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Two Mechanisms of Basic Fibroblast Growth Factor-induced Angiogenesis in Bladder Cancer¹

Molecular Angiogenesis Group, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital [T. O., R. B., A. L. H.] and Nuffield Department of Surgery [T. O., S. F.], University of Oxford, Oxford, OX3 9DU, and Department of Urology, Churchill Hospital, Oxford, OX3 7DL [T. O., D. C.], England

In the urine of patients with bladder cancer, levels of the angiogenic peptide basic fibroblast growth factor (bFGF) may be elevated 100-fold. To date, levels of expression of bFGF in bladder tumor tissue have not been determined, nor has the cellular source of the urinary bFGF been identified.

bFGF mRNA expression was quantified using RNase protection analysis in 32 primary bladder tumors and 8 normal bladder specimens. In addition, bFGF protein expression in the tumor cytosol was determined using a Quantikine ELISA, and bFGF protein expression was localized with immunohistochemistry.

bFGF mRNA expression was absent in 28 of 32 (87%) bladder cancers despite detectable expression in 7 of 8 (87%) normal bladder specimens (P = 0.0001). In only one tumor was bFGF mRNA expression higher than in normal bladder tissue. Median bFGF protein expression was also higher in the normal bladder specimens than in the superficial tumors (3800 pg/g protein versus 1140 pg/g protein; P < 0.02), but there was no statistically significant difference between protein expression in normal bladder and invasive cancers (3800 pg/g versus 3600 pg/g). Median bFGF protein expression was higher in invasive cancers than in superficial tumors (P < 0.05).

Intense bFGF immunoreactivity was seen in the basal lamina of normal transitional epithelium, in normal human detrusor muscle, and in vessels within tumors. Tumor cell immunoreactivity was rare and was usually weak. Only in the tumor which strongly overexpressed bFGF mRNA and protein was cytoplasmic staining detectable in the neoplastic cells.

There are two mechanisms of bFGF-induced angiogenesis in bladder cancer. Rarely, neoplastic cells synthesize bFGF but more commonly bFGF is released by degradation of epithelial basement membranes and detrusor muscle, from where it can diffuse into the tumor microenvironment and bind to blood vessels. Mechanisms of extracellular matrix degradation may be important in bladder cancer angiogenesis and progression and as such are potential therapeutic targets.

¹ This work was supported by The Private Patients Plan Research Scholarship of the Royal College of Surgeons of England (to T. O.), the Medical Research Council (to S. F.), and the Imperial Cancer Research Fund (to R. B., A. L. H.).

² To whom requests for reprints should be addressed. Phone: 01865-222457; Fax: 01865-222431.

Received 1/22/96. Accepted 10/31/96.

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