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Introduction: Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key Notch ligands that are implicated in tumour angiogenesis. DLL4-Notch signalling inhibits sprouting but promotes tumour growth through better perfused vessels. In contrast to, very little is known about JAG1- Notch signalling in tumour angiogenesis and its influence on tumour growth and progression. Objective: To study the functional difference between DLL4- and JAG1- Notch signalling in vitro and in vivo. Methods: Endothelial cells (ECs) were cultured on DLL4 or JAG1 coated plates and subjected to quantitative PCR to study the regulation of Notch target genes. Angiogenic assays were employed to study the functional effects of these two ligands in ECs. U87 cell lines over-expressing murine DLL4 (mDLL4) or murine JAG1 (mJAG1) were generated via lentiviral transduction. The growth of these cells in vitro or as subcutaneous tumours in mice was compared to that of control wild-type U87 cell line. Changes in vascular morphology, proliferation (MIB-1), necrosis (H&E), and markers of hypoxia (CA9) were then assessed. Results & Discussion: JAG1 was less potent than DLL4 in stimulation of Notch target genes in ECs. JAG1- and DLL4- Notch signaling had different effects on vessel formation. The growth of U87 mDLL4 and U87 mJAG1 cells was slower compared to wild-type U87 cell line in vitro, however mDLL4 and mJAG1 promoted U87 tumour growth compared to wild type control cells in vivo. Both ligands did not have any effect on U87 cell proliferation but significantly reduced tumoural necrosis compared to control tumours. U87 mDLL4 tumours were less hypoxic compared to control tumours. Interestingly, tumours over- expressing mDLL4 had less but larger vessels compared to control, whereas mJAG1 produced more yet functional vessels. Conclusion: JAG1- and DLL4-Notch signalling have different effects on vessel formation, which impacted on the growth of the tumours in vivo. © 2014 Asian Pacific Tropical Medicine Press.

Original publication

DOI

10.1016/S2222-1808(14)60523-5

Type

Journal article

Journal

Asian Pacific Journal of Tropical Disease

Publication Date

06/2014

Volume

4

Pages

229 - 229