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Metastasis Suppression by the Standard CD44 Isoform Does Not Require the Binding of Prostate Cancer Cells to Hyaluronate¹

The Johns Hopkins Oncology, Center, James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1001 [A. C. G., W. L., J. T. I.], and Forschungszentrum Karlsruhe, Institute of Genetics, Karlsruhe D-76021, Germany [J. P. S.]

Previous studies from this laboratory have demonstrated that down-regulation of the standard CD44 isoform at the mRNA and protein level is associated with the acquisition of high metastatic ability within the Dunning R-3327 system of rat prostate cancers. Additional studies demonstrated that transfection-induced enhanced expression of the standard CD44 isoform suppresses the metastatic ability of the AT3.1 Dunning subline without suppressing tumorigenicity. The standard CD44 isoform is a major cell surface receptor for the extracellular matrix glycosaminoglycan hyaluronate. In this study, an investigation was made to resolve whether the ability of the standard CD44 isoform to suppress metastasis of the AT3.1 prostate cancer cells critically requires enhanced hyaluronate binding. Highly metastatic Dunning AT3.1 rat prostate cancer cells were transfected with expression plasmids encoding either the wild-type or mutant standard CD44 isoform. The mutant standard CD44 isoform construct encoded a protein unable to bind to hyaluronate. Transfectants were isolated and characterized with regard to their level of standard CD44 isoform expression, hyaluronate binding, tumorigenicity, and metastatic ability. Expression of the wild-type standard CD44 isoform increased the hyaluronate binding of prostate cancer cells and suppressed their metastatic ability without suppressing their tumorigenicity. Expression of the mutant CD44 standard isoform did not increase hyaluronate binding; however, it equally suppressed the metastatic ability of the AT3.1 prostate cancer cells. These results demonstrate that the metastasis suppression by the standard CD44 isoform is independent of its ability to bind to hyaluronate.

¹ Supported by Specialized Programs of Research Excellence Grant CA 58236 (National Cancer Institute).

² To whom requests for reprints should be addressed, at Prostate Cancer Laboratories, Johns Hopkins Oncology Center, 422 North Bond Street, Baltimore, MD 21231-1001.

Received 3/ 3/98. Accepted 4/15/98.

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