The interactions between malignant plasma cells and the bone marrow microenvironment are critical for the development of multiple myeloma and the associated osteolytic bone disease. Only recently are studies beginning to elucidate mechanisms by which the altered microenvironment contributes to cancer progression in hematological malignancies. The contributions of the host microenvironment during the initial stages of myeloma development are poorly understood. In the studies presented in this dissertation, we (1) developed a new murine model of myeloma to enable investigation of the host bone marrow microenvironment in myeloma pathogenesis, (2) determined the role of bone marrow stromal cell-derived Dkk1 in myeloma cell establishment and growth, and (3) determined the role of decreased circulating adiponectin in myeloma pathogenesis. Many features of human myeloma bone disease are recapitulated in the well-characterized 5T Radl myeloma model, where transplantation of 5T myeloma cells into recipient mice of the C57Bl/KaLwRij substrain results in propagation of myeloma. Our studies utilized these mice as a tool to provide valuable insights into the development of human myeloma and the associated bone disease. After the initial identification of these factors in the C57Bl/KaLwRij mice, findings in patients, either from the literature or by direct examination of specimens, provide strong support that these changes have clinical relevance. The ultimate goal of this dissertation was to gain a better understanding of the mechanisms that precede myeloma bone disease. Our findings suggest that bone marrow stromal cell-derived Dkk1 and decreases in circulating adiponectin are important in myeloma pathogenesis.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09082010-095524 |
| Date | 09 September 2010 |
| Creators | Fowler, Jessica Aaron |
| Contributors | Simon Hayward, Claire Edwards, Florent Elefteriou, Barbara Fingleton |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-09082010-095524/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0143 seconds