Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.667351
Title: Contribution of bone marrow derived cells to four mouse models of gastrointestinal tumourigenesis
Author: Le Brenne, Arielle
ISNI:       0000 0004 5360 1643
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2014
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Abstract:
Introduction: Houghton and colleagues (2004) demonstrated bone marrow derived cells (BMDCs) to be the origin of epithelial cells in pre-invasive and malignant gastric tumours in Helicobacter felis infected mice. However, this has yet to be replicated in any other experimental scenario. Methods: To clarify the significance of Houghton’s observation we examined four mouse models of gastrointestinal tumourigenesis: the Tff1-/- mouse model of inflammatory gastric adenocarcinoma, the ApcMin/+ and Apc1322T mouse models of familial adenomatous polyposis, and the Il10-/- mouse model of colitis-associated colorectal adenocarcinoma, employing sex-mismatched bone marrow (BM) transplantation (male BM to female recipients) followed by the identification of BMDCs in tissues using Y-chromosome in situ hybridisation (ISH) detection and immunohistochemical phenotyping of cells. To investigate the mechanism for BMDC recruitment into tissues, osteopontin (Opn) mRNA isotopic ISH was employed. Results: In four mouse models there was not a single instance of a gastric gland or intestinal crypt with a patch of clonal Y-chromosome positive (Y+) cells. Y+ cells in the epithelium were very rare and were mostly positive for several markers of immune cells. In contrast, Y+ cells were frequently observed in the stroma. Quantification of BMD-myofibroblasts demonstrated increased recruitment into larger Apc1322T mouse tumours and desmoplastic reaction sites in Tff1-/- mouse tumours, but not into inflamed non-fibrotic tissues. Similarly, Opn mRNA expression was unaffected by inflammation but increased with tumour burden and in desmoplastic reaction sites. In the desmoplastic reaction sites of Tff1-/- mouse tumours, increased osteopontin mRNA expression correlated with increased BMD-myofibroblasts, therefore suggesting some chemoattraction was occurring. Conclusions: In four mouse models of gastrointestinal tumourigenesis BMDCs were not a source of reparative, pre-cancerous, or malignant epithelial cells. Analysis of BM contribution in the stroma demonstrated that BMD-myofibroblast engraftment is driven by increased tumour burden and fibrosis. In addition, the increased presence of BMD-myofibroblasts at desmoplastic reaction sites of Tff1-/- mouse tumours correlated with increased Opn mRNA expression, indicating that osteopontin may act as chemoattractant in desmoplasia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.667351  DOI: Not available
Keywords: Medicine ; Gastrointestinal cancer
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