Cancer Stem Cells in Glioblastoma Multiforme

Bradshaw, Amy; Wickremesekera, Agadha; Brasch, Helen D.; Chibnall, Alice M.; Davis, Paul F.; Tan, Swee T.; Itinteang, Tinte

doi:10.3389/fsurg.2016.00048

Cited by 59 publications

(65 citation statements)

References 41 publications

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“…The CSC concept proposes that cancer is caused by CSCs that possess the ability for uncontrolled growth and propagation [15] . CSCs have been demonstrated in many types of cancer including breast carcinoma [16] , glioblastoma [17] and oral cavity squamous cell carcinoma (OCSCC) [18][19][20] . We have recently identified and characterized three CSC subpopulations within MM to the brain: a Melan-A + subpopulation and a Melan-Asubpopulations that express embryonic stem cell (ESC) markers OCT4, SALL4, SOX2 and NANOG within the tumor, and a pSTAT3 + subpopulation localized to the CD34 + endothelium of microvessels within the tumor [21] .…”

Section: Introductionmentioning

confidence: 99%

Cancer stem cell subpopulations in metastatic melanoma to the brain express components of the renin-angiotensin system

Wickremesekera¹,

Brasch²,

Lee³

et al. 2019

JCMT

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Aim: There is increasing appreciation of the role of the renin-angiotensin system (RAS) in carcinogenesis with recent evidence showing expression of the RAS by cancer stem cells (CSCs) in different types of cancer. We have recently demonstrated the presence of three CSC subpopulations within metastatic melanoma (MM) to the brain: a Melan-A + subpopulation and a Melan-Asubpopulation within the tumor that express OCT4, SALL4, SOX2 and NANOG; and a pSTAT3 + subpopulation localized to the CD34 + endothelium of microvessels within the tumor. In this study we investigated the expression and localization of components of the RAS in relation to these CSCs in MM to the brain.Methods: 3, 3-diaminobenzidine immunohistochemical (IHC) staining of components of the RAS: pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) was performed on the same ten samples of MM to the brain included in our previous study. Immunofluorescence IHC staining of these components of the RAS was performed with embryonic stem cell markers OCT4 and NANOG, and endothelial marker CD34, on two of the samples of MM to the brain from the original cohort of ten patients. Western blotting (n = 5) and NanoString mRNA analysis (n = 4) were performed on samples of MM to the brain to confirm protein and mRNA expression of these components of the RAS, respectively.Results: DAB IHC staining showed the presence of PRR, ACE, ATIIR1 and ATIIR2 in all ten samples of MM to the brain. IF IHC staining showed that the CSC subpopulations in MM to the brain expressed PRR, ATIIR1 and ATIIR2; and a CSC subpopulation on the endothelium of the microvessels expressed ACE. Western blotting and NanoString mRNA analysis confirmed protein and mRNA expression of these components of the RAS, respectively. Conclusion:CSCs in MM to the brain expressed components of the RAS. Targeting the CSCs using modulators of the RAS may be a novel therapeutic approach for treating this aggressive cancer.

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Section: Introductionmentioning

confidence: 99%

Cancer stem cell subpopulations in metastatic melanoma to the brain express components of the renin-angiotensin system

Wickremesekera¹,

Brasch²,

Lee³

et al. 2019

JCMT

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“…Since then, GFAP is often used to mark cells with stem cell characteristics in glioma and to target neural stem cells to induce gliomagenesis in animal models (Kwon et al, 2008;J. Chen et al, 2012;Bradshaw et al, 2016;Guichet et al, 2016;Kanabur et al, 2016;Jiang et al, 2017;Welker, Jaros, An, & Beattie, 2017). In addition, GFAP is up-regulated in non-neoplastic astrocytes that become reactive in response to the growth of the tumor and do not reflect the differentiation state of neoplastic cells (Gullotta, Schindler, Schmutzler, & Weeks-Seifert, 1985;Yoshii et al, 1992; H. Y.…”

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confidence: 99%

Importance of GFAP isoform‐specific analyses in astrocytoma

Bodegraven

Asperen

Robe

et al. 2019

Glia

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Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.

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“…Importantly, 87% of the Sox2 positive cells at 5 dpt and 100% of the Sox2 positive cells at 10 dpt were GFAP positive. It was also observed in tissue from human gliomas that there was a substantial overlap between Sox2 and GFAP (Bradshaw et al, 2016). These data support that the putative cancer stem cells in these tumors express both Sox2 and GFAP and that GFAP is expressed by both stem cells and presumably differentiated cells.…”

Section: Resultsmentioning

confidence: 99%

Changes in tumor cell heterogeneity after chemotherapy treatment in a xenograft model of glioblastoma

Welker

Jaros

et al. 2017

Neuroscience

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Glioblastoma (GBM) is a highly aggressive brain cancer with limited treatments and poor patient survival. GBM tumors are heterogeneous containing a complex mixture of dividing cells, differentiated cells, and cancer stem cells. It is unclear, however, how these different cell populations contribute to tumor growth or whether they exhibit differential responses to chemotherapy. Here we set out to address these questions using a zebrafish xenograft transplant model (Welker et al., 2016). We found that a small population of differentiated vimentin positive tumor cells, but a majority of Sox2 positive putative cancer stem cells, were dividing during tumor growth. We also observed co-expression of Sox2 and GFAP, another suggested marker of glioma cancer stem cells, indicating that the putative cancer stem cells in GBM9 tumors expressed both of these markers. To determine how these different tumor cell populations responded to chemotherapy, we treated animals with temozolomide and assessed these cell populations immediately after treatment and 5 and 10 days after treatment cessation. As expected we found a significant decrease in dividing cells after treatment. We also found a significant decrease in vimentin positive cells, but not in Sox2 or GFAP positive cells. However, the Sox2 positive cells significantly increased 5 days after TMZ treatment. These data support that putative glioma cancer stem cells are more resistant to TMZ treatment and may contribute to tumor regrowth after chemotherapy.

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Cancer Stem Cells in Glioblastoma Multiforme

Cited by 59 publications

References 41 publications

Cancer stem cell subpopulations in metastatic melanoma to the brain express components of the renin-angiotensin system

Cancer stem cell subpopulations in metastatic melanoma to the brain express components of the renin-angiotensin system

Importance of GFAP isoform‐specific analyses in astrocytoma

Changes in tumor cell heterogeneity after chemotherapy treatment in a xenograft model of glioblastoma

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