Abstract
Glioblastoma multiforme (GBM) is the most common brain tumor with very aggressive and infiltrative. Extracellular matrix (ECM) plays pivotal roles in the infiltrative characteristics of GBM. To understand the invasive characteristic of GBM, it is necessary to study cell-ECM interaction in the physiologically relevant biomimetic model that recapitulates the GBM-specific ECM microenvironment. Here, we propose biomimetic GBM-specific ECM microenvironment for studying mode and dynamics of glioblastoma cell invasion. Using tissue decellularization process, we constructed a patient tissue-derived ECM (pdECM)-based three-dimensional in vitro model. In our model, GBM cells exhibited heterogeneous morphology and altered the invasion routes in a microenvironment-adaptive manner. We further elucidate the effects of inhibition of ECM remodeling-related enzymatic activity (Matrix metalloproteinase (MMP) 2/9, hyaluronan synthase (HAS)) on GBM cell invasion. Interestingly, after blocking both enzyme activity, GBM cells underwent morphological transition and switch the invasion mode. Such adaptability could render cell invasion resistant to anti-cancer target therapy. There results provide insight of how organ-specific matrix differentially regulates cancer cell phenotype, and have significant implications for the design of matrix with appropriate physiologically relevant properties for in vitro tumor model.
Highlights
Invasion and dissemination of cancer cells cause migration of neoplastic cells into surrounding tissues, resulting in mortality in tumor patients[1,2,3]
When the patient tissuederived ECM (pdECM) pre-gel was adjusted to physiological conditions, it behaved like a thermo-sensitive hydrogel
Previously mentioned studies have provided insight into the phenotypic and invasive characteristics of Glioblastoma multiforme (GBM) when cultured in 3D matrices, such as collagen I, Matrigel[23,24], or chemically functionalized HA13,21, these matrices may not completely recapitulate the GBM-specific extracellular matrix (ECM) microenvironment
Summary
Invasion and dissemination of cancer cells cause migration of neoplastic cells into surrounding tissues, resulting in mortality in tumor patients[1,2,3]. In addition to anatomical and physical aspects, there is accumulating evidence that specific extracellular matrix (ECM) components (such as hyaluronan, vitronectin, and tenascin-C) are unregulated at the border of the spreading GBM, and this may alter cellular invasiveness[7,10,11]. Despite the significance of a brain-specific ECM microenvironment for understanding GBM cell invasion, most culture systems have so far utilized matrix materials (either synthetic or derived from animals)[12,13,14,15]. Such systems have limited utility for expanding the use of in vitro models, to enhance the efficiency of anti-cancer drug screening or understand the mechanisms of invasion
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