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Title page for ETD etd-07192012-115011


Type of Document Dissertation
Author Matise, Lauren Alicia
Author's Email Address laurenmatise@gmail.com
URN etd-07192012-115011
Title Role of TGF-β signaling in carcinoma cell migration and tumor progression
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Albert Reynolds, PhD Committee Chair
Andries Zijlstra, PhD Committee Member
Harold Moses, MD Committee Member
Rebecca Cook, PhD Committee Member
Keywords
  • TGF-beta
  • tumor-stromal interactions
  • single cell invasion
  • collective cell invasion
  • mouse model
  • breast cancer
  • tumor microenvironment
Date of Defense 2012-06-22
Availability unrestricted
Abstract
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.

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