Isolation and characterization of tumorspheres from meningioma patients

Abstract

Purpose Meningiomas are the most common primary tumors of the central nervous system, and usually benign. However, there is an important group of patients with refractory meningiomas, who develop recurrent disease following surgery and radiation therapy. The existence of tumorspheres (TSs) might confer treatment resistance to refractory meningioma, however, it has not been clarified. We report the isolation and characterization of TSs derived from human meningioma specimens. Methods The meningioma specimens were obtained from patients and underwent TS assay. The TSs were chosen to be analyzed with immunocytochemistry for surface markers. We next identified a transcriptome molecular profiling of key markers associated with the three quantitative metrics defining cancer stem cell (CSC), meningioma, and recurrence. Lastly, we made mouse orthotopic meningioma models to examine the capacity of tumor replication. Results The success rate of TS formation was 26.1% (36 of 138) for all meningioma samples; 28.4% (33 of 116) for grade I meningiomas and 13.6 % (3 of 22) for grade II meningiomas. However, there was no statistically significant difference in isolation rate between grade I and II meningiomas. The meningioma TSs were immunoreactive for the stem cell markers (CD133 and nestin) and meningioma cell markers (EMA and Vimentin), whereas they are negative for mature neuronal marker (GFAP), indicating that these TSs can self-renew, have characteristic of meningioma, and be distinct from tumors of glial origin. Bioinformatic analyses showed that meningioma TSs possessed the characteristics of both meningiomas and CSCs, and had properties affecting the aggressiveness of meningiomas as well. An orthotopic xenograft showed that tumor xenografts replicated the histopathological features of the patient tumor. Conclusion The isolation and identification of TSs capable of forming meningiomas demonstrates a useful model for understanding meningioma development. These findings have provided better understanding of meningioma cell biology and suggested that meningioma stem-like cells may serve as a novel target in therapeutic resistant meningiomas. Using an orthotopic xenograft, we showed that meningioma TSs could replicate the patient tumor, demonstrating their potential as a patient derived xenograft for precision medicine.