Promotion of Angiogenesis by Globo-H Ceramide and Its Molecular Mechanism
| Autor: | Jing-Yan, Cheng, 程景彥 |
|---|---|
| Rok vydání: | 2014 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 103 Tumor angiogenesis is a critcal element of cancer progression and strategies for its selective blockade are still sought. Here we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation and intracellular Ca2+ mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared to cells expressing low levels of Globo-H. Clincally, GHCer+ breast cancer specimens contained higher vessel density than GHCer- breast cancer specimens (p=0.04, n=50). Many angiogenic factors and receptors, including VEGFA, FGF2, FGF13, MMP9, VEGFR2 and S1PR1, but not VEGFR1, S1PR2 and MMP2, were expressed after GHCer treatment. Using computer modeling, we predicted the regions on TRAX for binding to PLCβ1 and GHCer. The carbon chain of sphingosine and hexasaccharide motif of of GHCer interacted with hydrophobic groove and a polar-amino-acid region on TRAX, respectively, which was exactly the predicted binding region for PLCβ1. Such structural modeling provided further insight into the possible molecular basis for the replacement of PLCβ 1 from TRAX by GHCer. These findings suggest that GHCer is a newly identified natural inhibitor of PLCβ1. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCβ1 from TRAX to trigger Ca2+ mobilization. Together, our findings highlight the importance of GHCer as a target for cancer therapy by providing new information on its key role in tumor angiogenesis. In view of the angiogenetic activities of GHCer and our previous reports of its immunosuppressive effects as well as the expression of Globo-H on the breast cancer stem cells, Globo-H is an ideal target for cancer immunotherapy, with the use of Globo-H vaccine or anti-Globo-H monoclonal antibody. Our data further strengthened the scientific rationales for the ongoing phase II/III clinical trial of Globo-H vaccine in breast cancer. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|