APLN Drives Angiogenesis and Tumor Progression in Glioblastoma via TRAF2-Mediated Signaling

Background Glioblastoma (GBM) is the most prevalent primary intracranial tumor, conveying a dismal prognosis. APLN (Apelin) has been demonstrated to be associated with tumor angiogenesis. There are few studies about APLN in GBM. Our work aimed to delineate how APLN contributes to the specific pathological mechanisms of GBM. Methods Tissues were obtained from 45 GBM patients who underwent surgery at Binzhou Medical University Hospital from July 2020 to December 2022. To evaluate the pro-angiogenic function of APLN, Human umbilical vein endothelial cells (HUVECs) were either exposed to conditioned medium derived from GBM cells or transfected with APLN-overexpressing plasmids, followed by functional assays including CCK-8, Transwell, and tube formation. Potential signaling mechanisms were examined by high-throughput proteomics and Western blot. Additionally, an in vivo study was performed to confirm the principal findings. Results APLN was highly expressed in GBM tissues relative to normal tissues, and elevation in APLN expression correlated with unfavorable clinical outcomes. Overexpressed APLN in HUVECs and exposure of HUVECs to conditioned medium derived from GBM cells and was found to promote malignant biological behavior and stimulate angiogenic activities; these effects were reversed upon treatment with ML221 (APLN-specific receptor antagonist). Subsequent mechanistic proteomic studies identified TRAF2 as a potential mediator of APLN-driven angiogenesis. The therapeutic relevance was confirmed in vivo, where ML221 treatment effectively attenuated xenograft tumor growth. Conclusion Our findings establish APLN as a critical driver of GBM angiogenesis and tumor progression. The dependency of GBM malignancy on APLN signaling positions this pathway as a promising therapeutic target for future intervention.