Abstract
Glioblastoma exhibits phenotypic and genetic heterogeneity, aggressive invasiveness, therapeutic resistance, and tumor recurrence, which can be explained by the existence of glioma stem cells (GSCs). In this study, we visualized the spatiotemporal dynamics of invasion of human GSCs in an orthotopic xenograft mouse model using time-lapse imaging of organotypic brain slice cultures and three-dimensional imaging of optically cleared whole brains. GSCs implanted in the striatum exhibited directional migration toward axon bundles, perivascular area, and the subventricular zone around the inferior horn of the lateral ventricle. GSCs migrated in a helical pattern around axon bundles in the striatum and invaded broadly in both the rostral and caudal directions. GSCs in the corpus callosum migrated more rapidly and unidirectionally toward the contralateral side with pseudopod extension. These characteristics of GSC invasion shared histological features observed in glioblastoma patients. Spatiotemporal visualization techniques can contribute to the elucidation of the mechanisms underlying GSC invasion that may lead to the development of effective therapy for glioblastoma.
Highlights
Glioblastoma is the most common and aggressive form of primary brain tumors [1] and exhibits a high degree of phenotypic and genetic heterogeneity [2]
The invasion of U87 cells across the corpus callosum was not observed by Venus fluorescence (Fig. 1c), which was like a metastatic tumor in the human brain
Discussion invasion of Glioma stem cell (GSC) in a living organism has been previously reported by using time-lapse imaging of brain slice cultures, only a small area around the implanted site was analyzed [19, 20]
Summary
Glioblastoma is the most common and aggressive form of primary brain tumors [1] and exhibits a high degree of phenotypic and genetic heterogeneity [2]. Complete surgical removal of tumor cells is difficult because glioblastoma frequently invades across the corpus callosum resulting in bi-hemispheric lesions that have a “butterfly” appearance. The current standard treatment following surgical resection, which includes radiotherapy and chemotherapy with temozolomide, provides only a modest survival benefit [3]. The presence of glioma stem cells (GSCs) that have self-renewal and tumor-initiating capacity has been demonstrated [4,5,6]. GSCs are thought to be an underlying cause of therapeutic resistance and tumor recurrence [7,8,9]. Molecular markers that identify GSCs may be a key for the development of therapeutic
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