Investigating the role of fascin in murine models of inflammatory bowel disease and tumourigenesis

Stevenson, Richard P. (2014) Investigating the role of fascin in murine models of inflammatory bowel disease and tumourigenesis. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Recent evidence suggests that stem cells are important for cancer metastasis and that the epithelial-to-mesenchymal transition also involves a transition toward stemness. Current thinking suggests that lgr5, a 7-transmembrane spanning G-protein, also marks a certain population of stem cells capable of regenerating an intestinal crypt and that the specialised immune secretory paneth cell, is important for maintenance of the stem cell niche. We implicate fascin in regulating the balance of lgr5 stem cells during acute intestinal inflammation and in regenerating intestinal tissue. Fascin is an actin bundling protein that drives the assembly of filopodia through the cross-linking of actin filaments into straight bundles. Conserved from amoebas to man, fascin was originally purified from extracts of sea urchin oocytes and coelomocytes and later found in Drosophila as the singed gene product. It is involved in the invasion and metastasis of multiple epithelial cancer types through stabilisation of actin in invadopodia, finger like protrusions used by cancer cells to invade into and degrade the extra-cellular matrix. Fascin, whilst normally low or absent from epithelia, localises to the leading edges of migratory cells and is over-expressed in many cancers of the same epithelial origin including lung, colorectal, pancreatic and liver. Fascin has also recently been shown to increase during inflammatory bowel disease (IBD) conditions such as diverticulitis, Crohn’s disease and ulcerative colitis. In this thesis I have investigated the role of fascin in murine models of IBD and have demonstrated that fascin is required for the haematopoietic production of leucocytes, in response to inflammation and that the loss of fascin, in the presence of high Wnt levels, results in enhanced proliferation of intestinal epithelial cells. One of the serious consequences of IBD is the increased lifetime risk of the patient developing an intestinal malignancy secondary to the disease. The exact mechanism underlying the increase in malignancies has not yet been fully established, however it is postulated that chronic inflammation and the effect this has on the major molecular pathways involved in carcinogenesis underlies the transformation from benign to malignant disease. Highest fascin expression has been shown in the dysplastic, pre-malignant cells in human IBD tissues indicating an important role of fascin in the transformation of benign to malignant cells. In this thesis, I have demonstrated that loss of fascin impairs tumour initiation in inflammatory driven and spontaneous intestinal tumourigenesis models, which is likely, in part, to be as a consequence of reduced leucocytes, in particular neutrophils, which may be CXCL2 mediated.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Fascin, inflammation, IBD, cancer, mouse, neutrophils, CXCL2
Subjects: Q Science > Q Science (General)
R Medicine > RB Pathology
R Medicine > RD Surgery
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Beatson Institute of Cancer Research
Funder's Name: UNSPECIFIED
Supervisor's Name: Machesky, Professor Laura
Date of Award: 2014
Embargo Date: 14 April 2015
Depositing User: Dr Richard Stevenson
Unique ID: glathesis:2014-5107
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 22 Apr 2014 13:38
Last Modified: 22 Apr 2014 13:38
URI: http://theses.gla.ac.uk/id/eprint/5107

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