Hedgehog signaling and gastrointestinal cancer

Abstract

Hedgehog (Hh) signaling is critical for embryonic development and in differentiation, proliferation, and maintenance of multiple adult tissues. De-regulation of the Hh pathway is associated with birth defects and cancer. In the gastrointestinal tract, Hh ligands Sonic (Shh) and Indian (Ihh), as well as the receptor Patched (Ptch1), and transcription factors of Glioblastoma family (Gli) are all expressed during development. In the adult, Shh expression is restricted to the stomach and colon, while Ihh expression occurs throughout the luminal gastrointestinal tract, its expression being highest in the proximal duodenum. Several studies have demonstrated a requirement for Hh signaling during gastrointestinal tract development. However to date, the specific role of the Hh pathway in the adult stomach and intestine is not completely understood. The current review will place into context the implications of recent published data related to the biochemistry and cell biology of Hh signaling on the luminal gastrointestinal tract during development, normal physiology and subsequently carcinogenesis.

Fig. 1

Expression of hedgehog pathway molecules in the gastrointestinal (GI) tract. During development, Sonic hedgehog (Shh) is highly expressed in the stomach and its expression decreases along the intestine. Shh is expressed in the colon glands. Indian hedgehog (Ihh) expression peaks at the pyloric junction and is constant in the small intestine and colon. There are no studies addressing the pattern of Desert hedgehog (Dhh) expression in the developing GI tract. The Hh receptor Patched (Ptch1) and the Glioblastoma (Gli) transcriptional factor family proteins are expressed in the mesenchyme, mirroring Shh expression. In the adult GI tract, Shh expression is limited to the stomach and colon, with the proximal stomach being the main source of the morphogen. Ihh is expressed in the small intestine, with highest levels in the proximal duodenum. Ihh is also expressed in the colonic glands. Dhh expression has been reported in the gastric mucosa, but has not been localized in the small intestine. Ptch1, Gli proteins, and Smo are expressed primarily in the mesenchyme of the adult GI tract.