Fas ligand expression and tumour immune evasion; the role of prostaglandin E2 and the EP1 receptor

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dc.contributor.advisor Houston, Aileen M. en
dc.contributor.author O'Callaghan, Grace
dc.date.accessioned 2014-01-28T10:21:22Z
dc.date.issued 2013
dc.date.submitted 2013
dc.identifier.citation O'Callaghan, G. 2013. Fas ligand expression and tumour immune evasion; the role of prostaglandin E2 and the EP1 receptor. PhD Thesis, University College Cork. en
dc.identifier.uri http://hdl.handle.net/10468/1341
dc.description.abstract Background and Aim: During carcinogenesis, tumours develop multiple mechanisms to evade the immune system and suppress the anti-tumour immune response. Upregulation of Fas Ligand (FasL/CD95L) expression may represent one such mechanism. FasL is a member of the tumour necrosis factor superfamily that triggers apoptotic cell death following ligation to its receptor Fas. Numerous studies have demonstrated upregulated FasL expression in tumor cells, with FasL expression associated with numerous pro-tumorigenic effects. However, little is known about the mechanisms that regulate FasL expression in tumours. The cyclooxgenase (COX) signalling pathway may play an important role in colon carcinogenesis, via the production of prostaglandins, in particular PGE2. PGE2 signals through four different receptor subtypes, EP1 – EP4. Thus, the aim of this study was to investigate the effect of targeting the PGE2-FasL signaling pathway. Results: (i) PGE2 induces FasL expression via the EP1 receptor in colon cancer cells. (ii) Suppression of FasL expression in colon tumour cells in vivo significantly delays and reduces tumour growth. (iii) Blocking EP1 receptor signaling, or suppression of the EP1 receptor in colon tumour cells, reduces tumour growth in vivo. Suppression of tumour growth correlates in part with suppression of FasL expression. (iv) The reduction in tumour growth is associated with an improved anti-tumour immune response. Tumour infiltration by Treg cells and macrophages was reduced, and the cytotoxic activity of CTL generated from splenocytes isolated from these mice increased. Conclusion: 1) Targeting FasL expression by blocking PGE2-EP1 receptor signalling reduces tumour development in vivo. 2) The mechanism is indirect but is associated with an increased anti-tumour immune response. Thus, unraveling the mechanisms regulating FasL expression and the pro-tumorigenic effects of the EP1 receptor may aid in the search for new therapeutic targets against colon cancer. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Grace O'Callaghan. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject PGE2 en
dc.subject FasL en
dc.subject EP1 en
dc.subject.lcsh Tumor necrosis factor en
dc.subject.lcsh Death receptors en
dc.subject.lcsh Colon (Anatomy)--Cancer en
dc.title Fas ligand expression and tumour immune evasion; the role of prostaglandin E2 and the EP1 receptor en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text not available en
dc.check.info Indefinite en
dc.check.date 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder Health Research Board en
dc.description.status Not peer reviewed en
dc.internal.school Medicine en
dc.check.reason This thesis contains third party copyrighted materials for which permission was not given for online use en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat E-thesis on CORA only en
dc.internal.conferring Autumn Conferring 2013 en

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© 2013, Grace O'Callaghan. Except where otherwise noted, this item's license is described as © 2013, Grace O'Callaghan.
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