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Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells
- Source :
- Neoplasia: An International Journal for Oncology Research, Vol 15, Iss 7, Pp 815-825 (2013)
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2+ perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.
- Subjects :
- Cancer Research
Angiogenesis
Notch signaling pathway
Biology
lcsh:RC254-282
Neovascularization
Mice
In vivo
Cell Line, Tumor
Neoplasms
medicine
Animals
Humans
Protein Interaction Domains and Motifs
Antigens
Hypoxia
RGD motif
Neovascularization, Pathologic
Receptors, Notch
Tumor hypoxia
Calcium-Binding Proteins
Endothelial Cells
Membrane Proteins
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Tumor Burden
Cell culture
Immunology
Cancer research
Heterografts
Intercellular Signaling Peptides and Proteins
Proteoglycans
medicine.symptom
Signal transduction
Protein Binding
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 14765586
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Neoplasia
- Accession number :
- edsair.doi.dedup.....75f91a38c974f5c5b9f92834a2a26e0a