Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins

Hira, Vashendriya V.V.; Wormer, Jill R; Kakar, Hala; Breznik, Barbara; Swaan, Britt van der; Hulsbos, Renske; Tigchelaar, Wikky; Tonar, Zbyněk; Khurshed, Mohammed; Molenaar, Remco J.; Noorden, C. J. F. Van

doi:10.1369/0022155417749174

Cited by 38 publications

(59 citation statements)

References 217 publications

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“…We identified peri-arteriolar GSC niches in sections of GBM samples based on immunohistochemical localization of cancer stem cell marker CD133, smooth muscle actin (SMA) as smooth muscle cell marker and cytokine SDF-1α, which have been shown to be associated with GSC niches (Hira et al 2015 , 2018b ) (Fig. 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Juxtacrine signaling between endothelial cells and GBM cells (Calabrese et al 2007 ) is crucial to maintain the stem cell phenotype of GSCs (Zhu et al 2011 ; Schiffer et al 2014 ; Roos et al 2017 ). Recently, the different types of cancer stem cell niches, such as peri-vascular, peri-hypoxic, peri-immune, ECM and peri-arteriolar niches were integrated into one concept, the hypoxic peri-arteriolar GSC niche (Hira et al 2018a ), which mimics the HSC niche in bone marrow (Hira et al 2018b ). In the same study, GSC niches were found around 2% of the arterioles and 0% of venules and capillaries.…”

Section: Discussionmentioning

confidence: 99%

“…GSC stemness is tightly regulated by the GSC microenvironment, specific micro-anatomical regions within the tumor, named GSC niches (Ross et al 2017). Recently, Hira et al ( 2015 , 2018a , b ) reported that GSCs are exclusively localized in hypoxic peri-arteriolar niches at the edge of the lamina adventitia of the arterioles. In these regions, maintenance and protection of GSCs is achieved by remodeling of their own microenvironment (Lathia et al 2015 ) and by interactions with cells that are present in the niches (Hambardzumyan and Bergers 2015 ; Jackson et al 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Cysteine cathepsins B, X and K expression in peri-arteriolar glioblastoma stem cell niches

et al. 2018

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Glioblastoma (GBM) is the most lethal brain tumor also due to malignant and therapy-resistant GBM stem cells (GSCs) that are localized in protecting hypoxic GSC niches. Some members of the cysteine cathepsin family of proteases have been found to be upregulated in GBM. Cathepsin K gene expression is highly elevated in GBM tissue versus normal brain and it has been suggested to regulate GSC migration out of the niches. Here, we investigated the cellular distribution of cathepsins B, X and K in GBM tissue and whether these cathepsins are co-localized in GSC niches. Therefore, we determined expression of these cathepsins in serial paraffin sections of 14 human GBM samples and serial cryostat sections of two samples using immunohistochemistry and metabolic mapping of cathepsin activity using selective fluorogenic substrates. We detected cathepsins B, X and K in peri-arteriolar GSC niches in 9 out of 16 GBM samples, which were defined by co-expression of the GSC marker CD133, the niche marker stromal-derived factor-1α (SDF-1α) and smooth muscle actin as a marker for arterioles. The expression of cathepsin B and X was detected in stromal cells and cancer cells throughout the GBM sections, whereas cathepsin K expression was more restricted to arteriole-rich regions in the GBM sections. Metabolic mapping showed that cathepsin B, but not cathepsin K is active in GSC niches. On the basis of these findings, it is concluded that cathepsins B, X and K have distinct functions in GBM and that cathepsin K is the most likely GSC niche-related cathepsin of the three cathepsins investigated.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cysteine cathepsins B, X and K expression in peri-arteriolar glioblastoma stem cell niches

et al. 2018

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“…This explains the hypoxic areas that express hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) in which we found all periarteriolar niches adjacent to necrotic areas. 21,71 Second, members of the Notch family drive the arterial gene program, whereas the orphan receptor COUP-TFII suppresses this program and regulates venous specification. The homeobox gene Prox-1 encodes for the master switch of lymphatic specification.…”

Section: Arterioles Capillaries Venules and Lymph Vesselsmentioning

confidence: 99%

Glioma Stem Cell Niches in Human Glioblastoma Are Periarteriolar

Hira

Aderetti

Noorden

2018

J Histochem Cytochem.

