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Dll4-Notch signaling in regulation of tumor angiogenesis

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Abstract

Tumor angiogenesis is a complex process and involves the tight interplay of tumor cells, endothelial cells, phagocytes and their secreted factors, which may act as promoters or inhibitors of angiogenesis. Many signaling pathways involved in these processes such as vascular endothelial growth factor (VEGF), fibroblast growth factors, Wnt and mTOR signaling pathway. Though research has confirmed that VEGF can play an important role in tumor angiogenesis, and has designed a lot of drugs that target VEGF, both experimental and clinical studies showed that these pathways mentioned above including VEGF did not play key roles in tumor angiogenesis. With the deepening of the research, people find that of all the signaling pathways involved in tumor angiogenesis, Notch signaling is the most notable one and plays crucial role in tumor angiogenesis. It was previously recognized that the Notch signaling plays a key role only in physiological angiogenesis such as development, wound healing and pregnancy. However, an increasing number of studies have proved that Notch signaling is also involved in pathological angiogenesis such as tumor angiogenesis and plays a critical role in these processes. More importantly, compared to resistance caused by anti-VEGF or other signaling pathways, experimental evidence revealed that Notch was involved in anticancer drug resistance, indicating that targeting Notch could be a novel therapeutic approach to the treatment for cancer by overcoming drug resistance of cancer cells. More recently, research has demonstrated that Notch ligands Delta-like 4 (Dll4) plays a key role in tumor angiogenesis. Data show that Dll4 functions as a negative regulator of tumor angiogenesis and is upregulated in tumor vasculature. This review focus on recent insights into Dll4-Notch signaling in tumor angiogenesis and its mechanisms, which may be utilized for a potential pharmacological use as a target for anti-angiogenic cancer therapy.

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Acknowledgments

The authors thank the financial support from National Nature Science Foundation of China (81173174 and 30772766), Jiangsu Natural Science Foundation (BK2010085 and 210562), Educational Commission of Jiangsu Province (09KJA360002), Traditional Chinese Medicine Project of Jiangsu Province (LZ09022), Efficacy and Safety Evaluation of Traditional Chinese Medicine Key Laboratory Open Project of Jiangsu Province (P09013) and Jiangsu College Graduate Research and Innovation Projects (CXZZ11_0787).

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The authors declare that there is no conflict of interest.

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Liu, Z., Fan, F., Wang, A. et al. Dll4-Notch signaling in regulation of tumor angiogenesis. J Cancer Res Clin Oncol 140, 525–536 (2014). https://doi.org/10.1007/s00432-013-1534-x

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