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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:667351 |
| Date | January 2014 |
| Creators | Le Brenne, Arielle |
| Publisher | Queen Mary, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://qmro.qmul.ac.uk/xmlui/handle/123456789/8986 |
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