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Title: Identification of the genetic contexts underpinning CXCL8 potentiation in colecteral cancer and characterisation of its roles in tumour progression
Author: Campbell, Laura
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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The ability of pro-inflammatory Signalling to facilitate the initiation and progression of colorectal cancer (CRC) is well established. Expression of the pro-inflammatory CXC-chemokine, CXCL8, has been shown to be elevated in CRC, where it is associated with tumour size, stage and metastasis. However, further studies into the regulation of CXCL8 in CRC and the molecular mechanisms underlying CXCL8-induced tumour progression are required to support the use of CXCL8-targeted therapeutics in the treatment of CRC. The results presented in Chapter 3 highlight a number of genetic alterations which result in the potentiation of CXCL8 in CRC, as well as illustrating the dependence of several CRC cell lines on CXCL8 for their survival. Oncogenic K-Ras was shown to be capable of inducing CXCL8 signalling, involving both the MAPK and PI3K-Akt signalling pathways. Moreover, loss of the tumour suppressor genes, PTEN and APC, was shown to co-operate with mutant K-Ras to further enhance CXCL8 signalling. The results described in Chapter 4 present CXCL8 as a master regulator of receptor tyrosine kinase (RTK) signalling within the tumour microenvironment of CRC. Specifically, we have shown that both autocrine and paracrine CXCL8 signalling is capable of potentiating EGFR, c-MET, FGFR1 and VEGF signalling in tumour and stromal cells. Inhibition of CXCL8 signalling is therefore likely to impede tumour progression via the attenuation of a plethora of RTK signalling pathways. The findings described in this thesis therefore present CXCL8 and its receptors (CXCR1/2) as potential therapeutic targets in CRC, particularly in patients with oncogenic K-Ras, as well as loss of the PTEN and/or APC tumour suppressor genes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available