| Abstract: | Hedgehog (Hh) signaling is frequently activated in human cancer, including
esophageal cancer. Most esophageal cancers are diagnosed in the advanced stages,
therefore, identifying the very alterations that drive esophageal carcinogenesis
may help designing novel strategies to diagnose and treat the disease. Analysis
of Hh signaling in precancerous lesions is a critical first step in determining
the significance of this pathway for carcinogenesis. Here we report our data on
Hh target gene expression in 174 human esophageal specimens 28 esophageal
adenocarcinomas (EAC), 19 Barrett’s esophagus, 103 cases of esophageal
squamous cell carcinoma (ESCC), and 24 of squamous dysplastic lesions], and in
two rat models of esophageal cancer. We found that 96% of human EAC express Hh
target genes. We showed that PTCH1 expression is the most reliable biomarker. In
contrast to EAC, only 38% of ESCC express Hh target genes. We found activation
of Hh signaling in precancerous lesions of ESCCs and EACs in different degrees
(21% and 58% respectively). Expression of Hh target genes is frequently detected
in severe squamous dysplasia/ carcinoma in situ (p=0.04) and
Barrett’s esophagus (p=0.01). Unlike EAC, sonic hedgehog (Shh) expression
was rare in ESCCs. Consistent with the human specimen data, we found a high
percentage of Hh signaling activation in precancerous lesions in rat models.
These data indicate that Hh signaling activation is an early molecular event in
the development of esophageal cancer, particularly EAC. |
