A nuclear form of the heparin-binding epidermal growth factor-like growth factor precursor is a feature of aggressive transitional cell carcinoma.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the ErbB receptor ligand family, exists in distinct molecular forms with disparate biological activities. Previous studies have shown that the HB-EGF precursor, proHB-EGF, localizes to the cytoplasm of transitional cells of the human bladder urothelium and that the soluble form of the growth factor is an autocrine urothelial cell mitogen. In this study, we identify a potential role for proHB-EGF in transitional cell carcinoma (TCC) of the bladder. In an analysis of 33 TCC specimens and 8 normal controls, proHB-EGF, identified using an antibody directed against the cytoplasmic tail domain, localized to cell nuclei in a manner that correlated positively with tumor stage and grade (P < 0.001). The ability of proHB-EGF to localize to the nucleus was independently confirmed in a TCC cell line (TCCSUP), in which approximately 40% of transfected proHB-EGF was found to reside in the nuclear compartment. In Kaplan-Meier survival analysis, TCC patients with >20% proHB-EGF-positive cell nuclei demonstrated markedly reduced survival compared with patients with <20% proHB-EGF-positive nuclei (P < 0.005, log-rank test). In multivariate analysis, nuclear localization of proHB-EGF of >20% was an independent prognostic indicator of disease-specific mortality. This is the first report in any cell type that HB-EGF is capable of translocating to the cell nucleus. In addition, our findings suggest that nuclear proHB-EGF may play a role in disease progression in bladder cancer and possibly other cancers.

Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer.

PURPOSE: The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied. EXPERIMENTAL DESIGN: A total of 134 patients with bladder tumors (7 cis, 76 T(a), 27 T(1), 24 T(2)-T(4); 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied. Samples from 106 patients with bladder cancer and 12 controls were stained for MMP-9. Clinical follow-up data were available on 116 patients (median: 25 months; range: 4-36 months). RESULTS: MMP-9 was present in all urine samples analyzed. There were no differences between patients with cancer and patients with benign disorders. However, patients had significantly higher urinary MMP-9 than normal volunteers (P = 0.0167). Urinary MMP-9 was associated with bladder tumors of advanced stage (P = 0.0065) and large size (P < 0.0001) but not with grade (P = 0.14), multiplicity (P = 0.31), recurrence (P = 0.55), progression (P = 0.83), or survival (P = 0.55). Low MMP-9:TIMP-1 ratios in patients with nonmuscle-invasive tumors were associated with higher recurrence rates (P = 0.0035). Sixty percent (64 of 106) of bladder tumor specimens expressed MMP-9 compared with none of 12 normal urothelial biopsies (P < 0.0001). MMP-9 staining was associated with tumor size (P = 0.014), disease progression (P = 0.005), and poor disease-specific survival (P = 0.022) but was unrelated to tumor stage (P = 0.46), grade (P = 0.26), multiplicity (P = 0.85), or recurrence rate (P = 0.62). CONCLUSIONS: High urinary MMP-9 levels are associated with large bladder tumors. A low urinary MMP-9:TIMP-1 ratio may indicate a higher risk of intraluminal nonmuscle-invasive tumor recurrence and may assist in planning follow-up surveillance protocols.