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Modulation of endothelial signaling molecule expression by TGF-beta

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Title: Modulation of endothelial signaling molecule expression by TGF-beta
Author: Jarad, Mai yosef
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: Coomber, Brenda
Abstract: Transforming growth factor-beta (TGF-β) is a multifunctional cytokine expressed by most solid tumors and is an important modulator of cancer angiogenesis. Several signaling pathways interact in the process of regulating sprouting angiogenesis. It has been established that the
 Notch-1/Delta like ligand 4 (Dll4) signaling pathways affect many biological processes including angiogenic tip and stalk cell differentiation. Our laboratory previously observed that TGF-β1 produced by colorectal cancer cells down-regulates VEGFR2 in endothelial cells. Here I expand on those studies and propose that TGF-β, in combination with other factors, may modulate the phenotype of endothelial cells into tip or stalk cells and that endoglin (CD105) might affect the availability of TGF-β. In bovine aortic endothelial cells (BAEC), TGF-β1 at a dose of 5 ng/ml significantly down regulated Notch1 and Dll4 protein expression. A Matrigel cord formation assay demonstrated that in the 5 ng/ml TGF-β1 treated wells there was noticeable formation of less cords compared to other treatment combinations. In the presence of both soluble endoglin and 5 ng/ml of TGF-β1 the protein expression of VEGFR2 and Dll4 in BAEC was upregulated compared to the cells treated with 5 ng/ml of TGF-β1 alone. Endoglin levels used in this study affected TGF-β1 inhibitory effect on Notch1, Dll4 and VEGFR2 expression levels. This suggests that endoglin modulates TGF-β1 levels and therefore interferes with its influence on the Notch1/Dll4 and VEGF/VEGFR2 signaling pathways, which play an important role in regulating tumor angiogenesis.
Date: 2013-04
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