The VEGF/VEGFR2 system in ovarian cancer: From functional to pharmacological significance

The vascular endothelial growth factor receptor 2 (VEGFR2) is a tyrosine kinase receptor regulating a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis and cancer. VEGFR2 is activated by canonical VEGFs and non-canonical ligands, triggering intracellular signaling cascades that mediate its biological activity. Preclinical studies show that VEGFR2 plays a complex yet pivotal role in the progression of ovarian cancer (OC), a deadly disease with a global burden of more than 320,000 women in 2022. Several inhibitors of the VEGF/VEGFR2 axis have been developed and are currently approved or included in clinical trials/ preclinical studies for the therapy of different subtypes of OC. Originally developed as anti-angiogenics, anti-VEGF/VEGFR2 drugs are now well-known to also affect tumor cells, immune cells and cancer-associated fibroblasts (CAFs), also in OC. In this review we address the specific role of the VEGF/VEGFR2 axis in OC cells, and, from this perspective, we discuss the therapeutic significance of VEGFR2 targeting. Dissection of the molecular landscape modulated by the VEGF/VEGFR2 system in tumor cells in addition to stromal ones will facilitate ongoing translational efforts directed toward OC therapy. Significance statement: Anti-angiogenics blocking the VEGF/VEGFR2 axis are widely used to treat ovarian cancer, although resistance and poor response occur. Recent advances reveal that anti-VEGF/VEGFR2 drugs act on multiple compartments, including ovarian cancer cells. This review discusses the functional and pharmacological significance of the VEGF/VEGFR2 axis in ovarian cancer cells highlighting insights from preclinical and clinical studies. A deeper understanding of this pathway is essential for a safe/efficacious usage of anti-angiogenics targeting the VEGFR2 pathway in ovarian cancer.