Abstract
BACKGROUNDThe enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) degrades chondroitin-4-sulfate (C4S) and is reduced in malignant colonic and mammary tissues, but has not previously been evaluated in prostate cancer.METHODSARSB immunostaining was performed on two tissue microarrays (TMA) and analyzed by digital image analysis, generating ARSB H-scores for prevalence and intensity of epithelial, stromal, and combined epithelial and stromal immunostaining. Also, paired malignant and normal prostate tissues were analyzed for ARSB activity, C4S, total sulfated glycosaminoglycans, and versican content. The quantities of C4S and of the epidermal growth factor receptor that co-immunoprecipitated with versican were determined in the normal and malignant paired prostate tissues.RESULTS44 cases of prostate cancer were paired by age (± 5y), race, Gleason score (in order), and pathologic TNM score. The pairs differed by recurrence vs. non-recurrence of elevated PSA at 4 or more years. When TMA cores were analyzed for ARSB H-score, 18 of the 22 pairs had lower ARSB H-scores in the recurrent member of the pair, whereas higher initial PSA values were associated with recurrence in only 65% of the paired cases. In a second TMA, Gleason scores 6 and 7 were associated with higher ARSB H-scores than Gleason scores 8 and 9 for stroma, epithelium, and stroma and epithelium combined (p=0.052, p=0.015, p<0.0001, respectively) and were inversely correlated (r = −0.98, −0.97, and −0.99, respectively). In other paired normal and malignant prostate tissues, ARSB activity was significantly higher in the normal tissues, and C4S and versican values were lower (p<0.0001). C4S that co-immunoprecipitated with versican was greater in the malignant than in the normal tissue, whereas total EGFR that co-immunoprecipitated with versican was reduced.DISCUSSIONStudy findings suggest that ARSB may be useful as a prognostic biomarker in prostate cancer, and that the biological action of ARSB on chondroitin sulfate may impact upon versican’s effects in the tumor microenvironment.
Highlights
IntroductionArylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) is the lysosomal enzyme that removes the 4-sulfate group of N-acetylgalactosamine-4-sulfate at the non-reducing end of chondroitin4-sulfate (C4S) and dermatan sulfate and thereby regulates their degradation.[1,2] Recent studies demonstrated extra-lysosomal localization of arylsulfatase B (ARSB) in epithelial and endothelial membranes in human cells.[3,4,5,6,7] Decline in ARSB activity was shown in malignant mammary and colonic epithelial tissues and in metastatic colonic epithelial cells,[3,8,9,10] and the intensity and localization of ARSB immunostaining was reduced in higher grade colonic adenocarcinomas.[3]
Versican is an important extracellular matrix proteoglycan composed of three domains: the G1 domain has hyaluronan attachments that interact with the CD44 cell surface protein; the G2 domain has chondroitin sulfate attachments; and the G3 domain at the C-terminus has epidermal growth factor (EGF)-like repeats and a carbohydrate recognition domain.[13]
The total epidermal growth factor receptor (EGFR) in the malignant tissue increased to over three times the baseline value (Figure 5b). These results suggest that the increased C4S bound with versican in malignant prostate tissue may impede the binding of the stromal versican EGF-like repeats with epithelial EGFR
Summary
Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) is the lysosomal enzyme that removes the 4-sulfate group of N-acetylgalactosamine-4-sulfate at the non-reducing end of chondroitin4-sulfate (C4S) and dermatan sulfate and thereby regulates their degradation.[1,2] Recent studies demonstrated extra-lysosomal localization of ARSB in epithelial and endothelial membranes in human cells.[3,4,5,6,7] Decline in ARSB activity was shown in malignant mammary and colonic epithelial tissues and in metastatic colonic epithelial cells,[3,8,9,10] and the intensity and localization of ARSB immunostaining was reduced in higher grade colonic adenocarcinomas.[3]. Measurements of the intensity of ARSB immunostaining by digitized image analysis (H-scores) were calculated for prostate cancers in two small tissue microarrays (TMAs), and the associations of H-scores with recurrence vs nonrecurrence and Gleason score were determined. The enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) degrades chondroitin-4-sulfate (C4S) and is reduced in malignant colonic and mammary tissues but has not previously been evaluated in prostate cancer. Paired malignant and normal prostate tissues were analyzed for ARSB activity, C4S, total sulfated glycosaminoglycans and versican content. When TMA cores were analyzed for ARSB H-score, 18 of the 22 pairs had lower ARSB H-scores in the recurrent member of the pair, whereas higher initial PSA values were associated with recurrence in only 65% of the paired cases. CONCLUSIONS: Study findings suggest that ARSB may be useful as a prognostic biomarker in prostate cancer and that the biological action of ARSB on chondroitin sulfate may impact upon versican’s effects in the tumor microenvironment
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