Association of elevated levels of hyaluronidase, a matrix-degrading enzyme, with prostate cancer progression

Components of extracellular matrix and the matrix-degrading enzymes are some of the key regulators of tumor metastasis and angiogenesis. Hyaluronic acid (HA), a matrix glycosaminoglycan, is known to promote tumor 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) and prostate cancer (CaP) tissues and in conditioned media from epithelial 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 tissues. Furthermore, the hyaluronidase levels in tissues correlate well with the tumor grade. For example, the concentrations in a locally extended CaP lesion (191 ± 7.9 milliunits/mg protein) are the highest, followed by high-grade tumors (36.6 ± 2.9 milliunits/mg protein), and low-grade tumors (9.4 ± 1.4 milliunits/mg protein), respectively. Among the primary epithelial explant cultures, CaP cultures secrete at least 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 relatively well- differentiated cell line. We also show that prostatic hyaluronidase has an apparent M(r) ≃55,000, a pH optimum of 4.6, and is distinct from other well- characterized hyaluronidases.