Abstract
The dismal prognosis of glioblastoma is, at least in part, attributable to the difficulty in eradicating glioblastoma stem cells (GSCs). However, whether this difficulty is caused by the differential responses of GSCs to drugs remains to be determined. To address this, we isolated and characterized ten GSC lines from established cell lines, xenografts, or patient specimens. Six lines formed spheres in a regular culture condition, whereas the remaining four lines grew as monolayer. These adherent lines formed spheres only in plates coated with poly-2-hydroxyethyl methacrylate. The self-renewal capabilities of GSCs varied, with the cell density needed for sphere formation ranging from 4 to 23.8 cells/well. Moreover, a single non-adherent GSC either remained quiescent or divided into two cells in four-seven days. The stem cell identity of GSCs was further verified by the expression of nestin or glial fibrillary acidic protein. Of the two GSC lines that were injected in immunodeficient mice, only one line formed a tumor in two months. The protein levels of NOTCH1 and platelet derived growth factor receptor alpha positively correlated with the responsiveness of GSCs to γ-secretase inhibitor IX or imatinib, two compounds that inhibit these two proteins, respectively. Furthermore, a combination of temozolomide and a connexin 43 inhibitor robustly inhibited the growth of GSCs. Collectively, our results demonstrate that patient-derived GSCs exhibit different growth rates in culture, possess differential capabilities to form a tumor, and have varied responses to targeted therapies. Our findings underscore the importance of patient-derived GSCs in glioblastoma research and therapeutic development.
Highlights
Glioblastoma (GBM) is the most common malignancy in the central nervous system and accounts for more than 45% of all malignant brain tumors [1]
We found that NOTCH1 and PDGFRA were reciprocally expressed in some glioblastoma stem cell (GSC) lines (Figure 5B)
By using the MTS viability assay, we found that the viability of VTC-037/GSC (NOTCH1-negative/PDGFRA-positive) declined when cells were treated with imatinib (P value was 0.05)
Summary
Glioblastoma (GBM) is the most common malignancy in the central nervous system and accounts for more than 45% of all malignant brain tumors [1]. One important obstacle against effective treatment is the intra and inter-tumoral heterogeneity within GBMs, which is predominantly caused by the presence of selfrenewing GBM stem cells (GSCs) [5,6,7,8]. In addition to tumor microenvironment and a poor drug penetration through the blood-brain barrier into the tumor, GSCs are another contributing factor to therapeutic resistance because these cells are refractory to radiation and chemo drugs [9, 10]. The aggressive invasion of GBM cells, including GSCs, into the surrounding normal brain, often in non-expendable parts of the cranium, makes complete resection impossible and significantly increases resistance to the standard therapy regimen [3, 11, 12]. It is critical to measure therapeutic effects among GSCs from individual tumors
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