Membrane-Type Matrix Metalloproteinase-1 Expression and Activation of Gelatinase A as Prognostic Markers in Advanced Pediatric Neuroblastoma

BACKGROUND Recently a novel membrane-type matrix metalloproteinase-1 (MT-MMP-1) was discovered to be a specific activator of progelatinase A, and was correlated with tumor invasion. To the authors' knowledge, no information regarding the expression of MT-MMP-1 has been reported in childhood malignancies. In this study, the authors attempted to elucidate the specific mechanisms that underlay the invasive behavior of neuroblastoma (NB) cells with respect to the expression of MT-MMP-1 and its determined prognostic value, especially in pediatric patients with advanced Evans' Stage IV NB. METHODS Thirty specimens from surgically excised NB (mainly Stage IV) were collected retrospectively. The total levels of progelatinase A (68 kilodaltons [kD]) and its activated form (62 kD) in the tumor lysates were quantified by gelatin zymography. The expression of MT-MMP-1 was estimated by immunostaining with a monoclonal antibody (113-5B7). RESULTS Progelatinase A and the activated form were detected in each of the 30 specimens. The gelatinase A activation ratio, 62 kD/(62 kD + 68 kD), strongly correlated with the high levels of MT-MMP-1 expression found in specimens of advanced tumor stage. In the patients with advanced Stage IV NB, the activation ratio was strongly associated with unfavorable clinical outcome; the 5-year survival was 88.9% in the patients with a low activation ratio (≤26%) versus only 21.2% in the patients with a high activation ratio (>26%). CONCLUSIONS Gelatinase A activation correlates with high expression of MT-MMP-1 on NB cells and is associated strongly with advanced stage and poor clinical outcome. These results are consistent with the notion that MT-MMP-1 expression is an important prognostic determinant of the biologic behavior of NB. Cancer 1999;85:231–9. © 1999 American Cancer Society.