The Aging Microenvironment Shapes Angiogenic Remodeling in IBD-Associated Colorectal Carcinogenesis.

Abstract

Chronic intestinal inflammation establishes a pro-senescent microenvironment that fuels the stepwise evolution from inflammatory bowel disease (IBD) to colorectal cancer. Although cellular senescence initially functions as a tumor-suppressive barrier, the persistent accumulation of senescent cells can promote disease progression through the senescence-associated secretory phenotype (SASP). Key SASP mediators, including VEGF, IL-8/CXCL8, and matrix metalloproteinases (MMPs), reprogram endothelial and stromal compartments, driving aberrant neovascularization, vascular leakiness, extracellular-matrix remodeling, and tissue hypoxia that further reinforce inflammation and genomic instability. Emerging evidence also highlights marked heterogeneity among senescent epithelial, stromal, endothelial, and immune-cell populations within the inflamed intestinal mucosa, suggesting that distinct senescent subsets may differentially shape angiogenesis and malignant transformation. This review synthesizes current evidence linking inflammation-induced senescence to vascular dysfunction and the transition from IBD to colitis-associated colorectal cancer, and discusses therapeutic opportunities targeting the senescence-angiogenesis axis. By clarifying how the aging microenvironment reshapes intestinal angiogenesis, we propose a mechanistic framework for early intervention and cancer prevention in colitis-associated neoplasia.