REGULATION OF ENDOTHELIAL PLASTICITY BY TGFβ IN TUMORS Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 20, 2019
Creator
  • Xiao, Lin
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Tumor endothelial cells (TEC) are abnormal in morphology, structure, and function. They exhibit high cellular plasticity and may acquire stem-cell features in response to the aberrant tumor microenvironment. Such ability of TEC is prominently manifested in a process termed endothelial-mesenchymal transition, or EndMT. During EndMT, TEC lose their endothelial characteristics and gain fibroblast gene expression, transdifferentiating into mesenchymal cells in response to inflammatory factors, especially the chief inducer of EndMT, transforming growth factor beta (TGFβ). Although EndMT has been described as a physiological process in cardiac development during embryogenesis, in tumors EndMT may contribute to vascular abnormalities, generate tumor-promoting myofibroblasts, and lead to development of resistance to anti-cancer therapies that target the tumor vasculature. This thesis aims to understand the mechanisms that un derlie EndMT and identify regulatory factors that counteract this process in tumors. During the project, we developed an efficient TEC isolation method that allowed us to obtain highly pure TEC populations free of contaminating tumor or mesenchymal cells. We found that the TEC isolated from mammary tumors possessed a unique gene signature that was retained in culture. We also uncovered two distinct TEC populations that responded differently to TGFβ: some TEC transdifferentiated into myofibroblast-like cells, whereas others were more resistant to TGFβ challenge. In addition, basic fibroblast growth factor (bFGF), which is an important endothelial mitogen, preserved endothelial identity by opposing TGFβ-induced EndMT. Interestingly, TEC were found to possess an intrinsic protective mechanism whereby bFGF was up-regulated and secreted to neutralize the effect of TGFβ during EndMT. Further elucidation of the molecular pathways that regulate TEC heterogeneity and plasticity may facilitate the development of specific drugs to target myofibroblasts and to reverse myofibroblast differentiation in tumors and other fibrotic diseases.
Date of publication
Keyword
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Dudley, Andrew
  • Demore, Nancy
  • Snider, Natasha
  • Bautch, Vicki
  • Otey, Carol
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
Language
Parents:

This work has no parents.

Items