Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Tumor endothelial cells, which line the interior surface of tumor blood vessels, were considered genetically normal until recent findings showed that they can be aneuploid, and have compromised p53 signaling and excess centrosomes. However, the causes and effects of centrosome over-duplication and compromised p53 signaling in endothelial cells remain elusive. In this dissertation, I designed and performed various experiments to investigate these questions. I found that some BMP ligands induced BMPR1A-dependent excess centrosomes in primary human endothelial cells, likely though SMAD signaling. In addition, hypoxia and abrogated p53 signaling, but not inflammation, promoted centrosome over-duplication. These results contribute to our understanding of tumor microenvironment. I also demonstrated that excess centrosomes induced p53-dependent senescence in primary endothelial cells, indicating that the response of centrosome over-duplication is dependent on whether cells have intact cell cycle. This is the first evidence linking excess centrosomes and senescence, and may also help explain the abnormal morphology and function in tumor vasculature. Finally, I showed that loss of p53 induced angiogenesis in vitro by promoting endothelial cell migration and proliferation, but not in mouse retina vessels. In summary, my thesis work helps understand the causes and effects of centrosome over-duplication in endothelial cells, contributing to the studies on tumor microenvironment.