Breast to bone metastasis is a common event during breast cancer progression. The resultant lesions often cause extensive bone destruction that results in a number of complications including intense pain that dramatically affects the patients quality of life and leads to increased morbidity. Understanding the mechanisms through which breast cancer cells destroy bone can ultimately lead to the generation of new therapies that will successfully battle the disease. In the osteolytic tumor bone environment, activation of osteoclasts, the cells responsible for bone resorption, is critically dependent on proper signals derived from osteoblasts, the cells responsible for bone synthesis. Matrix metalloproteinases (MMPs) are a family of proteinases that have been implicated in mediating cell-cell communication in the tumor bone environment. Interestingly, in human breast-to-bone metastases samples, MMP-2 has been shown to be expressed by osteoblasts and osteocytes and MMP-7 and MMP-9 were found be localized to bone resorbing osteoclasts. In a bid to define the roles of host derived MMP-2, MMP-7 and MMP-9 in the tumor-bone microenvironment, the tibia of MMP-2, MMP-7 and MMP-9 null mice were injected with osteolytic luciferase tagged mammary tumor cell lines. Our studies demonstrated that osteoblast-derived MMP-2 impacts mammary tumor survival in the bone microenvironment by mediating the release of active TGF-β via the processing of a novel MMP-2 substrate, LTBP-3. Furthermore, our results showed that osteoclast-derived MMP-7 but not MMP-9 affect mammary tumor growth in the bone via the solubilization of RANKL that in turn induces osteoclastic resorption of the bone. Thus, this dissertation demonstrated that MMP-2 and MMP-7 support the vicious cycle of bone metastasis via two distinct mechanisms affecting two of the key components of the process, osteoblasts and osteoclasts. Therefore, these two MMPs and their substrates would be attractive targets for future drug therapies to treat patients suffering from breast cancer-induced lytic bone lesions.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07012009-161714 |
| Date | 07 July 2009 |
| Creators | Thiolloy, Sophie |
| Contributors | Lynn Matrisian, barbara Fingleton, Neil Bhowmick, jeffrey Davidson, gregory Mundy |
| 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-07012009-161714/ |
| 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. |
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