High expression of cathepsin B and plasminogen activator inhibitor type-1 are strong predictors of survival in glioblastomas
- 194 Downloads
In contrast to pilocytic astrocytomas (WHO grade I gliomas) that are circumscribed and cured by surgical resection, invasion is a hallmark of grades II–IV gliomas. Proteases play a major role in the invasion process and correlations between glioma grading, survival and protease expression have been demonstrated. In this study, we have chosen to study using different technical approaches (Q-RT-PCR, in situ hybridization and immunohistochemistry) the expression of five molecules involved in extracellular matrix degradation (cathepsin B, MMP2, MMP9, uPA and PAI-1) in glioblastomas in order to determine their prognostic impact among grade IV gliomas. Pilocytic astrocytomas were used as controls. Q-RT-PCR showed that transcripts of uPA, PAI-1, cathepsin B and MMP9 were significantly more expressed in glioblastomas (n = 52), in comparison to pilocytic astrocytomas (n = 17) (P = 0.049, P < 0.0001, P = 0.03 and P < 0.0001, respectively). On both univariate and multivariate analyses, cathepsin B and PAI-1 were strong predictors of overall survival among the group of glioblastomas (P < 0.0001 and P = 0.01, respectively). Immunohistochemical expression of cathepsin B further confirmed its prognostic value in an independent cohort of patients with glioblastoma. In situ hybridization showed that uPA is detected at the invasive edge of glioblastomas, whereas PAI-1 is more abundant in microvascular proliferation and pseudo-palisading cells than at the infiltrative edges. These results suggest that cathepsin B and PAI-1 are important biomarkers for the stratification of glioblastoma patients with respect to survival.
KeywordsGlioblastomas Invasion process Cathepsin B PAI-1 Proteases Prognostic biomarker
We are grateful to the neurosurgeons Profs. H. Dufour, F. Grisoli, J.C. Peragut, Drs G. Lena, B. Fuentes and P. Roche for providing tumor samples, to N. Dussault, A. Durand, C. Schiano, S. Gilles, P. Morando, E. Cassotte, L. Calvo, C. Cazeaux, M. Delmas and M.F. Trouche for excellent technical assistance. This work was supported by institutional grants to CRO2, by the INCA (Réseau Structurant Gliome RS019), by the INCA platform grant 2007, by the Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’adolescent (SFCE) and by the Association pour la Recherche sur les Tumeurs Cérébrales (ARTC, ARTC Sud). Frozen samples were provided by the AP-HM TumorBank (Authorization Number 2008-70).
- 13.Gole B, Duran Alonso MB, Dolenc V, Lah T (2009) Post-translational regulation of cathepsin B, but not of other cysteine cathepsins, contributes to increased glioblastoma cell invasiveness in vitro. Pathol Oncol Res [Epub ahead of print]Google Scholar
- 21.Lah TT, Obermajer N, Duran-Alonso MB, Kos J (2008) The cancer degradome; proteases and cancer biology: cysteine cathepsins and cystatins as cancer biomarkers. Springer, New YorkGoogle Scholar
- 34.Stoppelli MP, Andersen LM, Votta G, Andreasen PA (2008) The cancer degradome; proteases and cancer biology: engineered antagonists of uPA and PAI-1. Springer, New YorkGoogle Scholar