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Fibronectin Promotes the Malignancy of Glioma Stem-Like Cells Via Modulation of Cell Adhesion, Differentiation, Proliferation and Chemoresistance.

ABSTRACT: Glioma stem-like cells (GSCs) are regarded as the sources of oncogenesis, recurrence, invasion and chemoresistance in malignant gliomas. Growing evidence suggests that the microenvironment surrounding GSCs interacts with tumor cells to influence biological behavior; however, the functional mechanisms involved are still unclear. In the present study, we investigated the modulation of GSCs triggered by fibronectin (FN), a main component of the extracellular matrix (ECM), in terms of cell adhesion, differentiation, proliferation and chemoresistance. We demonstrated that pre-coated FN prompted increased adherence by GSCs, with increased matrix metallopeptidases (MMPs)-2 and -9 expression, in a concentration-dependent manner. Decreases in sox-2 and nestin levels, and increased levels of glial fibrillary acidic protein (GFAP) and β-tubulin were also found in GSCs, indicating cell differentiation driven by FN. Further investigation revealed that FN promoted cell growth, as demonstrated by the elevation of Ki-67, with the activation of p-ERK1/2 and cyclin D1 also evident. In addition, FN suppressed p53-mediated apoptosis and upregulated P-glycoprotein expression, making GSCs more chemoresistant to alkylating agents such as carmustine. In contrast, this effect was reversed by an integrin inhibitor, cilengitide. Activation of the focal adhesion kinase/paxillin/AKT signaling pathway was involved in the modulation of GSCs by FN. Focusing on the interactions between tumor cells and the ECM may be an encouraging aspect of research on novel chemotherapeutic therapies in future.

SUBMITTER: Yu Q

PROVIDER: S-EPMC5908975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To assess the effect of fibronectin (Fn) and porcine type I collagen (PCOL) on odontoblast-like cells in vitro.Rat odontoblast-like cells (MDPC-23 cells) were inoculated and cultured on Fn-coated or type I collagen-coated substrates. Proliferation assay, alkaline phosphatase activity (ALP activity), mRNA expression of hard tissue-forming markers, and Alizarin red staining were investigated over a period of 10 days.Cells maintained a high proliferation activity on Fn and PCOL even at a low seeding concentration (0.5×104/mL) as demonstrated by CCK-8 assay. The proliferation activity of cells on Fn increases in a concentration-dependent manner while it reached a plateau after 10 µg/mL. Cells adopted long, thin and spindle shape on Fn(10-50) and PCOL. Parallel actin filaments were observed in MDPC-23 cells cultured on Fn and PCOL. ALP activity was markedly up-regulated on Fn and PCOL-coated surfaces. Importantly, gene expression of BSP (Fn10: 2.44±0.32; Fn20: 3.05±0.01; Fn30: 2.90±0.21; Fn40: 2.74±0.30; Fn50: 2.64±0.12; PCOL: 2.20±0.03) and OCN (Fn10: 2.52±0.23; Fn20: 2.28±0.24; Fn30: 2.34±0.21; Fn40: 2.34±0.25; Fn50: 2.20±0.22; PCOL: 1.56±0.16) was significantly enhanced on Fn and PCOL substrates as compared with control; moreover, expression of integrin beta 1 (ITGB1), an ubiquitous cell surface receptor was augmented in Fn(10-50) and PCOL groups simultaneously. In accordance with the ALP activity and gene expression data, calcific deposition in cells grown on Fn(10-50) and PCOL was observed as well.Despite the limitation of this study, the findings indicate that a surface coating of Fn enhances the proliferation, differentiation and mineralization of odontoblast-like cells by activation of integrin beta 1 (ITG B1). The promoting effects of Fn on MDPC-23 cells were achieved at a comparatively lower coating concentration than type I collagen (300 µg/mL). Specifically, it is suggested that the optimum coating concentration of Fn to be 10 µg/mL.

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Fibronectin Promotes the Malignancy of Glioma Stem-Like Cells Via Modulation of Cell Adhesion, Differentiation, Proliferation and Chemoresistance.

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