The Vascular Notch Ligands Delta-Like Ligand 4 (DLL4) and Jagged1 (JAG1) Have Opposing Correlations with Microvascularization but a Uniform Prognostic Effect in Primary Glioblastoma: A Preliminary Study

Qiu, Xianxin; Chen, Long; Wang, Chenhong; Zhang, Lin; Chen, Bi-juan; You, Na; Chen, Yao; Wang, Xingfu

doi:10.1016/j.wneu.2015.10.058

Cited by 19 publications

(13 citation statements)

References 61 publications

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“…On both sides, EGFR status-dependent subgroups of GBs, genetically and clinically different, can be separated. The identification of alterations in shared nodes of convergence downstream of RTKs hast been an interesting approach in cancer [4,8,58].…”

Section: Discussionmentioning

confidence: 99%

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Navarro

San-Miguel

Megías

et al. 2020

Cells

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Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients.

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Section: Discussionmentioning

confidence: 99%

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Navarro

San-Miguel

Megías

et al. 2020

Cells

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“…A pivotal role of Notch signaling in controlling sprouting angiogenesis has been well established (32). It has also been well found that HEY1 overexpression inhibits angiogenesis (33). Thus, the alteration of Notch target genes in YY1-deficient ECs could contribute to abnormal sprouting angiogenesis and vascular defects.…”

Section: Ec-specific Deletion Of Yy1 Up-regulates Notch-dependent Genementioning

confidence: 98%

Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ

Zhang

Kim

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Angiogenesis, the formation of new blood vessels, is tightly regulated by gene transcriptional programs. Yin Ying 1 (YY1) is a ubiquitously distributed transcription factor with diverse and complex biological functions; however, little is known about the cell-type-specific role of YY1 in vascular development and angiogenesis. Here we report that endothelial cell (EC)-specificYY1deletion in mice led to embryonic lethality as a result of abnormal angiogenesis and vascular defects. Tamoxifen-inducible EC-specificYY1knockout (YY1iΔEC) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells.YY1iΔECmice also displayed severe impairment of retinal vessel maturation. In an ex vivo mouse aortic ring assay and a human EC culture system, YY1 depletion impaired endothelial sprouting and migration. Mechanistically, YY1 functions as a repressor protein of Notch signaling that controls EC tip-stalk fate determination. YY1 deficiency enhanced Notch-dependent gene expression and reduced tip cell formation. Specifically, YY1 bound to the N-terminal domain of RBPJ (recombination signal binding protein for Ig Kappa J region) and competed with the Notch coactivator MAML1 (mastermind-like protein 1) for binding to RBPJ, thereby impairing the NICD (intracellular domain of the Notch protein)/MAML1/RBPJ complex formation. Our study reveals an essential role of endothelial YY1 in controlling sprouting angiogenesis through directly interacting with RBPJ and forming a YY1-RBPJ nuclear repression complex.

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“…DLL4/Hey blockage leads to VEGFR2 upregulation, which restrains tumor progression by producing hyper-sprouting, thin, fragile, and nonfunctional tumor vessels (56,(65)(66)(67). Interestingly, Jagged1-associated Hey upregulation seems to have little effect on low-density and mature tumor vessel phenotype, and Jagged1 promotes tumor-spouting angiogenesis through distinct mechanisms (54,68,69). In contrast, HeyL potentially promotes neovascularization.…”

Section: Balance Between Heyl and Hey1/hey2 Regulates Cancer Neovascumentioning

confidence: 99%

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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The Vascular Notch Ligands Delta-Like Ligand 4 (DLL4) and Jagged1 (JAG1) Have Opposing Correlations with Microvascularization but a Uniform Prognostic Effect in Primary Glioblastoma: A Preliminary Study

Cited by 19 publications

References 61 publications

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

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