Mapping the intracellular molecular mechanisms of chemokine signalling within cancer

Keil, Gerald (2019) Mapping the intracellular molecular mechanisms of chemokine signalling within cancer. Doctoral thesis, University of East Anglia.

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Abstract

Chemokines are extracellular signalling molecules which function as chemoattractants for leukocytes by directing their migration towards sites of inflammation as part of the immune response. On epithelial cells chemokine receptor expression is normally low or absent. However during cancer progression, chemokine receptors can become overexpressed on cancer cells, whilst chemokines are frequently present at sites of metastasis. Consequently aberrant chemokine signalling is associated with both metastasis and a poor prognosis in cancer patients. The chemokine signalling network is therefore consider a potential therapeutic target for cancer treatment. The aim of the research undertaken in this thesis was to identify novel therapeutic targets involved in chemokine downstream signalling in cancer cells.

To investigate the chemokine downstream signalling pathway, a number of different chemokines and small molecules were used with their effects on cellular intracellular calcium signalling and migration of different leukemic and carcinoma cells assessed.

The findings from the screen identified a role for CCL2 and CCL3 signalling in the migration of PC-3 and MCF-7 cells respectively. In MCF-7 cells, CXCL12 intracellular calcium signalling was shown to be dependent on Gαi, Syk/Src, c-Raf, DOCK1/2/5 and Arp2/3. With DOCK1/2/5 also shown to be essential for CCL3 and CXCL12 intracellular calcium signalling in both MCF-7 and THP-1 cells, as well as for CXCL12 chemotaxis of Jurkat cells. For Arp2/3 its importance in chemokine signalling was specific to MCF-7 cells, whilst the roles of the microtubules and FAK were dependent on both the chemokine and cell type.

In this thesis DOCK1/2/5 was identified as a novel target for blocking leukemic T-cell migration (Jurkats) in response to CXCL12. In addition, Arp2/3 and the microtubules were implicated in chemokine signalling and therefore would warrant further investigation to establish their importance in cancer cell migration.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Gillian Aldus
Date Deposited: 13 Jun 2019 12:30
Last Modified: 13 Jun 2019 12:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/71379
DOI:

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