OVER EXPRESSION OF CD44V8-10 IN URINARY EXFOLIATED CELLS AS AN INDEPENDENT PROGNOSTIC PREDICTOR IN PATIENTS WITH UROTHELIAL CANCER

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Abstract
CD44 is a widely expressed cell surface adhesion molecule, of which various isoforms arise from alternative RNA splicing mechanisms. Over expression of specific CD44 splice variants, namely CD44v8-10, is evident in various malignant tumors and is considered to be associated with disease progression. In this study, we investigated whether the transcriptional level of CD44v8-10 relative to that of the standard CD44 isoform would predict the extent and prognosis of urothelial cancer. The CD44v8-10– to –standard CD44 ratio was measured in the tissue (40 urothelial cancer specimens and corresponding normal urinary tissue) and spontaneously voided urine samples of 150 patients with urothelial cancer and 50 with benign urological disease by reverse transcriptase-polymerase chain reaction using the set of primers capable of amplyfying all CD44 splice variant isoforms. Initially any CD44 variant isoforms were barely detectable in normal urinary tissues, whereas CD44v8-10 was predominantly expressed in most urothelial cancer specimens. Furthermore, the CD44v8-10– to –standard CD44 ratio in urothelial cancer was closely associated with tumor progression. We then compared the ratio in urothelial cancer tissue and urinary exfoliated cells, and noted a linear and significant correlation of these 2 values in the same patients. Therefore, we investigated whether the CD44v8-10– to –standard CD44 ratio in urinary exfoliated cells would predict the prognosis and disease progression. The mean ratio in the urinary exfoliated cells of patients with invasive urothelial cancer was significantly higher than in those with superficial urothelial cancer. Of the patients with superficial bladder cancer disease-free survival rate of those with an elevated versus a normal ratio was significantly lower. Moreover, of the patients with advanced urothelial carcinoma who underwent complete resection disease-free survival of those with an elevated CD44v8-10– to –standard CD44 ratio was significantly lower than that of patients with a normal ratio. These results indicate that CD44v8-10 is strongly expressed in tumor tissue and evident at high levels in urinary exfoliated cells of patients with invasive versus superficial urothelial cancer. An elevated CD44v8-10– to –standard CD44 ratio in urinary exfoliated cells may serve as a novel prognostic predictor and indicator of disease extent in patients with urothelial cancer.