Work

Synergistic Disruption of Survival and Metastatic Potential in Esophageal Adenocarcinoma Cells Through Combined Inhibition of HIF1α and CD73

Year: 2025

Type: article

Abstract: BACKGROUND/OBJECTIVES: Hypoxia promotes esophageal adenocarcinoma (EAC) aggressiveness through stabilization of hypoxia-inducible factor-1α (HIF-1α), which regulates pro-survival, pro-metastatic, and immunosuppressive pathways, including the ectoenzyme CD73 (NT5E). Although CD73 is a known hypoxia-responsive gene, its functional integration with HIF-1α signaling in EAC remains incompletely understood. This study aimed to define the relationship between HIF-1α and CD73 in EAC and to evaluate the therapeutic potential of their combined inhibition. METHODS: Gene expression and survival analyses were performed using CCLE and TCGA-ESCA datasets. CD73 and HIF-1α expression were evaluated in EAC patient tissues by immunohistochemistry. EAC cell lines were subjected to hypoxic conditions with genetic or pharmacologic inhibition of HIF-1α and/or CD73. Cell viability, migration, angiogenesis, VEGF secretion, and purinergic metabolite levels were assessed using luminescence assays, Boyden chamber migration assays, endothelial tube formation assays, ELISA, and targeted LC-MS/MS, respectively. RESULTS: NT5E expression was transcriptionally upregulated by HIF-1α under hypoxia and correlated with advanced disease stage and poor overall survival in EAC patients. While CD73 inhibition alone modestly reduced EAC cell viability, combined inhibition of HIF-1α and CD73 synergistically decreased tumor cell survival, particularly under hypoxic conditions, and significantly altered extracellular adenosine metabolism. Dual targeting further suppressed migration, reduced VEGF secretion, and impaired angiogenic signaling, indicating disruption of tumor microenvironmental pathways critical for metastasis and immune evasion. CONCLUSIONS: These findings identify CD73 as a direct hypoxia-responsive effector of HIF-1α in EAC and demonstrate that dual inhibition of HIF-1α and CD73 synergistically disrupts tumor cell survival and pro-metastatic signaling. This combinatorial strategy represents a mechanistically integrated therapeutic approach to overcome hypoxia-driven resistance in esophageal adenocarcinoma.

Source: Cancers

DOI: 10.3390/cancers17244016