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Title: The role of endoglin in angiogenesis and its potential as an anti-angiogenic therapeutic target
Authors: Zhai, Zhenhua
Issue Date: 2011
Publisher: Newcastle University
Abstract: Tumour growth and metastasis depend on the vascularization of tumours by angiogenesis. This is regulated by the combined action of several growth factors (e.g. vascular endothelial growth factor, VEGF) that are secreted by the growing tumour, and activate VEGF receptors (VEGFR) expressed on the surface of endothelial cells to stimulate new blood vessel formation. Therapies that target VEGF/VEGFR signalling have indicated that anti-angiogenic therapy may be a useful supplementary anti-cancer treatment in the clinic. In addition to VEGF, malignant cells secrete transforming growth factor (TGF)-β, which is thought to stimulate new blood vessel formation by interacting with endoglin, an endothelial co-receptor for TGF-β that regulates angiogenesis. However, it is not yet clear whether this property could also be utilised to inhibit angiogenesis and metastasis, consistent with endoglin acting as a therapeutic target in a clinical setting. Therefore, the aim of my project was to investigate the role of endoglin in tumour angiogenesis and metastasis and its potential as an anti-angiogenic therapeutic target. I used a conditional endoglin knockout mouse model, that was generated by combining a floxed endoglin allele with a tamoxifen inducible vascular specific Cre (Cdh5(PAC)Cre-ERT2). Angiogenesis was tested using the matrigel subdermal plug assay and was significantly less in endoglin-deficient adult mice compared with tamoxifen treated control mice. Subsequently, angiogenesis and metastasis were investigated using a subdermal lewis lung carcinoma (LLC) model. The growth of the primary tumours was initially reduced, suggesting that targeting endoglin may delay tumour progression at an early stage. However, there was no significant effect of endoglin loss on primary tumour growth at later stages of tumour progression. Furthermore, loss of endoglin was associated with a significant increase in metastases, in a similar way to recent findings for other anti-angiogenesis treatments. The reasons for this are not yet clear. iii In terms of animal health, endothelial specific loss of endoglin alone did not appear to cause any major adverse effects. Endoglin inducible knockout (Eng-iKOe) mice did not lose weight and appeared healthy (over two months). However, Eng-iKOe mice did exhibit abnormal venous enlargement close to matrigel plugs supplemented with angiogenic growth factors compared to control mice. There was no evidence for a similar response in the peritumoral vasculature. In parallel to the in vivo studies, I took advantage of combining the conditional Eng- iKO line and the „immortomouse‟ line to create conditionally immortalised Eng-iKO mouse lung endothelial cell lines (MLECs) to investigate the role of endoglin in regulating endothelial cell viability, proliferation and migration. In standard media, MLECs showed normal cell viability, proliferation and migration in the absence of endoglin. However, titration of the growth factor supplements did result in significant reduction in viability in the absence of endoglin, suggesting endoglin is important for maintaining endothelial cell viability. Although the exact mechanisms regulating the role of endoglin in angiogenesis are still unclear, this study has increased our understanding of the endothelial cell phenotype in pathophysiological conditions in the absence of endoglin. In particular, the finding that endoglin depletion delays tumour progression in the early stage but is associated with increased metastatic risk is important when considering appropriate utilisation of anti-endoglin therapy, which is already being given to cancer patients in phase I/II clinical trials.
Description: PhD Thesis
Appears in Collections:Institute of Genetic Medicine

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