Expression of CD44 and Variant Proteins in Human Colorectal Cancer and Its Relevance for Prognosis

Abstract

CD44 is a cell adhesion molecule often expressed in the form of various splice variants. The role of standard CD44 isoform (CD44s) and its variants in colorectal carcinogenesis is partly conflicting. Therefore, we compared the expression of CD44s (hermes-3) and its splice variants (v3 and v6) with traditional prognostic factors in 194 colorectal cancer patients treated at Kuopio University Hospital and followed up for a mean of 14 years. Formalin-fixed, paraffin-embedded tissue sections from 194 patients with colorectal carcinoma were examined immunohistochemically to detect the expression of different forms of CD44. The hypothesis that CD44s, CD44v3, and CD44v6 expression intensities and distribution in cancer cells correlated with survival was tested with the log-rank test, hazard ratios, and their confidence intervals. In high-grade tumours CD44s and CD44v6 expression intensities and CD44s percentages were stronger than in low-grade tumours. CD44v6, CD44v3, and CD44s expression intensities in tumour epithelium were also stronger in Dukes C and D tumours than in A and B tumours. In the univariate survival analysis patients with strong CD44s, CD44v3, and CD44v6 expression intensities in tumour epithelium had lower cancer-related survival than the patients who had weak CD44s, CD44v3, and CD44v6 expression intensities. Recurrence-free survival was also shorter in patients with intense signals for CD44v3 and CD44v6 in tumour epithelium. In the multivariate analysis the CD44v6 expression intensity in tumour epithelium predicted independently both cancer-related and recurrence-free survival in T1-4N0-3M0 and T1-3N0M0 cases. In addition, the CD44v3 expression intensity in tumour epithelium was a significant predictor of RFS in T1-3N0M0 cases. These results strongly suggest that the CD44 splice variants v6 and v3 have prognostic significance in colorectal cancer.