Hyaluronic Acid and Hyaluronidase in Prostate Cancer: Evaluation of Their Therapeutic and Prognostic Potential

摘要

Identification of accurate prognostic indicators could aid in individualization of treatment and better prediction of outcome or prostate cancer patients. Treatment modalities that target these molecules could effectively control CaP progression. The results of this project identify HYAL1 type hyaluronidase (HAase) as one such molecule. HA is a glycosaminoglycan and HAase is an enzyme that degrades HA into angiogenic fragments. Immunohistochemical analysis using archival radical prostatectomy CaP specimens from patients on whom there is 72 - 131 month follow-up show that HYAL1 and combined HA-HYAL1 inferences staining are independent predictors for biochemical recurrence. Studies on HYAL1 transfectants show that blocking HYAL1 expression in CaP cells, decreases growth by blocking cell cycle progression and invasive activity by 3-4-fold. HYAL1-AS transfectants show a 4-7-fold decrease in tumor growth, and generate tumors that are non-infiltrating and less vascularized. Transfectants expressing high HYAL1 levels also grow 4-fold slower and undergo apoptosis. High HYAL1 producing transfectants show either decreased tumor growth (3-fold) or do not form tumors. Microarray analysis data support the role of HYAL1 as molecular determinant of prostate cancer. Analysis of 21 HAase inhibitors identified some compounds that show higher specificity to inhibit HYAL1 activity.