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  1. Fulltext Role of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth
    Oon CE, Bridges E, Sheldon H, Sainson RCA, Jubb A, Turley H, et al.
    Oncotarget, 2017 Jun 20;8(25):40115-40131.
    PMID: 28445154 DOI: 10.18632/oncotarget.16969
    Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key Notch ligands implicated in tumour angiogenesis. They were shown to have opposite effects on mouse retinal and adult regenerative angiogenesis. In tumours, both ligands are upregulated but their relative effects and interactions in tumour biology, particularly in tumour response to therapeutic intervention are unclear. Here we demonstrate that DLL4 and JAG1 displayed equal potency in stimulating Notch target genes in HMEC-1 endothelial cells but had opposing effects on sprouting angiogenesis in vitro. Mouse DLL4 or JAG1 expressed in glioblastoma cells decreased tumour cell proliferation in vitro but promoted tumour growth in vivo. mDLL4-expressing tumours showed fewer but larger vessels whereas mJAG1-tumours produced more vessels. In both tumour types pericyte coverage was decreased but the vessels were more perfused. Both ligands increased tumour resistance towards anti-VEGF therapy but the resistance was higher in mDLL4-tumours versus mJAG1-tumours. However, their sensitivity to the therapy was restored by blocking Notch signalling with dibenzazepine. Importantly, anti-DLL4 antibody blocked the effect of JAG1 on tumour growth and increased vessel branching in vivo. The mechanism behind the differential responsiveness was due to a positive feedback loop for DLL4-Notch signalling, rendering DLL4 more dominant in activating Notch signalling in the tumour microenvironment. We concluded that DLL4 and JAG1 promote tumour growth by modulating tumour angiogenesis via different mechanisms. JAG1 is not antagonistic but utilises DLL4 in tumour angiogenesis. The results suggest that anti-JAG1 therapy should be explored in conjunction with anti-DLL4 treatment in developing anti-Notch therapies in clinics.
    Matched MeSH terms: Jagged-1 Protein/genetics; Jagged-1 Protein/metabolism*
  2. Squamous odontogenic tumor of the mandible: a case report demonstrating immunoexpression of Notch1, 3, 4, Jagged1 and Delta1
    Siar CH, Nakano K, Ng KH, Tomida M, Nagatsuka H, Kawakami T
    Eur J Med Res, 2010 Apr 08;15(4):180-4.
    PMID: 20554499
    BACKGROUND: Squamous odontogenic tumor (SOT) is a rare benign odontogenic epithelial neoplasm. A slow-growing painless expansive swelling is the common presenting symptom. Histopathologically, SOT can be easily misdiagnosed as an acanthomatous ameloblastoma. Although Notch receptors and ligands have been shown to play a role in cell fate decisions in ameloblastomas, the role of these cell signaling molecules in SOT is unknown.

    CASE REPORT: This paper describes a case of SOT affecting the anterior mandible of a 10-year-old Indian female. The patient was treated by local surgical excision and there has been no follow-up clinical record of recurrence 5 years after primary treatment. Histo?pathological examination revealed a solid, locally-infiltrative neoplasm composed of bland-looking squamatoid islands scattered in a mature fibrous connective tissue stroma and the diagnosis was SOT. Immunohistochemical evaluation showed positive reactivity of varying intensity in the neoplastic epithelial cells for Notch1, Notch3, Notch4, and their ligands Jagged1 and Delta1. Expression patterns showed considerable overlap. No immunoreactivity was detected for Notch2 and Jagged2.

    CONCLUSIONS: Present findings suggest that Notch receptors and their ligands play differential roles in the cytodifferentiation of SOT.

    Matched MeSH terms: Jagged-1 Protein
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