Dataset Information

A minority subpopulation of CD133(+) /EGFRvIII(+) /EGFR(-) cells acquires stemness and contributes to gefitinib resistance.

ABSTRACT:

Aims

To study the contribution of epidermal growth factor receptor variant III (EGFRvIII) to glioblastoma multiforme (GBM) stemness and gefitinib resistance.

Methods

CD133(+) and CD133(-) cells were separated from EGFRvIII(+) clinical specimens of three patients with newly diagnosed GBM. Then, RT-PCR was performed to evaluate EGFRvIII and EGFR expression in CD133(+) and CD133(-) cells. The tumorigenicity and stemness of CD133(+) cells was verified by intracranial implantation of 5 × 10(3) cells into immunodeficient NOD/SCID mice. Finally, cells were evaluated for their sensitivity to EGFR tyrosine kinase inhibition by gefitinib.

Results

RT-PCR results showed that the sorted CD133(+) cells expressed EGFRvIII exclusively, while the CD133(-) cells expressed both EGFRvIII and EGFR. At 6-8 weeks postimplantation, CD133(+) /EGFRvIII(+) /EGFR(-) cells formed intracranial tumors. Cell counting kit-8 results showed that the IC50 values of the three isolated EGFRvIII(+) cell lines treated with gefitinib were 14.44, 16.00, and 14.66 ?M, respectively, whereas the IC50 value of an isolated EGFRvIII(-) cell line was 8.57 ?M.

Conclusions

EGFRvIII contributes to the stemness of cancer stem cells through coexpression with CD133 in GBMs. Furthermore, CD133(+) /EGFRvIII(+) /EGFR(-) cells have the ability to initiate tumor formation and may contribute to gefitinib resistance.

SUBMITTER: Liu XJ

PROVIDER: S-EPMC6493376 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

A minority subpopulation of CD133(+) /EGFRvIII(+) /EGFR(-) cells acquires stemness and contributes to gefitinib resistance.

Liu Xu-Jie XJ Wu Wen-Tao WT Wu Wei-Hua WH Yin Feng F Ma Si-Hai SH Qin Jia-Zhen JZ Liu Xiu-Xiu XX Liu Yi-Nan YN Zhang Xiao-Yan XY Li Peng P Han Shuo S Liu Kai-Yu KY Zhang Jin-Ming JM He Qi-Hua QH Shen Li L

CNS neuroscience & therapeutics 20130410 7

<h4>Aims</h4>To study the contribution of epidermal growth factor receptor variant III (EGFRvIII) to glioblastoma multiforme (GBM) stemness and gefitinib resistance.<h4>Methods</h4>CD133(+) and CD133(-) cells were separated from EGFRvIII(+) clinical specimens of three patients with newly diagnosed GBM. Then, RT-PCR was performed to evaluate EGFRvIII and EGFR expression in CD133(+) and CD133(-) cells. The tumorigenicity and stemness of CD133(+) cells was verified by intracranial implantation of 5 ...[more]

PMID: 23575351

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Project description:BackgroundThe treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors like erlotinib has not met expectations for glioblastoma therapy, even for EGFR-overexpressing tumors. We determined possible mechanisms of therapy resistance using the unique BS153 glioblastoma cell line, which has retained amplification of the egfr gene and expression of EGFR variant (v)III.MethodsFunctional effects of erlotinib, gefitinib, and cetuximab on BS153 proliferation, migration, and EGFR-dependent signal transduction were systematically compared in vitro. The tumor-initiating capacity of parental and treatment-resistant BS153 was studied in Naval Medical Research Institute/Foxn1(nu) mice. Potential mediators of resistance were knocked down using small interfering (si)RNA.ResultsErlotinib and gefitinib inhibited proliferation and migration of BS153 in a dose-dependent manner, whereas cetuximab had no effect. BS153 developed resistance to erlotinib (BS153(resE)) but not to gefitinib. Resistance was associated with strong upregulation of EGFRvIII and subsequent activation of the phosphatidylinositol-3-OH kinase (PI3K) pathway in BS153(resE) and an increased expression of the regulatory 110-kDa delta subunit of PI3K (p110δ). Knockdown of EGFRvIII in BS153(resE) largely restored sensitivity to erlotinib. Targeting PI3K pharmacologically caused a significant decrease in cell viability, and specifically targeting p110δ by siRNA partially restored erlotinib sensitivity in BS153(resE). In vivo, BS153 formed highly invasive tumors with an unusual growth pattern, displaying numerous satellites distant from the initial injection site. Erlotinib resistance led to delayed onset of tumor growth as well as prolonged overall survival of mice without changing tumor morphology.ConclusionsEGFRvIII can mediate resistance to erlotinib in EGFR-amplified glioblastoma via an increase in PI3Kp110δ. Interfering with PI3Kp110δ can restore sensitivity toward the tyrosine kinase inhibitor.

Dataset Information

A minority subpopulation of CD133(+) /EGFRvIII(+) /EGFR(-) cells acquires stemness and contributes to gefitinib resistance.

Aims

Methods

Results

Conclusions

Publications

A minority subpopulation of CD133(+) /EGFRvIII(+) /EGFR(-) cells acquires stemness and contributes to gefitinib resistance.

Similar Datasets

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