Esophageal cancer is the sixth leading cause of cancer death worldwide and the 
seventh leading cause of cancer death in the U.S. male population. Ionizing 
radiation exposure is a risk factor for development of esophageal squamous cell 
carcinoma, a histological subtype of esophageal cancer that is highly aggressive 
and is associated with poor patient prognosis. This study investigated the 
effects of ionizing radiation on the microenvironment and intercellular 
communication as it relates to esophageal carcinogenesis. We demonstrate that 
normal esophageal epithelial cells exhibited increased migration and invasion 
when cultured in the presence of irradiated stromal fibroblasts or with 
conditioned medium derived from irradiated stromal fibroblasts. Cytokine 
antibody arrays and ELISAs were used to identify hepatocyte growth factor (HGF) 
as an abundant protein that is secreted by esophageal fibroblasts at twofold 
increased levels in culture medium after γ irradiation. Reverse transcription 
qPCR analysis confirmed an approximately 50% increase in mRNA levels for HGF at 
1 h in irradiated fibroblasts compared to unirradiated controls. Recombinant HGF 
stimulated increased wound healing, migration and invasion of esophageal 
epithelial cells, while blocking antibodies against HGF significantly decreased 
migration and invasion of epithelial cells in coculture with irradiated 
fibroblasts. Since HGF is known to direct cell migration, invasion and 
metastasis in a variety of tissues, including the esophagus, its modulation by 
ionizing radiation may have important implications for nontargeted pathways that 
influence radiation carcinogenesis in the esophagus.