Extracellular Matrix Degradation Products Inhibit Esophageal Cancer Cell Proliferation and Migration

Biological materials composed of extracellular matrix (ECM) or its components have been successfully used for tissue repair and reconstruction. Preclinical studies, along with a cohort study following stage T1A esophageal adenocarcinoma (EAC) resection, have shown that ECM biomaterials can restore esophageal mucosa and submucosa without cancer recurrence. However, the molecular mechanisms underlying these effects remain largely unexplored. The present study investigates the in vitro effects of ECM degradation products from nonmalignant esophageal (eECM) and urinary bladder (ubECM) sources on EAC cell proliferation, migration, and associated signaling pathways. Both eECM and ubECM significantly inhibited OE33 cell proliferation, with eECM exhibiting a stronger effect-reducing proliferation to 25% at 24 h and 7% at 72 h compared with pepsin control (p < 0.001). A high-throughput cell surface marker screen followed by gene and protein expression analysis revealed that both ECM sources downregulated CD164 and CXCR4, reducing CXCR4 protein levels by approximately 50% (p = 0.006 for eECM, p = 0.007 for ubECM). Notably, only eECM significantly suppressed OE33 cell migration (p ≤ 0.0001) and downregulated bone morphogenetic protein 4 BMP4 expression, along with its downstream targets pSMAD1/5/8, ID2, and SNAI2, thereby reducing epithelial-mesenchymal transition. These findings support the concept that biochemical cues from nonmalignant ECM modulate neoplastic cell behavior. Given the involvement of PI3K-Akt and BMP4 signaling in EAC progression, ECM-based strategies may warrant further investigation as potential therapeutic approaches following esophageal cancer resection.