Investigating Murine Models of Non Small Cell Lung Cancer
| atmire.migration.oldid | 1471 | |
| dc.contributor.advisor | Jirik, Frank | |
| dc.contributor.author | Downey, Charlene | |
| dc.date.accessioned | 2013-09-24T21:24:26Z | |
| dc.date.available | 2014-03-24T07:00:11Z | |
| dc.date.issued | 2013-09-24 | |
| dc.date.submitted | 2013 | en |
| dc.description.abstract | Lung cancer is the leading cause of cancer-related mortality worldwide. Adenocarcinoma, the most common subtype is primarily characterized by a combination of p53 and K-ras mutations. The activating K-ras mutation is frequently induced from carcinogens found within tobacco smoke, and is responsible for promoting an inflammatory microenvironment in the lung, which further enhances tumor progression. M2 polarized macrophages, the most common infiltrating cell type found within tumors, have been demonstrated to have several tumor-promoting effects such as promoting angiogenesis, suppressing inflammation and assisting with metastasis. However, there is conflicting evidence to the role of macrophages in lung cancer and in response to therapy. Using a mouse model that closely recapitulates features of human adenocarcinoma formation, in addition to syngeneic cell lines derived from both primary lung adenocarcinomas and metastases, we developed a model of quantifying tumor vasculature and areas of necrosis in 3-D ex vivo. In addition, we investigated the role of macrophage infiltration in tumor growth and in response to a vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) using subcutaneous, metastatic and spontaneously-derived lung adenocarcinomas. We found that despite the similar genetic background of the tumors, macrophage infiltration differed between tumor sites, and this appeared to result in differential response to DMXAA. Moreover, tumor-associated M2 macrophages were repolarized to a cytotoxic M1 phenotype in response to DMXAA; a novel role for this agent. In addition, we found that lung tumor development and progression in the K-rasLA1/+ mice was accelerated when crossed with Msh2-deficient mice, a key effector protein in the mismatch repair pathway, thus highlighting a role for MSH2 as a tumor suppressor in the development of lung cancer. In summary, lung cancer progression, which is based on exposure to external carcinogens, acquired mutations within tumor cells, and on infiltrating stromal cells such as macrophages within the tumor microenvironment, is a complex occurrence. Studying each of these facets using mouse models that closely echo human tumor progression may bring us closer to understanding human disease progression. | en_US |
| dc.description.embargoterms | 6 months | en_US |
| dc.identifier.citation | Downey, C. (2013). Investigating Murine Models of Non Small Cell Lung Cancer (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26631 | en_US |
| dc.identifier.doi | http://dx.doi.org/10.11575/PRISM/26631 | |
| dc.identifier.uri | http://hdl.handle.net/11023/1019 | |
| dc.language.iso | eng | |
| dc.publisher.faculty | Graduate Studies | |
| dc.publisher.faculty | Medicine | |
| dc.publisher.institution | University of Calgary | en |
| dc.publisher.place | Calgary | en |
| dc.rights | University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. | |
| dc.subject | Molecular | |
| dc.subject | Oncology | |
| dc.subject | Pathology | |
| dc.subject | Molecular | |
| dc.subject.classification | Mouse models | en_US |
| dc.subject.classification | Non small cell lung cancer | en_US |
| dc.subject.classification | Vessels | en_US |
| dc.subject.classification | Macrophages | en_US |
| dc.subject.classification | Micro-CT | en_US |
| dc.subject.classification | Syngeneic | en_US |
| dc.subject.classification | Cell Lines | en_US |
| dc.title | Investigating Murine Models of Non Small Cell Lung Cancer | |
| dc.type | doctoral thesis | |
| thesis.degree.discipline | Biochemistry and Molecular Biology | |
| thesis.degree.grantor | University of Calgary | |
| thesis.degree.name | Doctor of Philosophy (PhD) | |
| ucalgary.item.requestcopy | true |