Transforming growth factor-beta (TGF-β) has a dual role during tumor progression initially as a suppressor and then as a promoter. Much is known about the contribution of TGF-β signaling to tumorigenesis, yet, the role of TGF-β in epithelial-stromal migration during tumor progression is poorly understood. In this dissertation, we hypothesized that TGF-β is a critical regulator of tumor-stromal interactions that promote mammary tumor cell migration and metastasis. Fluorescently-labeled murine mammary carcinoma cells, isolated from either MMTV-PyVmT TGF-β receptor II knockout (TβRII KO) or TβRIIfl/fl control mice, were combined with mammary fibroblasts and xenografted onto the chicken embryo chorioallantoic membrane. Intravital microscopy of xenografts revealed that fibroblast-stimulated carcinoma cells utilize TGF-β signaling to drive single cell/strand migration but migrate collectively in the absence of TGF-β signaling. At epithelial-stromal boundaries, single cell/strand migration of TβRIIfl/fl carcinoma cells was characterized by α-SMA and vimentin expression, while collective migration of TβRII KO carcinoma cells was identified by E-cadherin+/p120+/β-catenin+ clusters. TβRII KO tumors exhibited a two-fold greater metastasis than TβRIIfl/fl tumors, attributed to enhanced extravasation ability. In TβRII KO tumor epithelium compared to TβRIIfl/fl epithelium, Igfbp4 and Tspan13 expression was upregulated while Col1α2, Bmp7, Gng11, Vcan, Tmeff1, and Dsc2 expression was downregulated. Downregulation of Tmeff1 was correlated with disease progression of TGF-β-insensitive mammary cancer. Our findings concerning TGF-β signaling in stromal-epithelial interactions are important in identifying migratory mechanisms that can be targeted as recourse for breast cancer treatment.
In the second part of this dissertation, the timing of TGF-β signaling in relation to tumor progression was investigated through the creation of an inducible dominant-negative TβRII (dnTβRII) mouse model (MMTV-PyVmT;MMTV-rtta;dnTβRII). We hypothesized that attenuation of TGF-β signaling prior to tumorigenesis leads to increased metastasis. Results indicated that animals with attenuated TGF-β signaling prior to tumor palpation exhibited increased tumor latency and enhanced metastasis of dnTβRII-expressing carcinoma cells. These animals had an increased MDSC tumor population, as well as increased carcinoma cell secretion of MCP-1/CCL2. Our inducible dnTβRII model has therapeutic implications in determining the necessary timing of therapeutic inhibition of TGF-β signaling during cancer progression.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07192012-115011 |
| Date | 26 July 2012 |
| Creators | Matise, Lauren Alicia |
| Contributors | Andries Zijlstra, PhD, Rebecca Cook, PhD, Albert Reynolds, PhD, Harold Moses, MD |
| 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-07192012-115011/ |
| 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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