VEGF-A expression increases during the OLK-to-carcinoma transition, with angiogenic activity paralleling the histological grade.198 In Barrett’s esophagus, premalignant cells secrete VEGF to activate VEGFR2-dependent PLC-PKC-ERK signaling, fostering autocrine proliferation loops and paracrine angiogenesis; owing to the accumulation of VEGF, macrophage-secreted MMP-9 degrades ECM barriers, amplifying perilesional neovascularization.199,200 Key signaling pathways related to precancerous angiogenesis include the Hedgehog pathway and the HIF-1α pathway. This evidence concerns the gene VEGFA and esophageal adenocarcinoma.