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|Title:||Modulation of Tumour Burden in Mouse Lungs by Oncostatin M|
|Abstract:||Lung cancer is the leading cause of cancer-related mortality, resulting in more deaths than breast, colorectal, and pancreatic cancers combined in North America. As such, research regarding the underlying mechanisms and pathogenesis of the disease is critical. Inflammation induced by inflammatory cytokines, such as gp130 cytokines, has been implicated in chronic lung diseases, and more recently in the development of lung cancer. The roles of gp130 cytokines IL-6 and Oncostatin M (OSM) in lung cancer has yet to be fully elucidated, although these cytokines have been noted to contribute to the pro-tumour cytokine environment as well as the growth and survival of certain tumour cells. Based on previous findings that overexpression of OSM increased tumour burden in a mouse model of lung cancer, it is hypothesized that OSM is a key player in the establishment and progression of pulmonary tumours in mice, and depletion or elevation of OSM activity modulates tumour burden in the B16F10 mouse melanoma model, as well as the induced mutant K-ras mouse model of lung cancer, independently of direct action on tumour cells. Findings presented in this thesis demonstrate that pulmonary OSM overexpression enhances tumour burden in the B16 pulmonary melanoma metastases mouse model of lung cancer, whereas pulmonary overexpression of IL-6 did not. In addition, although OSM overexpression resulted in increased lung IL-6 and eosinophil recruitment in this model, neither IL-6 nor eosinophils were required in the induction of increased tumour burden, as assessed in IL-6 deficient (IL-6 -/-) or eosinophil deficient (GATA-1 -/-) mice. While preliminary experiments suggested accelerated tumour burden due to OSM overexpression in the inducible oncogenic K-ras mouse model, experiments in mutant K-ras +/- transgenic OSMRβ -/- mice determined that OSMRβ was not required for the development of tumours in this model. In studies completed to examine the mechanisms underlying the effects of OSM on tumour burden, direct stimulation of K-ras tumour cell lines LLC and LKR-13 with OSM in vitro did not alter tumour cell proliferation. Furthermore, conditioned media from mouse lung fibroblasts (MLFs) treated with OSM, as well as co-cultures with MLFs treated with OSM, did not alter LLC or B16F10 cell proliferation. This suggests that direct stimulation of tumour cells or indirect stimulation through fibroblasts may not contribute to mechanisms by which OSM stimulates increased tumour burden in vivo. Co-cultures of tumour cells and cells collected in bronchoalveolar lavage (BAL) fluid from mice treated with AdDel70 or AdOSM in vivo caused an increase in tumour cell proliferation, however adherent macrophage populations did not. The in vitro work suggests other mechanisms or multiple cell types are required in addition to macrophages or fibroblasts. Collectively, the work presented in this thesis supports a pro-tumorigenic role of Oncostatin M in mouse models of tumour growth in lungs, through an IL-6 and eosinophil independent mechanism.|
|Appears in Collections:||Open Access Dissertations and Theses|
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|Laura Izakelian - Masters Thesis Final.pdf||Thesis||14.87 MB||Adobe PDF||View/Open|
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