Abstract 4367749: Cancer Accelerates Atherosclerosis via a TNF-Driven Angiogenic Pathway

Background: Cardiovascular disease (CVD) and cancer are the leading causes of global mortality, and emerging evidence indicates a complex, bidirectional relationship between these conditions. Our epidemiologic analyses link cancer diagnosis to elevated atherosclerotic risk, yet direct evidence and underlying mechanisms remain poorly defined. Hypothesis: Cancer directly promotes atherosclerosis progression. Methods: We performed RNA sequencing on aortic tissues from atheroprone mice injected subcutaneously with colorectal cancer cells or control buffer, examining effects across diverse genetic backgrounds, diets, and ages. Apoe-deficient mice underwent carotid ligation followed by tumor inoculation; plaques were assessed histologically. Serum biomarkers were identified using O-link proteomics. Human endothelial cells were treated with tumor-conditioned media and evaluated by RT-qPCR and angiogenesis assays. Therapeutically, tumor-bearing mice received systemic TNF-neutralizing antibody or vascular-targeted AAV-mediated LRG1 knockdown. Human Biobank vascular tissues and clinical databases were utilized to confirm translational relevance. Results: LRG1 was consistently elevated in the aortas of tumor-bearing mice across multiple experimental models. Tumor-bearing mice exhibited significantly increased plaque burden, intraplaque neovascularization, and hemorrhage compared to controls. TNF levels were elevated in tumor-bearing mice. Conditioned media from cancer cells robustly induced endothelial LRG1 expression and promoted endothelial tube formation, effects effectively reversed by TNF blockade. In vivo, treatment with either TNF-neutralizing antibody or endothelial-targeted LRG1 knockdown markedly attenuated tumor-induced plaque neovascularization and intraplaque hemorrhage. Analysis of human vascular tissues further confirmed elevated vascular TNF-LRG1 signaling in cancer patients. Conclusion: Our findings demonstrate that cancer accelerates atherosclerosis via a TNF-driven LRG1-dependent mechanism, promoting intraplaque neovascularization and instability. Targeting this inflammatory-angiogenic pathway effectively mitigates tumor-induced vascular remodeling, highlighting novel therapeutic strategies to manage cardiovascular risk among cancer patients.