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Survival of primary brain tumor (glioblastoma) patients is seriously hampered by glioma stem cells (GSCs) that are distinct therapy-resistant self-replicating pluripotent cancer cells. GSCs reside in GSC niches, which are specific protective microenvironments in glioblastoma tumors. We have recently found that GSC niches are hypoxic periarteriolar, whereas in most studies, GSC niches are identified as hypoxic perivascular. The aim of this review is to critically evaluate the literature on perivascular GSC niches to establish whether these are periarteriolar, pericapillary, perivenular, and/or perilymphatic. We found six publications showing images of human glioblastoma tissue containing perivascular GSC niches without any specification of the vessel type. However, it is frequently assumed that these vessels are capillaries which are exchange vessels, whereas arterioles and venules are transport vessels. Closer inspection of the figures of these publications showed vessels that were not capillaries. Whether these vessels were arterioles or venules was difficult to determine in one case, but in the other cases, these were clearly arterioles and their perivascular niches were similar to the periarteriolar niches we have found. Therefore, we conclude that in human glioblastoma tumors, GSC niches are hypoxic periarteriolar and are structurally and functionally look-alikes of hematopoietic stem cell niches in the bone marrow.

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“…Because of the homology of the hypoxic peri-arteriolar HSC niches in bone marrow and the hypoxic peri-arteriolar GSC niches in glioblastoma tumors, we postulate the hypothesis that plerixafor treatment in combination with standard therapies is beneficial for glioblastoma patients as well. This hypothesis is based on the assumption that plerixafor treatment can mobilize GSCs out of their protective niches, which results in GSC differentiation and their sensitization to radiotherapy and chemotherapy [8,12,13,15]. In a single-arm phase I/II clinical trial including 29 glioblastoma patients, intravenous administration of plerixafor was combined with radiotherapy and temozolomide chemotherapy [35,36].…”

mentioning

confidence: 99%

CXCR4 Antagonists as Stem Cell Mobilizers and Therapy Sensitizers for Acute Myeloid Leukemia and Glioblastoma?

Hira

Noorden

Molenaar

2020

Biology

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Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs), which are slowly-dividing and therefore therapy-resistant. GSCs are localized in protective hypoxic peri-arteriolar niches where these aforementioned stemness properties are maintained. We previously showed that hypoxic peri-arteriolar GSC niches in human glioblastoma are functionally similar to hypoxic peri-arteriolar hematopoietic stem cell (HSC) niches in human bone marrow. GSCs and HSCs express the receptor C-X-C receptor type 4 (CXCR4), which binds to the chemoattractant stromal-derived factor-1α (SDF-1α), which is highly expressed in GSC niches in glioblastoma and HSC niches in bone marrow. This receptor-ligand interaction retains the GSCs/HSCs in their niches and thereby maintains their slowly-dividing state. In acute myeloid leukemia (AML), leukemic cells use the SDF-1α-CXCR4 interaction to migrate to HSC niches and become slowly-dividing and therapy-resistant leukemic stem cells (LSCs). In this communication, we aim to elucidate how disruption of the SDF-1α-CXCR4 interaction using the FDA-approved CXCR4 inhibitor plerixafor (AMD3100) may be used to force slowly-dividing cancer stem cells out of their niches in glioblastoma and AML. Ultimately, this strategy aims to induce GSC and LSC differentiation and their sensitization to therapy.

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Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins

Cited by 38 publications

References 217 publications

Cysteine cathepsins B, X and K expression in peri-arteriolar glioblastoma stem cell niches

Cysteine cathepsins B, X and K expression in peri-arteriolar glioblastoma stem cell niches

Glioma Stem Cell Niches in Human Glioblastoma Are Periarteriolar

CXCR4 Antagonists as Stem Cell Mobilizers and Therapy Sensitizers for Acute Myeloid Leukemia and Glioblastoma?

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