequently, the functional consequences of CD44s down-regulation in colon carcinomas may be just as significant as the consequences of up-regulation of other CD44 isoforms.