Cell and Experimental Pathology
Oliver Jay Broom
Involvement of eicosanoid signalling in epithelial cell migration
Academic Dissertation by due permission of the Faculy of Medicine, Lund University, Sweden to be defended at the main lecture hall, Pathlogy building,
Malmö University Hospital , Malmö on Friday 26th of October, 2007 at 9,00
For the degree of Doctor of Philosophy, Faculty of Medicine
Faculty opponent: Docent Johanna Ivaska, University of Turku and VTT Biotechnology Centre, Turku, Finland
The development of inflammatory bowel diseases (IBD) and colon cancer (CC) has been shown to involve the up-regulation of inflammatory mediators and the machinery producing them such as the eicosanoids. Changes in the expression of extracellular matrix proteins and their related integrin receptors have also been shown to be important in the advancement IBD and CC. In light of this, we have investigated the role of eicosanoids in cell migration a key process in IBD and CC. This was through direct stimulation, with the eicosanoid leukotriene D4 (LTD4) or indirectly through inducing cyclooxygenase-2 (COX-2; an enzyme involved in the production of various eicosanoids) expression, by activating integrin collagen receptors. We observed that direct stimulation with LT D4, induced intestinal epithelial cell migration, through activation of the CysLT1 receptor, phosphotidylinositol-3 kinase, Vav2 and Rac localisation to membrane ruffles. Indirect stimulation, by activating COX-2 expression in a ?2?1 integrin dependent manner was able to elicit a migratory response. The integrin dependent COX-2 expression was shown to be mediated through the activation of CD47 and its associated G?i3 protein, which in turn lead to protein kinase C?, the Ras GTPase and NF?B activation. COX-2 expression is synonymous with activation of the protein. Inhibition of COX-2 expression or specifically inhibiting COX-2 activity, resulted in cell adhesion being favoured over cell migration in a CD47 dependent manner.
Thus understanding cellular mechanisms leading to cell migration may reveal novel targets and lead to new therapeutic strategies in treating IBD and CC.