Tumor angiogenesis-targeted therapy is one of the major therapeutic strategies for the treatment of tumor in various preclinical and clinical studies. Current targets for inhibiting tumor angiogenesis have a bad effect to healthy vessels, and alternative cell surface markers that positively discriminate pathological angiogenesis from stable vessels are needed.

Apelin⁺ tumor endothelial cells were demonstrated in previous work to be efficiently targeted to restrict tumor growth. However, the secreted peptide presents a challenge for drug development, whereas its receptor, Apj, is expressed on the cell surface and may be more tractable for selectively targeting tumor vessels with small-molecule drugs.

In a recent study published in Cell Reports, Prof. ZHOU Bin’s lab at CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of Chinese Academy of Sciences built an Apj-CreER knockin mouse line using CRISPR/Cas9 to mark Apj⁺ cells, and found that genetic and pharmacological targeting of Apj⁺ vessels could inhibit tumor growth.

Taking advantage of genetic lineage tracing (Apj-CreER; Rosa-GFP), researchers established four different tumor models (xenograft tumor model, orthotopic tumor model, chemically induced liver cancer and genetically modified mammary cancer models) and found that Apj is specifically expressed in tumor newly generated vessels (angiogenesis) rather than other adult organ healthy vessels.

Through a series of experiments in vitro and tissue specific gene knockout strategy (Apj-CreER; Rosa-GFP; Flk1 fl/fl), they found that the upregulation of Apj is regulated by hypoxia signaling and VEGF/VEGFR2 pathway during this process.

To further understand the pathological significance of Apj receptor activity in tumor blood vessels, researchers used three kind of cell ablation technologies (Apj-CreER; Rosa-GFP/DTA, a newly generated knockin mouse tool Apj-DTRGFP-Luc, and the Apj antagonist) after the subcutaneous transplantation tumor model being set up.

They found that the ablation of Apj⁺ vessels could significantly inhibit tumor angiogenesis and restrict tumor growth.

This study further revealed the relationship between angiogenesis and malignant tumor proliferation, and provided a potential therapeutic target for tumor vessel-targeted drug development.

The incidence of tumor increases rapidly in recent years due to the severe environmental pollution, aging of the population, unhealthy lifestyle, tremendous stress and so on. Therefore, the prevention and treatment of tumor are a hot topic and a main focus in biomedical field.