Annexin A2 is a key determinant of GBM aggressiveness by controlling cancer cell dissemination and proliferation.
Francesca Maule, University of Padova, corso Stati Uniti 4, 35127 Padova, Italy; Silvia Bresolin, University of Padova, corso Stati Uniti 4, 35127 Padova, Italy; Elena Rampazzo, Institute of Pediatric Research – IRP, corso Stati Uniti 4, 35127 Padova, Italy; Daniele Boso, University of Padova, corso Stati Uniti 4, 35127 Padova, Italy; Alessandro Della Puppa, University Hospital of Padova, via Giustiniani 2, 35128 Padova, Italy; Giuseppe Lombardi, Istituto Oncologico Veneto – IOV, via Gattamelata 64, 35128 Padova, Italy; Benedetta Accordi, University of Padova, corso Stati Uniti 4, 35127 Padova, Italy; Giuseppe Basso, University of Padova, corso Stati Uniti 4,35127 Padova, Italy; Luca Persano, Institute of Pediatric Research – IRP, corso Stati Uniti 4, 35127 Padova, Italy
Increasing evidence underlines the importance of imaging techniques (MRI and PET) in order to improve the extent of resection of Glioblastoma (GBM) tumours, which is considered an important prognostic factor in these patients. However, despite the recent introduction of 5-ALA fluorescent imaging into the surgical management of GBM, progression free survival of patients has been increased of only 6 months. Thus, the identification and possible targeting of the molecular mechanisms involved in GBM cell heterogeneity and dissemination (responsible for resection escape) is becoming a particularly relevant issue. In this context, Annexin A2 (lipocortin II, ANXA2,) is a phospholipid-binding protein expressed in a variety of cell types, including cancer cells, which serves as a co-receptor for plasminogen and tissue plasminogen activator (t-PA). For this reason, ANXA2 expression has been associated to a more invasive and migratory phenotype in many tumours, including leukemia, breast, gastric, pancreatic, lung and prostate cancer, hepatoma and also brain tumours.
In this study, we report that ANXA2 is over-expressed in gliomas in different cohorts of patients (from our centre and from public databases) and demonstrated that ANXA2 expression could be considered an independent prognostic factor in GBM. Moreover, we show that ANXA2 targeting, by using neutralizing antibodies or gene silencing techniques, is sufficient to dramatically inhibit primary GBM cell migration and extracellular matrix invasion together with a massive redistribution of intracellular actin filaments. In addition, ANXA2 down-regulation is associated to a partial induction of GBM cell differentiation as shown by a significant reduction of the stem cell markers CD133 and Nestin and the up-regulation of the astrocytic marker GFAP. Finally, we generated an ANXA2-dependent gene signature suggesting, beyond cell migration and invasion, its involvement also in the regulation of the cell cycle and proliferation, thus making ANXA2 a reasonable target for GBM therapy.
In conclusion, our data support the idea that ANXA2 is a fundamental mediator of GBM cell aggressiveness by controlling cell dissemination and, in part, cell cycle dynamics.