This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pham, H. T. Articles by Lokeshwar, V. B. Search for Related Content PubMed Articles by Pham, H. T. Articles by Lokeshwar, V. B.

Tumor-derived Hyaluronidase: A Diagnostic Urine Marker for High-Grade Bladder Cancer¹

Department of Urology, University of Miami School of Medicine, Miami, Florida, 33101

The detection of high-grade bladder tumors prior to invasion is crucial for a good prognosis. We recently found that the levels of hyaluronic acid (HA), a glycosaminoglycan, are elevated in the urine of bladder cancer patients, and small angiogenic HA fragments are present in the urine of high-grade bladder cancer patients. Hyaluronidase is an enzyme that degrades HA into small angiogenic fragments. We compared the urinary hyaluronidase levels of normal individuals and patients with bladder cancer or other genitourinary conditions, using a substrate (HA)-gel technique and an ELISA-like assay. Among the 139 specimens analyzed, the urinary hyaluronidase levels in patients with G2/G3 tumors (33.4 ± 4.5 milliunits/mg protein) are 5–8-fold higher than those in normal individuals (4.2 ± 1.2 milliunits/mg protein) and those in patients with G1 tumors (6.5 ± 1.7 milliunits/mg protein) or other genitourinary conditions (7.4 ± 1.4 milliunits/mg protein; P < 0.001). Urinary hyaluronidase measurement shows a sensitivity of 100% and a specificity of 88.8% to detect high-grade bladder (G2/G3) tumors. Thus urinary hyaluronidase measurement is a simple, noninvasive yet highly specific and sensitive method for high-grade bladder cancer detection. The increase in urinary hyaluronidase levels is due to the secretion of a tumor-associated hyaluronidase into the urine because the hyaluronidase levels in G2/G3 tumor tissues are also higher (6–7-fold) than those in normal bladder and G1 tumor tissues (P < 0.001). The bladder tumor-associated hyaluronidase activity is distinct from other hyaluronidases, has a pH optimum of 4.3, and is attributed to two proteins with molecular masses of 65 kD (p65) and 55 kD (p55).

¹ This work was supported by an American Cancer Society Institutional Grant (to V. B. L.), the Stanley Glaser Award (to V. B. L.), the Urology Residents' Research Fund (to H. T. P.), and the Weeks Endowment Fund (to N. L. B. and V. B. L.).

² To whom requests for reprints should be addressed, at Department of Urology (M-800), University of Miami School of Medicine, P. O. Box 016960, Miami, FL 33101. Phone: (305) 243-6321; Fax: (305) 243-6893; E-mail: BLOKESHW@UMMEDNET. MED.MIAMI.EDU.

Received 8/16/96. Accepted 12/20/96.

This article has been cited by other articles:

				G. C. Daginakatte and D. H. Gutmann Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth Hum. Mol. Genet., May 1, 2007; 16(9): 1098 - 1112. [Abstract] [Full Text] [PDF]

				V. B. Lokeshwar, V. Estrella, L. Lopez, M. Kramer, P. Gomez, M. S. Soloway, and B. L. Lokeshwar HYAL1-v1, An Alternatively Spliced Variant of HYAL1 Hyaluronidase: A Negative Regulator of Bladder Cancer Cancer Res., December 1, 2006; 66(23): 11219 - 11227. [Abstract] [Full Text] [PDF]

				K. N. Sugahara, T. Hirata, H. Hayasaka, R. Stern, T. Murai, and M. Miyasaka Tumor Cells Enhance Their Own CD44 Cleavage and Motility by Generating Hyaluronan Fragments J. Biol. Chem., March 3, 2006; 281(9): 5861 - 5868. [Abstract] [Full Text] [PDF]

				V. B. Lokeshwar, W. H. Cerwinka, T. Isoyama, and B. L. Lokeshwar HYAL1 Hyaluronidase in Prostate Cancer: A Tumor Promoter and Suppressor Cancer Res., September 1, 2005; 65(17): 7782 - 7789. [Abstract] [Full Text] [PDF]

				V. B. Lokeshwar, W. H. Cerwinka, and B. L. Lokeshwar HYAL1 Hyaluronidase: A Molecular Determinant of Bladder Tumor Growth and Invasion Cancer Res., March 15, 2005; 65(6): 2243 - 2250. [Abstract] [Full Text] [PDF]

				K. N. Sugahara, T. Murai, H. Nishinakamura, H. Kawashima, H. Saya, and M. Miyasaka Hyaluronan Oligosaccharides Induce CD44 Cleavage and Promote Cell Migration in CD44-expressing Tumor Cells J. Biol. Chem., August 22, 2003; 278(34): 32259 - 32265. [Abstract] [Full Text] [PDF]

