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In vivo assessment of Delta like‐4 function in tumour development
Author(s) -
Sainson Richard C. A.,
Li JiLiang,
Harrington Laura,
Shi Wen,
Heikamp Emily,
Leek Russel,
Harris Adrian L
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a16
Subject(s) - angiogenesis , notch signaling pathway , in vivo , cancer research , biology , neovascularization , immunohistochemistry , blood vessel , pathology , cell growth , microbiology and biotechnology , signal transduction , immunology , medicine , endocrinology , genetics
Tumour survival, progression and diffusion to other organs are dependent on the formation of new blood vessels. In recent years, anti‐angiogenic therapy, especially through blockage of the VEGF signaling pathway, has proven itself to be an attractive approach to starve growing tumours. However, characterization of new pathways involved in angiogenesis remains critical in order to prevent cancer progression through the use of more effective multi‐therapies. Several studies have highlighted the role of Notch signaling in vascular development and maintenance during physiological and pathological angiogenesis. Delta like‐4 (Dll4), the most recently identified Notch ligand is endothelial‐specific and is expressed mainly in arteries and within the tip of growing vessels. We have previously demonstrated that Dll4 is strongly upregulated within the vasculature of clear renal cell carcinomas and within bladder tumours, where it is associated with vessel maturation. In order to further investigate the role of Dll4 signaling in tumour development, we have ectopically overexpressed Dll4 within several tumour cell lines. Although Dll4 overexpression had minimal effects on tumour cell properties in vitro, the in vivo growth of tumour cells expressing Dll4 was stimulated when compared to parental cells. In addition, exogenous expression of a soluble and inhibitory extracellular form of Dll4 (D4EC‐Fc) substantially reduced tumour growth. Finally, immunohistochemistry staining of the resulting tumours strongly indicated that Dll4 and D4EC‐Fc mediate their effects via changes in vessel quantity, perfusion and maturity.