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Theses Doctoral

Notch Signaling in Tumor Angiogenesis

Kangsamaksin, Thaned

Notch signaling plays an important role in developmental and pathological angiogenesis. Notch ligands, Dll4 and Jag1, have been implicated in tumor angiogenesis. Inhibition of Dll4-mediated Notch signaling results in hypersprouting of non-functional vasculature in tumors. We have constructed and analyzed pan-Notch ligand inhibitors, Notch1 decoys 1-24 and 1-36, which are based on the extracellular EGF-like repeats of Notch1. Both Notch1 decoys block angiogenesis in in vitro endothelial cell-based assays and in the mouse retina. We also show that they similarly inhibit Dll4- and Jag1-induced Notch signaling in vitro and result in a significant decrease in tumor growth and tumor vasculature in mouse and human tumor xenograft models. Interestingly, truncated Notch1 decoy variants, Notch1 decoys 1-13 and 10-24, act as ligand-specific Notch inhibitors. Notch1 decoy 1-13 is Dll4-specific whereas Notch1 decoy 10-24 is Jag1-specific.
Ligand-specific Notch1 decoys effectively reduce tumor growth in tumor xenograft models in the mouse, including Mm5MT-FGF4, KP1-VEGF, LLC, and B16-F10. Notch1 decoy 1-13 has been demonstrated to increase tumor vasculature by increasing endothelial sprouting and number of tip cells. However, similar to the previously reported effects of Dll4 blockade, the tumor vessels are poorly perfused and hardly functional. On the other hand, Jag1-specific Notch1 decoy 10-24 significantly reduces tumor vessel density and disrupting endothelial-pericyte interactions, causing the impaired vascular structure and attenuated vascular perfusion. In addition, Notch1 decoys 1-13, 10-24, and 1-24 show an anti-metastatic potential in causing a delay of lung metastasis in the B16-F10 tumor model. Unlike gamma-secretase inhibitors and Dll4-blocking agents, Notch1 decoys do not cause GI-associated toxicity or vascular neoplasms. Therefore, our Notch1 decoys may represent a novel alternative and may hold future promise for Notch-targeted cancer therapy.

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More About This Work

Academic Units
Pathobiology and Molecular Medicine
Thesis Advisors
Kitajewski, Jan K.
Degree
Ph.D., Columbia University
Published Here
November 5, 2017