Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth

Cheng, Lin; Huang, Zhi; Zhou, Wenchao; Wu, Qiulian; Donnola, Shannon; Liu, James K.; Fang, Xiaoguang; Sloan, Andrew E.; Mao, Yonghui; Lathia, Justin D.; Wang, Min; McLendon, Roger E.; Rich, Jeremy; Bao, Shideng

doi:10.1016/j.cell.2013.02.021

Cited by 729 publications

(755 citation statements)

References 52 publications

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“…smooth muscle cells, pericytes). 16,[25][26][27][28][29] One possible explanation for this discrepancy is that the lineage specification may be linked to the GBM/GSC subtypes. Given that neural stem cells are known to transdifferentiate into endothelial cells, 30 the proneural GSC subtype may have the potential to give rise to endothelial cells rather than stromal cells.…”

Section: Discussionmentioning

confidence: 99%

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

Kim

Hitomi

et al. 2015

Cell Death Differ

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Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs.

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Section: Discussionmentioning

confidence: 99%

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

Kim

Hitomi

et al. 2015

Cell Death Differ

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“…GSCs and matched NSTCs were isolated from GBM surgical specimens or patient-derived GBM xenografts using Papain Dissociation System as previously reported. 3,7,8,22,42 T4121 xenograft was derived from an adult GBM tumor (WHO grade IV), 22 and D456 (D456-MG) xenograft was derived from a pediatric GBM. 43 To isolate total glioma cells from GBM tumors, subcutaneous xenografts were collected and cut into small pieces and then were isolated using the Papain Dissociation System (Worthington Biochemical, Lakewood, NJ, USA) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…The cancer stem cell property of GSCs was confirmed by functional analyses (including in vitro limiting dilution assay, cell differentiation assay and in vivo tumorigenic assay) to assess the self-renewal potential, multi-lineage differentiation potency and in vivo tumor formation capacity of GSCs as described previously. 3,7,8,22,42 Preferential expressions of GSC markers SOX2, OLIG2, L1CAM, CD15 and CD133 in GSC populations were validated. The enriched GSCs were constantly maintained as GBM xenografts and were only dissociated, sorted and cultured in vitro for functional experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Lentivirus packaging and transduction were conducted as described previously. 22,42 Cells stably expressing shCD9, shgp130, CD9-Flag or STAT3-C-Flag were enriched by puromycin selection for positive clones.…”

Section: Methodsmentioning

confidence: 99%

“…Orthotopic GBM xenografts were established through intracranial implantation of GBM cells as previous described. 8,42,48 Female C57BL/6 athymic/nude mice or NOG (NOD/Shiscid/IL-2Rgnull) immunocompromised mice of 4-6 weeks were purchased from Charles River Laboratories and were housed with no more than five animals per cage in a vivarium of Lerner Research Institute, Cleveland Clinic. Briefly, GSCs expressing luciferase were transduced with shCD9 and/or STAT3-C expressing vector or control vector, and then GSCs (D456 or T4121; 5 × 10 3 cells per mouse) were transplanted into the right frontal lobes of each mouse through intracranial injection (1 mm anterior, 2.5 mm lateral to the bregma and at a depth of 3.5 mm).…”

Section: Methodsmentioning

confidence: 99%

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Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

et al. 2016

Self Cite

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Glioblastoma (GBM) is the most malignant and lethal brain tumor harboring glioma stem cells (GSCs) that promote tumor propagation and therapeutic resistance. GSCs preferentially express several critical cell surface molecules that regulate the prosurvival signaling for maintaining the stem cell-like phenotype. Tetraspanin CD9 has recently been reported as a GSC biomarker that is relevant to the GSC maintenance. However, the underlying molecular mechanisms of CD9 in maintaining GSC property remain elusive. Herein, we report that CD9 stabilizes the IL-6 receptor glycoprotein 130 (gp130) by preventing its ubiquitindependent lysosomal degradation to facilitate the STAT3 activation in GSCs. CD9 is preferentially expressed in GSCs of human GBM tumors. Mass spectrometry analysis identified gp130 as an interacting protein of CD9 in GSCs, which was confirmed by immunoprecipitation and immunofluorescent analyses. Disrupting CD9 or gp130 by shRNA significantly inhibited the self-renewal and promoted the differentiation of GSCs. Moreover, CD9 disruption markedly reduced gp130 protein levels and STAT3 activating phosphorylation in GSCs. CD9 stabilized gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote the BMX-STAT3 signaling in GSCs. Importantly, targeting CD9 potently inhibited GSC tumor growth in vivo, while ectopic expression of the constitutively activated STAT3 (STAT3-C) restored the tumor growth impaired by CD9 disruption. Collectively, we uncovered a critical regulatory mechanism mediated by tetraspanin CD9 to maintain the stem cell-like property and tumorigenic potential of GSCs.

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Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

et al. 2020

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Brain metastases are life‐threatening complications of triple‐negative breast cancer, melanoma, and a few other tumor types. Poor outcome of cerebral secondary tumors largely depends on the microenvironment formed by cells of the neurovascular unit, among which pericytes are the least characterized. By using in vivo and in vitro techniques and human samples, here we show that pericytes play crucial role in the development of metastatic brain tumors by directly influencing key steps of the development of the disease. Brain pericytes had a prompt chemoattractant effect on breast cancer cells and established direct contacts with them. By secreting high amounts of extracellular matrix proteins, pericytes enhanced adhesion of both melanoma and triple‐negative cancer cells, which might be particularly important in the exclusive perivascular growth of these tumor cells. In addition, pericytes secreted insulin‐like growth factor 2 (IGF2), which had a very significant pro‐proliferative effect on mammary carcinoma, but not on melanoma cells. By inhibiting IGF2 signaling using silencing or picropodophyllin (PPP), we could block the proliferation‐increasing effect of pericytes on breast cancer cells. Administration of PPP (a blood–brain barrier‐permeable substance) significantly decreased the size of brain tumors in mice inoculated with triple‐negative breast cancer cells. Taken together, our results indicate that brain pericytes have significant pro‐metastatic features, especially in breast cancer. Our study underlines the importance of targeting pericytes and the IGF axis as potential strategies in brain metastatic diseases.

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Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth

Cited by 729 publications

References 52 publications

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

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