Contribution of Bone Marrow Derived Cells to Four Mouse Models of Gastrointestinal Tumourigenesis.
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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.
AuthorsLe Brenne, Arielle
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