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Title page for ETD etd-10092013-140015

Type of Document Dissertation
Author Pickup, Michael William
Author's Email Address michael.pickup@vanderbilt.edu
URN etd-10092013-140015
Title Effects of alterations to the tumor microenvironment driven by transforming growth factor beta on tumor progression
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Barbara Fingleton Committee Chair
Ambra Pozzi Committee Member
Andries Zijlstra Committee Member
Timothy Blackwell Committee Member
  • Breast Cancer
  • TGF-Beta
  • Fibroblast
  • Tumor Microenvironment
Date of Defense 2013-09-27
Availability unrestricted
Dissertation under the direction of Professor Harold L. Moses

Transforming Growth Factor Beta (TGF-β) is acts as both a tumor suppressor and promoter in the context of epithelial tumor progression. In epithelial cells, active TGF-β signaling promotes cell cycle arrest to slow tumor growth but also promotes EMT and cell motility to enhance tumor cell metastasis. We sought to address TGF-β signaling role in tumor progression through its effects on stromal cells and microenvironmental changes. Interestingly, as with epithelial TGF- β signaling, we found active TGF-β signaling in fibroblasts to present with the same dichotomous relationship. We found that TGF-β can promote fibroblast activation which in turn drives the expression of numerous matrix remodeling genes. The phenotypic outcome of this matrix remodeling promotes tumor cell metastasis. Alternatively, abrogation of TGF-β signaling in fibroblasts also promotes tumor cell metastasis. Albeit, this occurs through a different mechanism involving altered chemokine expression to promote chemotaxis of tumor promoting myeloid cells. Gene expression analysis of stroma from reduction mammoplasty as well as breast cancer patients suggests that TGFβR2 is lost as breast cancer progresses from normal mammary tissue to invasive ductal carcinoma. Importantly, this loss of TGFβR2 in the stroma of breast cancer patients is associated with poor patient outcome and rick of recurrence. This work shows the importance of TGF-β signaling as a central player in numerous biological process which effects tumor progression through the tumor microenvironment. As this signaling axis in the tumor microenvironment is certainly important in the progression of human breast cancer, the therapeutic targeting of the TGF-β pathway will need to consider stromal effects for efficacious use.

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