EXPRESSION OF SCATTER FACTOR IN HUMAN BLADDER-CARCINOMA

Background: Scatter factor (SF) is a protein secreted by stromal (supp orting) cells that induces disruption of intercellular junctions and s timulates motility and invasiveness of carcinoma cells. SF is also a p otent 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 tha t the accumulation of SF within tumors might promote progression to a more malignant phenotype. Purpose: This study was designed to determin e if SF is overexpressed in carcinoma of the bladder and to evaluate t he potential mechanisms that might account for such overproduction. Me thods: We measured the SF content in urine from 20 patients with carci noma of the bladder and various control groups. We also measured expre ssion of SF in bladder tumor extracts, histologic sections of tumors, and cell culture models, using a variety of techniques, including enzy me-linked immunosorbent assays, immunohistochemistry, and Western and Northern blot analyses. Statistical comparisons were performed using t wo-tailed t tests. Results: Urinary SF content was found to be signifi cantly elevated in patients with bladder carcinoma as compared with no rmal control subjects (P < .001), patients with benign prostatic hyper trophy (P = .0055), and patients with prostate carcinoma, another geni tourinary malignancy (P = .002). Extracts of bladder cancers, especial ly those from high-grade, invasive tumors, contained very high levels of SF. Both SF and its proto-oncogene (c-met)-encoded receptor were de tected in bladder carcinoma tissue sections by immunostaining. Three d ifferent bladder carcinoma cell lines produced no detectable SF but pr oduced very high titers of a high-molecular-weight (> 30 kd), heat-sen sitive protein that stimulates SF production by stromal cell types. Hi gh 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 i nteraction in which dysplastic or carcinomatous urothelium secretes fa ctors that stimulate SF expression by bladder wall stromal cells. Impl ication: Quantitation of SF in the urine and tumor deserves further st udy as a possible marker of urothelial malignancy.