Epidermal growth factor receptor activity is elevated in glioma cancer stem cells and is required to maintain chemotherapy and radiation resistance

Pang, Lisa Y.; Saunders, Lauren; Argyle, David

doi:10.18632/oncotarget.19868

Cited by 30 publications

(23 citation statements)

References 68 publications

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“…The membrane receptors EGFR and VEGFR2 have been found to be differentially elevated in glioblastoma. 50–54 Therefore, staining of activated EGFR, p-EGFR, and VEGFR2 was analyzed in glioblastoma and in bone marrow (Fig. 7).…”

Section: Resultsmentioning

confidence: 99%

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Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Hira

Breznik

Vittori

et al. 2019

J Histochem Cytochem.

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Glioblastoma is the most aggressive primary brain tumor. Slowly dividing and therapy-resistant glioblastoma stem cells (GSCs) reside in protective peri-arteriolar niches and are held responsible for glioblastoma recurrence. Recently, we showed similarities between GSC niches and hematopoietic stem cell (HSC) niches in bone marrow. Acute myeloid leukemia (AML) cells hijack HSC niches and are transformed into therapy-resistant leukemic stem cells (LSCs). Current clinical trials are focussed on removal of LSCs out of HSC niches to differentiate and to become sensitized to chemotherapy. In the present study, we elaborated further on these similarities by immunohistochemical analyses of 17 biomarkers in paraffin sections of human glioblastoma and human bone marrow. We found all 17 biomarkers to be expressed both in hypoxic peri-arteriolar HSC niches in bone marrow and hypoxic peri-arteriolar GSC niches in glioblastoma. Our findings implicate that GSC niches are being formed in glioblastoma as a copy of HSC niches in bone marrow. These similarities between HSC niches and GSC niches provide a theoretic basis for the development of novel strategies to force GSCs out of their niches, in a similar manner as in AML, to induce GSC differentiation and proliferation to render them more sensitive to anti-glioblastoma therapies.

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Section: Resultsmentioning

confidence: 99%

“…6–8,46–49 VEGF receptor 2 (VEGFR2) and phosphorylated epidermal growth factor receptor (p-EGFR) have been included as these receptors have been found to be highly elevated in GSCs in glioblastoma. 50–54…”

Section: Introductionmentioning

confidence: 99%

Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Hira

Breznik

Vittori

et al. 2019

J Histochem Cytochem.

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“…One of the reasons for the ineffectiveness of the therapies is GSCs. GSCs have a high tumor initiation capacity and are resistant to chemotherapy and radiotherapy [41]. Therefore, it is essential to eradicate GSCs to cure glioblastomas.…”

Section: Discussionmentioning

confidence: 99%

Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction

Suzuki

Yamamoto

Sanomachi

et al. 2019

Cancers

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Glioblastoma is a primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of epidermal growth factor receptors (EGFRs) due to amplification, mutation, or both of the EGFR gene is common in glioblastomas. However, glioblastomas are resistant to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and overcoming resistance is essential. Brexpiprazole is a new, safe serotonin-dopamine activity modulator used for schizophrenia and depression that was recently reported to have anti-CSC activity and function as a chemosensitizer. Here, we examined its chemosensitization effects on osimertinib, a third-generation EGFR-TKI with an excellent safety profile, in glioma stem cells (GSCs), which are CSCs of glioblastoma. Brexpiprazole treatment sensitized GSCs to osimertinib and reduced the expression of survivin, an antiapoptotic factor, and the pharmacological and genetic inhibition of survivin mimicked the effects of brexpiprazole. Moreover, co-treatment of brexpiprazole and osimertinib suppressed tumor growth more efficiently than either drug alone without notable toxicity in vivo. This suggests that the combination of brexpiprazole and osimertinib is a potential therapeutic strategy for glioblastoma by chemosensitizing GSCs through the downregulation of survivin expression.

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“…This suggests that radiation itself may activate survival pathways through a mechanism that at least partially involves CAIX. PI3K/Akt is one of the pathways stimulated by radiation that is known to be involved in the inhibition of cell death via apoptosis; further, several studies have also linked overexpression and activation of EGFR with radiation resistance in cancer [ 112 , 113 , 114 , 115 , 116 , 117 , 118 ]. EGFR inhibitors can sensitise cancer cells to radiation both in vitro and in vivo, with positive results also observed in a Phase III trial in head and neck cancer [ 119 , 120 ].…”

Section: Caix and Radiation Responses And Other Mechanismsmentioning

confidence: 99%

Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness

et al. 2018

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Carbonic anhydrase IX has been under intensive investigation as a therapeutic target in cancer. Studies demonstrate that this enzyme has a key role in pH regulation in cancer cells, allowing these cells to adapt to the adverse conditions of the tumour microenviroment. Novel CAIX inhibitors have shown efficacy in both in vitro and in vivo pre-clinical cancer models, adversely affecting cell viability, tumour formation, migration, invasion, and metastatic growth when used alone. In co-treatments, CAIX inhibitors may enhance the effects of anti-angiogenic drugs or chemotherapy agents. Research suggests that these inhibitors may also increase the response of tumours to radiotherapy. Although many of the anti-tumour effects of CAIX inhibition may be dependent on its role in pH regulation, recent work has shown that CAIX interacts with several of the signalling pathways involved in the cellular response to radiation, suggesting that pH-independent mechanisms may also be an important basis of its role in tumour progression. Here, we discuss these pH-independent interactions in the context of the ability of CAIX to modulate the responsiveness of cancer to radiation.

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Epidermal growth factor receptor activity is elevated in glioma cancer stem cells and is required to maintain chemotherapy and radiation resistance

Cited by 30 publications

References 68 publications

Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction

Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness

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