Abstract
In solid tumours, elevated interstitial fluid pressure (osmotic and hydrostatic pressure) is a barrier to drug delivery and correlates with poor prognosis. Glioblastoma (GBM) further experience compressive force when growing within a space limited by the skull. Caveolae are proposed to play mechanosensing roles, and caveola‐forming proteins are overexpressed in GBM. We asked whether caveolae mediate the GBM response to osmotic pressure. We evaluated in vitro the influence of spontaneous or experimental down‐regulation of caveola‐forming proteins (caveolin‐1, CAVIN1) on the proteolytic profile and invasiveness of GBM cells in response to osmotic pressure. In response to osmotic pressure, GBM cell lines expressing caveola‐forming proteins up‐regulated plasminogen activator (uPA) and/or matrix metalloproteinases (MMPs), some EMT markers and increased their in vitro invasion potential. Down‐regulation of caveola‐forming proteins impaired this response and prevented hyperosmolarity‐induced mRNA expression of the water channel aquaporin 1. CRISPR ablation of caveola‐forming proteins further lowered expression of matrix proteases and EMT markers in response to hydrostatic pressure, as a model of mechanical force. GBM respond to pressure by increasing matrix‐degrading enzyme production, mesenchymal phenotype and invasion. Caveola‐forming proteins mediate, at least in part, the pro‐invasive response of GBM to pressure. This may represent a novel target in GBM treatment.
Highlights
Solid tumours are exposed to osmotic and mechanical stresses
We have previously demonstrated that the expression of caveolin-1 and CAVIN1 correlates with GBM invasiveness 12 and that GBM cells respond to osmotic pressure by increased production of matrix-degrading enzymes, epithelial-to-mesenchymal transition (EMT) markers and invasion.[19]
The results indicate that the down-regulation of either CAV1 (Figure S2a,b) or CAVIN1 (Figure S2c,d) did not affect the cell response to pressure when we quantified the mRNA expression of matrix proteases (Figure S2a,c) or EMT markers (Figure S2b,d)
Summary
Solid tumours are exposed to osmotic and mechanical stresses Both preclinical and clinical studies indicate that tumours are generally poorly perfused, and tumour interstitial fluid pressure (IFP) is increased compared to normal tissue, with both increased hydrostatic pressure and oncotic pressure. This results from a combination of factors, including inefficient lymphatic drainage of soluble proteins, leaky and dysfunctional blood vessels, increased fibroblast numbers, thicker collagen fibres and accumulation of inflammatory factor-secreting cells.[1-3]. The expression of both caveolin-1 and CAVIN1 are increased in GBM compared to normal samples and are associated with shorter patient survival time and correlated with expression of the matrix proteases uPA and gelatinases.[12]. We investigated whether caveolae mediate the pro-invasive response to pressure in GBM cells
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