Abstract
Nitric oxide (NO) is synthesized by the enzyme family of nitric oxide synthases (NOS) and plays an important role in tumor growth and angiogenesis. The expression of two of the NOS isoforms, the endothelial and inducible isoforms (eNOS and iNOS, respectively), were evaluated in bladder tissue from patients with transitional cell carcinoma (TCC). The specimens were procured from 58 patients with TCC and 14 cases of normal bladder mucosa were used as a control group. NOS immunohistochemistry was performed and microvessal density (MVD) was determined. iNOS specific proteins were found in 47 of 58 bladder cancer specimens but not in control bladder tissue. The endothelial cells in both normal urothelium and tumor tissue showed a highly positive eNOS immunostaining. The MVD was 39.3±19.5 and 29.3±10.5 in TCC positive and negative for iNOS, respectively (P<0.01). A correlation between iNOS immunoreactivity and tumor grade in bladder carcinoma could not be verified. These results indicate that NO generation from iNOS in the malignant epithelium and from eNOS in tumor stroma play a important role in tumor angiogenesis.
Similar content being viewed by others
References
Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, Klein S, Shields PG, Billiar TR, Harris CC (1998) Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Cancer Res 58: 334
Andrade SP, Hart ID, Piper PJ (1992) Inhibitors of nitric oxide synthase selectively reduce flow in tumor associated neovasculature. Br J Pharmacol 107: 1092
Chhatwal VJ, Ngoi SS, Chan ST, Chia YW, Moochhala SM (1994) Aberrant expression of nitric oxide synthase in human polyps, neoplastic colonic mucosa and surrounding peritumoral normal mucosa. Carcinogenesis 15: 2081
Edwards P, Cendan JC, Topping DB, Moldawer LL, MacKay S, Copeland EMIII, Lind DS (1996) Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J Surg Res 63: 49
Forstermann U, Kleinert H (1995) Nitric oxide synthase expression and expressional control of three isoforms. Arch Pharmacol 352: 351
Fujimoto H, Ando Y, Yamashita T (1997) Nitric oxide synthase activity in human lung cancer. Jpn J Cancer Res 88: 1190
Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA, Ziche M (1998) Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst 90: 587
Geller DA, Billiar TR (1998) Molecular biology of nitric oxide synthases Cancer Metastasis Rev 17: 7
Jansson OT, Morcos E, Brundin L, Lundberg JON, Adolfsson J, Soderhall M, Wiklund NP (1998) The role of nitric oxide in bacillus Calmette-Guerin mediated anti-tumor effects in human bladder cancer. Br J Cancer 78: 588
Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S (1995) Roles of nitric in tumor growth. Proc Natl Acad Sci U S A 92: 4392
Klotz T, Bloch W, Volberg C, Engelmann U, Addicks K (1998) Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82: 1897
Klotz T, Bloch W, Jacobs G, Niggemann S, Engelmann U, Addicks K (1999) Immunolocalization of inducible and constitutive nitric oxide synthases in human bladder cancer. Urology 54: 416
Leibovich SJ, Polverini PJ, Fong TW, Harbow LA, Koch AE (1994) Production of angiogenetic activity by human monocytes requires an L-arginine/nitric oxide-synthase-dependent effector mechanism. Proc Natl Acad Sci U S A 91: 4190
Macdonald JE (1996) Nitric oxide synthase inhibitors. Ann Rep Med Chem 23: 221
Mayer B, Andrew P (1998) Nitric oxide synthases catalytic function and progress towards selective inhibition. Arch Pharmacol 358: 127
Mitropoulis D, Petris D, Kiroudi A, Kyriakou G, Rasdan A, Zervas A, Dimopoulos C. (2000) The effect of intravesical Bacillus Calmette-Guerin (BCG) instillations on the expression of inducible nitric oxide synthase (iNOS) in humans. Eur Urol 2000 38: 516
Moncada S, Higgs A (1993) The L-arginine nitric oxide pathway. N Engl J Med 329: 2002
Moochala S, Chhatwal VJS, Ngoi SS, Chia YW, Rauff A (1996) Nitric synthase activity and expression in human colorectal cancer. Carcinogenesis 17: 1171
Pitzele BS (1997) The modulation of the action of isoforms of nitric oxide synthase. Expert Opin Ther Patients 7: 717
Shochina M, Fellig Y, Sughayer M, Pizov G, Vitner K, Podeh D, Hochberg A, Ariel I (2001) Nitric oxide synthase immunoreactivity in human bladder carcinoma. J Clin Pathol 54: 248
Swana HS, Smith SD, Perrotta PL, Saito N, Wheeler MA, Weiss RM (1999) Inducible nitric oxide synthase with transitional cell carcinoma of the bladder. J Urol 161: 630
Thomsen LL, Lawton FG, Knowles RG, Beesley JE, Riverros-Moreno V, Moncada S (1994) Nitric oxide synthase activity in human gynecological cancer. Cancer Res 54: 1352
Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S (1995) Nitric oxide synthase activity in human breast cancer. Br J Cancer 72: 41
Weidner N, Semple J, Welch W (1991) Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med 324: 1
Wolf H, Haeckel C, Roessner A (2000) Inducible nitric oxide synthase expression in human urinary bladder cancer. Virchows Arch 437: 662
Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, Bicknell R (1997) Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 99: 2625
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lin, Z., Chen, S., Ye, C. et al. Nitric oxide synthase expression in human bladder cancer and its relation to angiogenesis. Urol Res 31, 232–235 (2003). https://doi.org/10.1007/s00240-003-0302-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00240-003-0302-9