Hedgehog signaling activation in the development of squamous cell carcinoma and adenocarcinoma of esophagus

Hedgehog (Hh) signaling is frequently activated in human cancer, includingesophageal cancer. Most esophageal cancers are diagnosed in the advanced stages,therefore, identifying the very alterations that drive esophageal carcinogenesismay help designing novel strategies to diagnose and treat the disease. Analysisof Hh signaling in precancerous lesions is a critical first step in determiningthe significance of this pathway for carcinogenesis. Here we report our data onHh target gene expression in 174 human esophageal specimens [28 esophagealadenocarcinomas (EAC), 19 Barrett’s esophagus, 103 cases of esophagealsquamous cell carcinoma (ESCC), and 24 of squamous dysplastic lesions], and intwo rat models of esophageal cancer. We found that 96% of human EAC express Hhtarget genes. We showed that PTCH1 expression is the most reliable biomarker. Incontrast to EAC, only 38% of ESCC express Hh target genes. We found activationof Hh signaling in precancerous lesions of ESCCs and EACs in different degrees(21% and 58% respectively). Expression of Hh target genes is frequently detectedin severe squamous dysplasia/ carcinoma in situ (p=0.04) andBarrett’s esophagus (p=0.01). Unlike EAC, sonic hedgehog (Shh) expressionwas rare in ESCCs. Consistent with the human specimen data, we found a highpercentage of Hh signaling activation in precancerous lesions in rat models.These data indicate that Hh signaling activation is an early molecular event inthe development of esophageal cancer, particularly EAC.