Patient-derived glioblastoma stem cells respond differentially to targeted therapies

Pratik Kanabur, Sujuan Guo, Gary R. Simonds, Deborah F. Kelly, Robert G. Gourdie, Scott S. Verbridge, Zhi Sheng

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)86406-86419
Number of pages14
JournalOncotarget
Volume7
Issue number52
DOIs
StatePublished - Jan 1 2016

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Glioblastoma
Stem Cells
Therapeutics
temozolomide
Cell Line
Platelet-Derived Growth Factor alpha Receptor
Nestin
Amyloid Precursor Protein Secretases
Connexin 43
Glial Fibrillary Acidic Protein
Growth
Heterografts
Neoplasms
Proteins
Cell Count

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Kanabur, P., Guo, S., Simonds, G. R., Kelly, D. F., Gourdie, R. G., Verbridge, S. S., & Sheng, Z. (2016). Patient-derived glioblastoma stem cells respond differentially to targeted therapies. Oncotarget, 7(52), 86406-86419. https://doi.org/10.18632/oncotarget.13415
Kanabur, Pratik ; Guo, Sujuan ; Simonds, Gary R. ; Kelly, Deborah F. ; Gourdie, Robert G. ; Verbridge, Scott S. ; Sheng, Zhi. / Patient-derived glioblastoma stem cells respond differentially to targeted therapies. In: Oncotarget. 2016 ; Vol. 7, No. 52. pp. 86406-86419.
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Kanabur, P, Guo, S, Simonds, GR, Kelly, DF, Gourdie, RG, Verbridge, SS & Sheng, Z 2016, 'Patient-derived glioblastoma stem cells respond differentially to targeted therapies', Oncotarget, vol. 7, no. 52, pp. 86406-86419. https://doi.org/10.18632/oncotarget.13415

Patient-derived glioblastoma stem cells respond differentially to targeted therapies. / Kanabur, Pratik; Guo, Sujuan; Simonds, Gary R.; Kelly, Deborah F.; Gourdie, Robert G.; Verbridge, Scott S.; Sheng, Zhi.

In: Oncotarget, Vol. 7, No. 52, 01.01.2016, p. 86406-86419.

Research output: Contribution to journalArticle

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AU - Kanabur, Pratik

AU - Guo, Sujuan

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