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dc.contributor.authorLe Brenne, Arielle
dc.date.accessioned2015-09-29T16:33:16Z
dc.date.available2015-09-29T16:33:16Z
dc.date.issued2014-04
dc.identifier.citationLe Brenne, A. 2014. Contribution of Bone Marrow Derived Cells to Four Mouse Models of Gastrointestinal Tumourigenesis. Queen Mary University of London.en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/8986
dc.descriptionPhDen_US
dc.description.abstractIntroduction: 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.en_US
dc.description.sponsorshipSaint Bartholomew'ʹs and The Royal London Charitable Foundationen_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectMedicineen_US
dc.subjectGastrointestinal canceren_US
dc.titleContribution of Bone Marrow Derived Cells to Four Mouse Models of Gastrointestinal Tumourigenesis.en_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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