EXPRESSION OF SCATTER FACTOR IN HUMAN BLADDER-CARCINOMA

Background: Scatter factor (SF) is a protein secreted by stromal (supporting) cells that induces disruption of intercellular junctions and stimulates motility and invasiveness of carcinoma cells. SF is also a potent inducer of angiogenesis (new blood vessel formation), a process required for tumor growth and dissemination, Invasion and angiogenesis are characteristics of biologically aggressive tumors, suggesting that the accumulation of SF within tumors might promote progression to a more malignant phenotype. Purpose: This study was designed to determine if SF is overexpressed in carcinoma of the bladder and to evaluate the potential mechanisms that might account for such overproduction. Methods: We measured the SF content in urine from 20 patients with carcinoma of the bladder and various control groups. We also measured expression of SF in bladder tumor extracts, histologic sections of tumors, and cell culture models, using a variety of techniques, including enzyme-linked immunosorbent assays, immunohistochemistry, and Western and Northern blot analyses. Statistical comparisons were performed using two-tailed t tests. Results: Urinary SF content was found to be significantly elevated in patients with bladder carcinoma as compared with normal control subjects (P < .001), patients with benign prostatic hypertrophy (P = .0055), and patients with prostate carcinoma, another genitourinary malignancy (P = .002). Extracts of bladder cancers, especially those from high-grade, invasive tumors, contained very high levels of SF. Both SF and its proto-oncogene (c-met)-encoded receptor were detected in bladder carcinoma tissue sections by immunostaining. Three different bladder carcinoma cell lines produced no detectable SF but produced very high titers of a high-molecular-weight (> 30 kd), heat-sensitive protein that stimulates SF production by stromal cell types. High titers of a similar SE-inducing activity were detected in vivo, in bladder carcinoma extracts, and in the urine of patients with bladder carcinoma. Conclusions: Our results suggest that SF is overproduced in bladder carcinomas and accumulates within the tumor and in the urine. Overproduction of SF may result from an abnormal urothelial-stromal interaction in which dysplastic or carcinomatous urothelium secretes factors that stimulate SF expression by bladder wall stromal cells. Implication: Quantitation of SF in the urine and tumor deserves further study as a possible marker of urothelial malignancy.