Mitochondrial network in glioma's invadopodia displays an activated state both in situ and in vitro: potential functional implications

Abstract

Gliomas are typically characterized by their infiltrative nature, and the prognosis can be linked to the invasive nature of the tumoral cells. Glioblastoma multiforme are very invasive cancers and this contributes to their lethality. The invadopodia are considered essential for their motility. Human glioma cell invadopodia were examined with transmission electron and immunofluorescent microscopy. By electron microscopy, in situ gliomas (fibrillary astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, pilocytic astrocytoma) show mitochondria with a dense matrix condensed configuration, indicating an active state. The mitochondria were frequently in close contact with an extended smooth endoplasmic reticulum displaying an endoplasmic reticulum subfraction associated with mitochondria. Mitochondria were seen within the filopodia that were penetrating into the extracellular matrix. The activated mitochondria and smooth endoplasmic reticulum were also detected within the invadopdia, which was associated microblood vessels. Fluorescent microscopy confirmed that D54 and U251 glioma cells growing in vitro also contained filopodia with mitochondria. The U251 glioma cells' filopodia that penetrated through 1.2-μm pores of transwell chambers also contained mitocondria, suggesting that the mitochondria are actively involved in the invasion process. Migration and invasion of tumor cells requires an increase in cellular motility and involves formation of lamellipodia, protrusions of the plasma membrane, and individual filopodia [ 1 ]. Gliomas are typically characterized by their infiltrative nature, resulting in a poorly demarcated interface between tumor and normal brain tissue. Their poor prognosis can be linked to the invasive nature of these cells. The motility of these tumor cells is correlated with the presence of invadopodia [ 2 ], and, consequently, more insight is necessary into their structural and molecular aspects. Evidence of robust invadopodia activity in glioblastoma multiforme cells has been reported [ 3 , 4 ]. Because of the significant impact of invadopodia in oncological events such as cell invasion and matrix degradation, more insight into structural and molecular aspects is needed [ 2 ]. The dynamic assembly of invadopodia is still not well understood [ 2 ], and little is known of the alterations in mitochondrial structure and function that contribute to cell mobility [ 5 ]. This paper describes two prominent structural features of the mitochondrial network present within the glioma´s invadopodia that we have recently observed. We believe these two features (activated mitochondria and smooth ER, along with mitochondria contained within the filopodia) might provide researchers with possible targets for future therapies that can control glioma invasiveness.