Abstract
The high mortality in glioblastoma multiforme (GBM) patients is primarily caused by extensive infiltration into adjacent tissue and subsequent rapid recurrence. There are no clear therapeutic strategies that target the infiltrative subpopulation of GBM mass. Using mesenchymal mode of invasion, the GBM is known to widely infiltrate by interacting with various unique components within brain microenvironment such as hyaluronic acid (HA)-rich matrix and white matter tracts. However, it is unclear how these GBM microenvironments influence the strategies of mesenchymal invasion. We hypothesize that GBM has different strategies to facilitate such invasion through adaptation to their local microenvironment. Using our in vitro biomimetic microenvironment platform for three-dimensional GBM tumorspheres (TSs), we found that the strategies of GBM invasion were predominantly regulated by the HA-rich ECM microenvironment, showing marked phenotypic changes in the presence of HA, which were mainly mediated by HA synthase (HAS). Interestingly, after inhibition of the HAS gene, GBM switched their invasion strategies to a focal adhesion (FA)-mediated invasion. These results demonstrate that the microenvironmental adaptation allowed a flexible invasion strategy for GBM. Using our model, we suggest a new inhibitory pathway for targeting infiltrative GBM and propose an importance of multi-target therapy for GBM, which underwent microenvironmental adaptation.
Highlights
Tumor cells possess a broad pattern of invasion mechanism, such as individual and collective cell migration, in response to different conditions, efforts to understand how ECM composition, mechanical properties, and topography influence on the mechanisms of tumor invasion have been ongoing for decades[4,5,6,7,8,9,10,11]
The components of the ECM in brain tumor tissue have not been fully elucidated yet, it has been reported that amorphous ECM at the invasive front of proliferating glioblastoma multiforme (GBM) is highly expressed such as glycosaminoglycans (GAGs), especially hyaluronic acid (HA)[31,32,33], and they strongly up-regulated fibrous and adhesive ECM proteins,[34]
Whereas there was no change in FA kinase (FAK) expression, vinculin expression was increased in GBM than in normal tissue (Fig. S1)
Summary
Tumor cells possess a broad pattern of invasion mechanism, such as individual and collective cell migration, in response to different conditions, efforts to understand how ECM composition, mechanical properties (e.g., stiffness or porosity), and topography influence on the mechanisms of tumor invasion have been ongoing for decades[4,5,6,7,8,9,10,11]. These research have indicated that the glioblastoma cells migrate individually with the mesenchymal mode of motility in a traction-dependent manner, so called saltatory migration[25,26,27] In this process, the GBM cells generate a strong adhesion force at the focal contacts on ECM by intensively concentrating the integrins[25]. Proteolytic enzymes including matrix metalloproteases (MMPs) are intensively involved in ECM remodeling at these focal sites[25,29] For this reason, targeting the proteolytic process in mesenchymal movement of GBM cells has been highlighted as a promising therapy to inhibit wide invasion. Despite intensive efforts, there has been little improvement offered by the new therapeutic strategies
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