Abstract
BACKGROUND.
Cleavage of membrane‐anchored heparin‐binding epidermal growth factor‐like growth factor (proHB‐EGF) yields a soluble HB‐EGF isoform (sHB‐EGF), which is an activating epidermal growth factor receptor (EGFR) ligand and a C‐terminal fragment HB‐EGF‐C acting directly in the nucleus. In bladder cancer, overexpression of both HB‐EGF and EGFR have been observed, but to the authors' knowledge the prognostic significance of different modes of HB‐EGF signaling have remained unclear.
METHODS.
Expression and intracellular localization of HB‐EGF and EGFR were examined by immunohistochemistry in paraffin‐embedded specimens from 121 patients who underwent cystectomy for bladder cancer. Tumor stage was pTis/pT1 in 7 patients, pT2 in 41 patients, pT3 in 55 patients, and pT4 in 18 patients. Lymph node metastases were present in 32 patients.
RESULTS.
Using an antibody directed against the C‐terminal domain, HB‐EGF expression was detected in the cytoplasm or in the nucleus of tumor cells. EGFR staining was uniform at the plasma membrane. The actuarial 5‐year cancer‐specific survival of patients with tumors with predominant nuclear HB‐EGF staining was 28% compared with 57% if HB‐EGF staining was predominantly cytoplasmic (P = .027). Disease outcome of patients with a ‘mixed’ HB‐EGF staining pattern was found to be between that of the 2 former groups. In agreement with previous studies, strong EGFR expression was associated with poor prognosis. Despite strong EGFR expression, predominant cytoplasmic HB‐EGF staining was associated with a more favorable outcome, whereas a predominant nuclear pattern defined a subgroup with extremely poor prognosis (5‐year tumor‐specific survival of 55% vs 13%, respectively; P = .026).
CONCLUSIONS.
The current study results confirm that EGFR expression is significantly correlated with disease‐specific mortality but that the outcome is also influenced by the mode of HB‐EGF signaling. Additional nuclear HB‐EGF signaling, indicative of increased cleavage of proHB‐EGF, appears to enhance the adverse activities. Cytoplasmic HB‐EGF staining likely reflects proHB‐EGF, which may also exert antiproliferative effects. Cancer 2007. © 2007 American Cancer Society.