Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.654112
Title: Chemokine-mediated metastasis in malignant melanoma
Author: Lanati, Silvia
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2011
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Abstract:
Malignant melanoma is the most lethal form of skin cancer due to the metastatic spread of the disease. Chemokines have been shown to play a key role in the metastatic cascade. The chemokine receptor CCR7 and its ligand CCL21 were shown to be involved in migration of CCR7 expressing melanoma cells towards a gradient of CCL21 released by lymphatic endothelial cells (LEC) and promote metastasis at the draining lymph node (LN) in in vivo tumour models. I therefore tested the hypothesis that growth of CCR7 -expressing tumours towards LEC is CCL21-dependent in vivo, that LECs promoted this growth through a chemokine-mediated mechanism without increasing the lymphatic clearance at the front of the tumour and that a recombinant human antibody, namely Chemotrap-1, that binds soluble CCL21, could inhibit chemokine-mediated lymphatic metastasis in vivo. I used in vitro migration assays in a modified Boyden chamber and an in vivo mouse model of directional tumour growth and tumour metastasis to determine the chemokine-mediated ability of melanoma cells to migrate and to test the effect of inhibitory antibodies. During the study on Chemotrap-1, I tested the binding affinity for the chemokine ligand CXCL 12, using specifically designed ELlSAs and tested the affinity for CXCL 12 in vitro and in vivo by migration assays. CCR7 was endogenously expressed in all melanoma cells examined, its overexpression promoted in transit metastasis in vivo and a CCL21 neutralising antibody inhibited its migratory potential. LEC depots in vivo did not promote any increase in lymphatic clearance that would have altered the directional tumour growth of subcutaneous melanoma tumours. Chemotrap-1 inhibited in vitro cell migration, LN metastasis in vivo and it also bound to CXCL 12. These results show the key role of the CCR7/CCL21 axis in lymphatic metastasis in malignant melanoma and highlight the therapeutic potential of Chemotrap-1 to target lymphatic metastasis CCL21- and CXCL 12-mediated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.654112  DOI: Not available
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