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Title: The role of LYVE-1 in tumour metastasis and inflammation
Author: Royston, Daniel John
ISNI:       0000 0004 2724 1971
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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The lymphatic metastasis of tumours to lymph nodes (LN) is a frequent event in many cancers and heralds a poor clinical outcome. Comparison of lymphatic endothelial cells (LECS) from metastasizing murine T-241/VEGF-C fibrosarcomas and normal dermis revealed a tumour-specific LEC profile, characterized by the elevated expression of functionally significant molecules such as endothelial specific adhesion molecule (ESAM) and the TGF-~ coreceptor endoglin (CD105). Moreover, similar induction of ESAM and endoglin by human tumour Iymphatics was seen to dramatically correlate with LN metastasis. To further investigate interactions between tumour cells and Iymphatics, the role of lymphatic endothelial hyaluronan receptor LYVE-1 in LN metastasis was investigated. Using LYVE-1 mAbs and LYVE-1-1- mice, it was shown that a deficiency or perturbation of LYVE-1 expressed by tumour Iymphatics potentiated the lymphatic spread of spontaneously metastasizing T-241/VEGF-C fibrosarcomas and induced de novo metastasis by indolent parental T-241 tumours. Subsequent in vitro experiments using mAbs suggested that LYVE-1 exerts a blocking or 'gatekeeper' function, preventing pro-metastatic tumour cell-LEC interactions. Although largely restricted to the Iymphatics, LYVE-1 is also expressed in murine lung by type I alveolar epithelial cells (AECs). Using a bleomycin model of lung inflammation it was shown that LYVE-1-1- mice are unable to clear infiltrating leukocytes following acute lung injury. Furthermore, in vivo and in vitro experiments using blocking mAb reveal a critical role for LYVE-1 in the transepithelial migration of leukocytes across the alveolar epithelium, an essential step in the resolution of acute lung inflammation. These findings identify a specific role for LYVE-1 in cancer metastasis and the resolution of acute inflammation in the lung.
Supervisor: Jackson, David G. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available