ASSOCIATION OF ELEVATED LEVELS OF HYALURONIDASE, A MATRIX-DEGRADING ENZYME, WITH PROSTATE-CANCER PROGRESSION

Components of extracellular matrix and the matrix-degrading enzymes ar e some of the keg regulators of tumor metastasis and angiogenesis. Hya luronic acid (HA), a matrix glycosaminoglgcan, is known to promote tum or cell adhesion and migration, and its small fragments are angiogenic . We have compared levels of hyaluronidase, an enzyme that degrades HA , in normal adult prostate (NAP), benign prostate hyperplasia (BPH) an d prostate cancer (CaP) tissues and in conditioned media from epitheli al explant cultures, using a sensitive substrate(HA)-gel assay and an ELISA-like assay. The results show a significant elevation (3-10-fold) of this enzyme in tumor tissues compared to that in NAP and BPH tissu es. Furthermore, the hyaluronidase levels in tissues correlate well wi th the tumor grade. For example, the concentrations in a locally exten ded CaP lesion (191 +/- 7.9 milliunits/mg protein) are the highest, fo llowed by high-grade tumors (36.6 +/- 2.9 milliunits/mg protein), and low-grade tumors (9.4 +/- 1.4 milliunits/mg protein), respectively. Am ong the primary epithelial explant cultures, CaP cultures secrete at l east 10-fold higher levels of hyaluronidase than those secreted by NAP and BPH cultures. Furthermore, among the established prostate cancer cell lines, DU145, an androgen-unresponsive metastatic line, secretes 4-fold more hyaluronidase than LNCaP, an androgen-responsive and relat ively well-differentiated cell line, We also show that prostatic hyalu ronidase has an apparent M(r) approximate to 55,000, a pH optimum of 4 .6, and is distinct from other well-characterized hyaluronidases.