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Most newly diagnosed prostate cancer patients have clinically organ-con®ned disease. However, limited knowledge about which prostate cancer is aggressive and likely to progress, or when it will recur, has severely impeded individualized selection of therapy and prediction of outcome. Routine biochemical (i.e. prostate-speci®c antigen), surgical and pathologic parameters offer a glimpse of the biological potential of a given tumour, but this is often not enough to predict accurately which patient will progress. Molecules associated with prostate cancer growth, metastasis and angiogenesis may be better predictors of prostate cancer progression. Our laboratory is working on two such molecules: hyaluronic acid (HA) and hyaluronidase (HAase).HA is a non-sulphated glycosaminoglycan which promotes tumour cell adhesion and migration, and protects tumour cells from immune surveillance. HAase is an enzyme which degrades HA into small angiogenic fragments. Although the association of HA with tumour metastasis has already been established, our laboratory showed for the ®rst time, using prostate cancer and bladder cancer as model systems, that HAase is associated with cancer. We have previously isolated angiogenic HA fragments from the urine of bladder cancer patients, demonstrating the presence of an active 'HA± HAase system' in cancer. We have also shown that measuring urinary levels of HA and HAase (HA±HAase test) is a simple non-invasive, highly sensitive (92%) and speci®c method (85%) for detecting bladder cancer, to the prostate cancer model. MethodHA (mg/mg protein) and HAase (mU/mg protein) levels in tissues and culture-conditioned media (CM) were measured by the HA-HAase test. Several complementary techniques were used to study the expression of HA and HAase in prostate cancer. ResultsHA levels were elevated seven to eight-fold in low grade (Gleason score: 5/6) and high-grade (Gleason score: 7) prostate cancer and metastatic prostate cancer tissues, compared with normal prostate (NP) and benign prostatic hyperplasia (BPH) tissues. Measurement of HA in CM showed that stromal ®broblast cultures from low-grade and high-grade prostate cancer secreted 3.4 to seven-fold more HA than NP and BPH ®broblast cultures.HAase level measurement showed that while HAase levels are increased marginally in low-grade prostate cancer, they are elevated 10±14-fold in high-grade prostate cancer and 100-fold in metastatic prostate cancer tissues, compared with NP and BPH tissues. In culture CM, high-grade prostate cancer epithelial explant cultures and aggressive androgen-independent prostate cancer lines secreted 10±20-fold more HAase than low-grade prostate cancer, NP and BPH explant cultures, RT-PCR, cloning and sequence analysis showed the expression of HYAL1-type HAase in invasive prostate cancer cells, which was further con®rmed by immunoblot analysis.To evaluate whether HA and HAase can serve as prognostic indictors, we began by localizing these two molecules in prostate tissue (n 57). Immunohistochemistry showed that HA staining in...

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