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.
Highlights
Glioblastomas are the most common brain tumors found in humans (Jovcevska et al, 2013)
Primary antibodies against matrix metallopeptidase (MMP)2/-9, t-/p-Focal adhesion kinase (FAK), p-paxillin, t-/p-AKT, P-glycoprotein, p-ERK1/2 and cyclin D1 for western blotting were purchased from Cell Signaling Technology (Danvers, MA, USA)
We demonstrated that FN modulated the biological characteristics of Glioma stem-like cells (GSCs) in many aspects
Summary
Glioblastomas are the most common brain tumors found in humans (Jovcevska et al, 2013). Various research groups have proposed diverse hypotheses accounting for treatment failure in some patients with malignant glioma, including O6-methylguaninine-DNA-methytransferase gene methylation, isocitrate dehydrogenase gene mutations, aberrant ATP-binding cassette (ABC) transporter expression, p53 mutations and deletions, DNA repair deregulation, micro (mi)RNAs and long non-coding RNAs (Zeng et al, 2017). In addition to such concerns, the impact of the tumor microenvironment in various stem cell niches have been described in recent studies (Faissner and Reinhard, 2015), with several breakthroughs as a result of successfully growing stem cells on naturally-derived and synthesized substrates (Lee et al, 2012). Knowledge on how the ECM regulates stemness will increase our understanding of regenerative medicine, and suggest new pathways to be exploited in our efforts to counter cancer
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