Abstract
Glioblastoma (GBM) is the most devastating tumor of the brain, characterized by an almost inevitable tendency to recur after intensive treatments and a fatal prognosis. Indeed, despite recent technical improvements in GBM surgery, the complete eradication of cancer cell disseminated outside the tumor mass still remains a crucial issue for glioma patients management. In this context, Annexin 2A (ANXA2) is a phospholipid-binding protein expressed in a variety of cell types, whose expression has been recently associated with cell dissemination and metastasis in many cancer types, thus making ANXA2 an attractive putative regulator of cell invasion also in GBM.Here we show that ANXA2 is over-expressed in GBM and positively correlates with tumor aggressiveness and patient survival. In particular, we associate the expression of ANXA2 to a mesenchymal and metastatic phenotype of GBM tumors. Moreover, we functionally characterized the effects exerted by ANXA2 inhibition in primary GBM cultures, demonstrating its ability to sustain cell migration, matrix invasion, cytoskeletal remodeling and proliferation. Finally, we were able to generate an ANXA2-dependent gene signature with a significant prognostic potential in different cohorts of solid tumor patients, including GBM.In conclusion, we demonstrate that ANXA2 acts at multiple levels in determining the disseminating and aggressive behaviour of GBM cells, thus proving its potential as a possible target and strong prognostic factor in the future management of GBM patients.
Highlights
Glioblastoma multiforme (GBM) is the highest grade glioma, considered as the most aggressive primary brain tumor in the adult [1]
Failure of multimodal treatments, which include surgery, radio- and adjuvant chemo-therapy, has often been associated to: i) the intrinsic highly infiltrative phenotype of GBM cells [5, 6]; ii) the presence of cancer cells endowed with stemlike features, which have been reported to be resistant to standard chemotherapies [7,8,9]
Most GBM tumors recur within 2 cm from the original tumor margin
Summary
Glioblastoma multiforme (GBM) is the highest grade glioma (grade IV), considered as the most aggressive primary brain tumor in the adult [1]. Failure of multimodal treatments, which include surgery, radio- and adjuvant chemo-therapy, has often been associated to: i) the intrinsic highly infiltrative phenotype of GBM cells [5, 6]; ii) the presence of cancer cells endowed with stemlike features, which have been reported to be resistant to standard chemotherapies [7,8,9]. In this context, the introduction of 5-ALA in order to improve the identification and surgical eradication of disseminated GBM cells, www.impactjournals.com/oncotarget significantly increased patient survival [10, 11]. These considerations make relevant the identification and potential targeting of the molecular mechanisms sustaining GBM cell heterogeneity and dissemination
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