				J. T. Posey, M. S. Soloway, S. Ekici, M. Sofer, F. Civantos, R. C. Duncan, and V. B. Lokeshwar Evaluation of the Prognostic Potential of Hyaluronic Acid and Hyaluronidase (HYAL1) for Prostate Cancer Cancer Res., May 15, 2003; 63(10): 2638 - 2644. [Abstract] [Full Text] [PDF]

				M. Sanchez-Carbayo Use of High-Throughput DNA Microarrays to Identify Biomarkers for Bladder Cancer Clin. Chem., January 1, 2003; 49(1): 23 - 31. [Abstract] [Full Text] [PDF]

				E. L. J. Hiltunen, M. Anttila, A. Kultti, K. Ropponen, J. Penttinen, M. Yliskoski, A. T. Kuronen, M. Juhola, R. Tammi, M. Tammi, et al. Elevated Hyaluronan Concentration without Hyaluronidase Activation in Malignant Epithelial Ovarian Tumors Cancer Res., November 15, 2002; 62(22): 6410 - 6413. [Abstract] [Full Text] [PDF]

				M. Slevin, S. Kumar, and J. Gaffney Angiogenic Oligosaccharides of Hyaluronan Induce Multiple Signaling Pathways Affecting Vascular Endothelial Cell Mitogenic and Wound Healing Responses J. Biol. Chem., October 18, 2002; 277(43): 41046 - 41059. [Abstract] [Full Text] [PDF]

				V. B. Lokeshwar, G. L. Schroeder, R. I. Carey, M. S. Soloway, and N. Iida Regulation of Hyaluronidase Activity by Alternative mRNA Splicing J. Biol. Chem., September 6, 2002; 277(37): 33654 - 33663. [Abstract] [Full Text] [PDF]

				A. Vlahou, P. F. Schellhammer, S. Mendrinos, K. Patel, F. I. Kondylis, L. Gong, S. Nasim, and G. L. Wright Jr. Development of a Novel Proteomic Approach for the Detection of Transitional Cell Carcinoma of the Bladder in Urine Am. J. Pathol., April 1, 2001; 158(4): 1491 - 1502. [Abstract] [Full Text] [PDF]

				G. P. Hemstreet III, S. Yin, Z. Ma, R. B. Bonner, W. Bi, J. Y. Rao, M. Zang, Q. Zheng, B. Bane, N. Asal, et al. Biomarker Risk Assessment and Bladder Cancer Detection in a Cohort Exposed to Benzidine J Natl Cancer Inst, March 21, 2001; 93(6): 427 - 436. [Abstract] [Full Text] [PDF]

				M. Burchardt, T. Burchardt, A. Shabsigh, A. De La Taille, M. C. Benson, and I. Sawczuk Current Concepts in Biomarker Technology for Bladder Cancers Clin. Chem., May 1, 2000; 46(5): 595 - 605. [Abstract] [Full Text] [PDF]

				D. A. Godin, P. C. Fitzpatrick, A. B. Scandurro, P. C. Belafsky, B. A. Woodworth, R. G. Amedee, D. J. Beech, and B. S. Beckman PH-20: A Novel Tumor Marker for Laryngeal Cancer Arch Otolaryngol Head Neck Surg, March 1, 2000; 126(3): 402 - 404. [Abstract] [Full Text] [PDF]

				U. Novak, S. S. Stylli, A. H. Kaye, and G. Lepperdingerm Hyaluronidase-2 Overexpression Accelerates Intracerebral but not Subcutaneous Tumor Formation of Murine Astrocytoma Cells Cancer Res., December 1, 1999; 59(24): 6246 - 6250. [Abstract] [Full Text] [PDF]

				V. B. Lokeshwar, M. J. Young, G. Goudarzi, N. Iida, A. I. Yudin, G. N. Cherr, and M. G. Selzer Identification of Bladder Tumor-derived Hyaluronidase: Its Similarity to HYAL1 Cancer Res., September 1, 1999; 59(17): 4464 - 4470. [Abstract] [Full Text] [PDF]

				N.-S. Chang Hyaluronidase enhancement of TNF-mediated cell death is reversed by TGF-beta 1 Am J Physiol Cell Physiol, December 1, 1997; 273(6): C1987 - C1994. [Abstract] [Full Text] [PDF]

				V. B. Lokeshwar and M. G. Selzer Differences in Hyaluronic Acid-mediated Functions and Signaling in Arterial, Microvessel, and Vein-derived Human Endothelial Cells J. Biol. Chem., September 1, 2000; 275(36): 27641 - 27649. [Abstract] [Full Text] [PDF]

				V. B. Lokeshwar, D. Rubinowicz, G. L. Schroeder, E. Forgacs, J. D. Minna, N. L. Block, M. Nadji, and B. L. Lokeshwar Stromal and Epithelial Expression of Tumor Markers Hyaluronic Acid and HYAL1 Hyaluronidase in Prostate Cancer J. Biol. Chem., April 6, 2001; 276(15): 11922 - 11932. [Abstract] [Full Text] [PDF]