ELTD1 Review: New Regulator of Angiogenesis in Glioma

Glioblastoma (GBM) is a severe brain cancer in which angiogenesis is controlled by G protein-coupled receptors (GPCRs), such as Epidermal Growth Factor Latrophilin and seven transmembrane domain-containing protein 1 (ELTD1), which are crucial for tumor progression. ELTD1 is an understudied GPCR with a broad expression profile in various tissues, including the human brain, especially in the cerebral cortex. It plays a significant role in angiogenesis and tumorigenesis and is regulated by interconnected VEGF and DLL4/Notch pathways. ELTD1 also modulates the JAK/STAT3/HIF-1α signaling axis, affecting the response of cells to low-oxygen conditions and promoting cell proliferation. However, their specific ligands and functional mechanisms remain unclear. ELTD1 expression is associated with different outcomes in various cancers. For example, in GBM, higher ELTD1 levels are linked to more mature and less leaky blood vessels, potentially enhancing drug delivery and therapeutic success. It also has divergent prognostic implications in renal, ovarian, and colorectal cancer. Additionally, ELTD1 overexpression in central nervous system endothelial cells suggests that it is a potential biomarker for multiple sclerosis. Therapeutically, blocking ELTD1 inhibits vessel formation, possibly slowing tumor growth. Initial therapies used polyclonal antibodies, but the shift has been towards more targeted monoclonal antibodies, particularly in preclinical glioma models. This review aimed to translate these insights into effective clinical treatments. However, several gaps remain in our knowledge regarding ELTD1 ligands and their potential involvement in other physiological or pathological processes that future research can address to elucidate the role of ELTD1 in cancer, through angiogenesis and other intracellular pathways.