Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

Karina Kristoffersen; Mette Kjølhede Nedergaard; Mette Villingshøj; Rehannah Borup; Helle Broholm; Andreas Kjær; Hans Skovgaard Poulsen; Marie-Thérése Stockhausen

doi:10.4161/cbt.28876

Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

Karina Kristoffersen, Mette Kjølhede Nedergaard, Mette Villingshøj, Rehannah Borup, Helle Broholm, Andreas Kjær, Hans Skovgaard Poulsen, Marie-Thérése Stockhausen

4 Citations (Scopus)

Abstract

BACKGROUND: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC.

METHODS: Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice.

RESULTS: By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control.

CONCLUSION: Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies.

Original language	English
Journal	Cancer Biology & Therapy
Volume	15
Issue number	7
Pages (from-to)	862-877
Number of pages	16
ISSN	1538-4047
DOIs	https://doi.org/10.4161/cbt.28876
Publication status	Published - Jul 2014

Keywords

Animals
Brain Neoplasms
Cell Proliferation
Cell Survival
Dipeptides
Female
Gene Expression
Glioblastoma
Heterografts
Humans
Mice, SCID
Neoplasm Transplantation
Neoplastic Stem Cells
Receptors, Notch
Signal Transduction

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kristoffersen, K., Nedergaard, M. K., Villingshøj, M., Borup, R., Broholm, H., Kjær, A., Poulsen, H. S., & Stockhausen, M-T. (2014). Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature. Cancer Biology & Therapy, 15(7), 862-877. https://doi.org/10.4161/cbt.28876

Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature. / Kristoffersen, Karina; Nedergaard, Mette Kjølhede; Villingshøj, Mette et al.

In: Cancer Biology & Therapy, Vol. 15, No. 7, 07.2014, p. 862-877.

Research output: Contribution to journal › Journal article › Research › peer-review

Kristoffersen, K, Nedergaard, MK, Villingshøj, M, Borup, R, Broholm, H, Kjær, A, Poulsen, HS & Stockhausen, M-T 2014, 'Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature', Cancer Biology & Therapy, vol. 15, no. 7, pp. 862-877. https://doi.org/10.4161/cbt.28876

Kristoffersen K, Nedergaard MK, Villingshøj M, Borup R, Broholm H, Kjær A et al. Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature. Cancer Biology & Therapy. 2014 Jul;15(7):862-877. doi: 10.4161/cbt.28876

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title = "Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature",

abstract = "BACKGROUND: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC.METHODS: Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice.RESULTS: By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control.CONCLUSION: Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies.",

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author = "Karina Kristoffersen and Nedergaard, {Mette Kj{\o}lhede} and Mette Villingsh{\o}j and Rehannah Borup and Helle Broholm and Andreas Kj{\ae}r and Poulsen, {Hans Skovgaard} and Marie-Th{\'e}r{\'e}se Stockhausen",

year = "2014",

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doi = "10.4161/cbt.28876",

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journal = "Cancer Biology & Therapy",

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T1 - Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

AU - Kristoffersen, Karina

AU - Nedergaard, Mette Kjølhede

AU - Villingshøj, Mette

AU - Borup, Rehannah

AU - Broholm, Helle

AU - Kjær, Andreas

AU - Poulsen, Hans Skovgaard

AU - Stockhausen, Marie-Thérése

PY - 2014/7

Y1 - 2014/7

N2 - BACKGROUND: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC.METHODS: Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice.RESULTS: By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control.CONCLUSION: Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies.

AB - BACKGROUND: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC.METHODS: Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice.RESULTS: By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control.CONCLUSION: Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies.

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KW - Cell Proliferation

KW - Cell Survival

KW - Dipeptides

KW - Female

KW - Gene Expression

KW - Glioblastoma

KW - Heterografts

KW - Humans

KW - Mice, SCID

KW - Neoplasm Transplantation

KW - Neoplastic Stem Cells

KW - Receptors, Notch

KW - Signal Transduction

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DO - 10.4161/cbt.28876

M3 - Journal article

C2 - 24755988

SN - 1538-4047

VL - 15

SP - 862

EP - 877

JO - Cancer Biology & Therapy

JF - Cancer Biology & Therapy

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