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      Integrating the glioblastoma microenvironment into engineered experimental models

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          Abstract

          Glioblastoma (GBM) is the most lethal cancer originating in the brain. Its high mortality rate has been attributed to therapeutic resistance and rapid, diffuse invasion – both of which are strongly influenced by the unique microenvironment. Thus, there is a need to develop new models that mimic individual microenvironmental features and are able to provide clinically relevant data. Current understanding of the effects of the microenvironment on GBM progression, established experimental models of GBM and recent developments using bioengineered microenvironments as ex vivo experimental platforms that mimic the biochemical and physical properties of GBM tumors are discussed.

          Abstract

          Glioblastoma (GBM), the most common form of brain cancer, is extremely lethal due to its rapid progression, resistance to treatment and high rates of recurrence. As reviewed here, the microenvironment that surrounds GBM tumors drives their progression. Development of effective treatments for GBM will require better experimental models that account for the tumor microenvironment and thus, can provide clinically translatable results. This review focuses on using biomaterials to create tumor-mimetic microenvironments as experimental platforms for cell culture.

          Most cited references154

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          Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.

          Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy. Copyright © 2013 Elsevier Inc. All rights reserved.
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            The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells.

            Glioblastoma multiforme (GBM) is a malignant astrocytoma of the central nervous system associated with a median survival time of 15 months, even with aggressive therapy. This rapid progression is due in part to diffuse infiltration of single tumor cells into the brain parenchyma, which is thought to involve aberrant interactions between tumor cells and the extracellular matrix (ECM). Here, we test the hypothesis that mechanical cues from the ECM contribute to key tumor cell properties relevant to invasion. We cultured a series of glioma cell lines (U373-MG, U87-MG, U251-MG, SNB19, C6) on fibronectin-coated polymeric ECM substrates of defined mechanical rigidity and investigated the role of ECM rigidity in regulating tumor cell structure, migration, and proliferation. On highly rigid ECMs, tumor cells spread extensively, form prominent stress fibers and mature focal adhesions, and migrate rapidly. As ECM rigidity is lowered to values comparable with normal brain tissue, tumor cells appear rounded and fail to productively migrate. Remarkably, cell proliferation is also strongly regulated by ECM rigidity, with cells dividing much more rapidly on rigid than on compliant ECMs. Pharmacologic inhibition of nonmuscle myosin II-based contractility blunts this rigidity-sensitivity and rescues cell motility on highly compliant substrates. Collectively, our results provide support for a novel model in which ECM rigidity provides a transformative, microenvironmental cue that acts through actomyosin contractility to regulate the invasive properties of GBM tumor cells.
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              Balancing forces: architectural control of mechanotransduction.

              All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.
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                Author and article information

                Journal
                Future Sci OA
                Future Sci OA
                FSO
                Future Science OA
                Future Science Ltd (London, UK )
                2056-5623
                August 2017
                24 March 2017
                : 3
                : 3
                : FSO189
                Affiliations
                [1 ]Department of Bioengineering, University of California, Los Angeles, CA 90095-1600, USA
                Author notes
                *Author for correspondence: seidlits@ 123456g.ucla.edu

                Authors contributed equally

                Article
                10.4155/fsoa-2016-0094
                5583655
                28883992
                fecf1d1e-6184-496a-9e7b-d4c00f82ffea
                © 2017 Future Science Ltd

                This work is licensed under a Creative Commons Attribution 4.0 License

                History
                : 21 December 2016
                : 22 February 2017
                Categories
                Review

                biomaterials,extracellular matrix,glioblastoma,microenvironment

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