Loss of apelin blocks the emergence of sprouting angiogenesis in experimental tumors

Area of Science:

• Oncology
• Molecular Biology
• Vascular Biology

Background:

• Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) are crucial in cancer treatment but often face resistance.
• Alternative pro-angiogenic factors are upregulated upon VEGF pathway inhibition, necessitating the identification of new therapeutic targets.

Purpose of the Study:

• To investigate the role of apelin, a G-protein-coupled receptor ligand, in tumor growth and angiogenesis.
• To evaluate the efficacy of targeting apelin in combination with VEGF receptor tyrosine kinase inhibitor (sunitinib) for cancer therapy.

Main Methods:

• Utilized mouse models (Lewis lung carcinoma 1 and B16F10 melanoma) with apelin deficiency.
• Administered sunitinib alone or in combination with apelin targeting strategies.
• Assessed tumor growth, microvessel density, angiogenic sprouting, and endothelial cell (EC) differentiation using gene expression and single-cell RNA sequencing.

Main Results:

• Loss of apelin significantly delayed tumor growth when combined with sunitinib.
• Combined therapy markedly reduced tumor vessel density and microvessel remodeling.
• Apelin deficiency decreased angiogenic sprouting and prevented EC tip cell differentiation, indicating a crucial role in neovascularization initiation.

Conclusions:

• Apelin acts as a potent pro-angiogenic factor supporting tumor neovascularization.
• Targeting apelin in combination with VEGF signaling inhibition presents a promising adjuvant therapy for advanced tumors.
• This dual-targeting strategy may overcome resistance to current anti-angiogenic treatments.