Abstract
Both hydrostatic and osmotic pressures are altered in the tumour microenvironment. Glioblastoma (GBM) is a brain tumour with high invasiveness and poor prognosis. We hypothesized that physical and osmotic forces regulate glioblastoma (GBM) invasiveness. The osmotic pressure of GBM cell culture medium was adjusted using sodium chloride or water. Alternatively, cells were subjected to increased hydrostatic force. The proteolytic profile and epithelial–mesenchymal transition (EMT) were investigated using zymography and real-time qPCR. The EMT markers assessed were Snail-1, Snail-2, N-cadherin, Twist and vimentin. Invasion was investigated in vitro using extracellular matrix-coated Transwell inserts. In response to osmotic and mechanical pressure, GBM cell lines U87 and U251 and patient-derived neural oncospheres upregulated the expression of urokinase-type plasminogen activator (uPA) and/or matrix metalloproteinases (MMPs) as well as some of the EMT markers tested. The adherent cell lines invaded more when placed in media of increased osmolality. Therefore, GBM respond to osmotic or mechanical pressure by increasing matrix degrading enzyme production, and adopting a phenotype reminiscent of EMT. Better understanding the molecular and cellular mechanisms by which increased pressure promotes GBM invasiveness may help to develop innovative therapeutic approaches.
Highlights
Both hydrostatic and osmotic pressures are altered in the tumour microenvironment
While hypoosmotic stress had essentially no effect on urokinase-type plasminogen activator (uPA) production, there was an increase in uPA in response to hyperosmolality which was more dramatic in the conditioned medium of the adherent cell lines compared to that of the oncospheres
Densitometric quantification revealed that uPA was increased 2–3 fold in U87, 3–4 fold in U251, and by ~50% in 081024 cells (Fig. 1b) by the highest hyper-osmolality (440 and 415 mOsmol/kg for adherent and oncosphere cells, respectively)
Summary
Both hydrostatic and osmotic pressures are altered in the tumour microenvironment. Glioblastoma (GBM) is a brain tumour with high invasiveness and poor prognosis. In response to osmotic and mechanical pressure, GBM cell lines U87 and U251 and patient-derived neural oncospheres upregulated the expression of urokinase-type plasminogen activator (uPA) and/or matrix metalloproteinases (MMPs) as well as some of the EMT markers tested. While tissue-type plasminogen activator (tPA) plays a role in the fibrinolytic process, uPA is involved in cell migration and tissue remodelling, thereby playing a major role in cancer development and spreading This role is especially crucial in glioblastoma[9,10,11]. Reports showed that the MMPs play pivotal roles in the invasiveness of GBM by degrading surrounding tissue, activating signal transduction, releasing ECM-bound growth factors, activating www.nature.com/scientificreports growth factors, increasing tumour cell motility, and promoting angiogenesis[12,13,14,15]. We hypothesized that pressure characteristic of the GBM microenvironment, i.e. dysregulated osmotic and mechanical pressure, promote GBM cell invasiveness
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