Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours

Abstract

Activation of the Hedgehog (Hh) signalling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is associated with tumorigenesis in skin, the cerebellum and skeletal muscle. Here we show that a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumours in vivo. Unlike in Gorlin's syndrome tumours, pathway activity and cell growth in these digestive tract tumours are driven by endogenous expression of Hh ligands, as indicated by the presence of Sonic hedgehog and Indian hedgehog transcripts, by the pathway- and growth-inhibitory activity of a Hh-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added Hh ligand. Our results identify a group of common lethal malignancies in which Hh pathway activity, essential for tumour growth, is activated not by mutation but by ligand expression.

Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment

“…Previous studies have shown that cyclopamine induces apoptosis in small-cell lung cancer cell lines 16 and rapid death of cells from freshly resected medulloblastomas. 28 Addition of exogenous SHH-N protein reduced cyclopamineinduced apoptosis, suggesting that the cells could be rescued from apoptosis by further stimulation of the Hh pathway. The fact that cyclopamine can induce apoptosis that is partially blocked by SHH suggests that aberrant expression of the Hh signalling components in colorectal tumour-derived cells is important for cell survival.…”

“…Cyclopamine, a known inhibitor of the Hh pathway, [12][13][14]28 was used to test whether Hh signalling influences colorectal tumour cell survival. Treatment of both adenoma-and carcinoma-derived colorectal epithelial cells with cyclopamine reduced cell yield and induced apoptotic cell death.…”

Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas

“…Prior studies have demonstrated that Hh pathway activation represents a characteristic feature of pancreatic cancer. 13,36,37 In addition to being required for exocrine pancreatic cancer growth, Hh signaling seems to promote a non-pancreatic gastrointestinal pattern of cellular differentiation. 22 Additional recent studies have demonstrated that forced Hh pathway activation in adult pancreas induces the formation of undifferentiated pancreatic carcinoma and that Hh also cooperates with oncogenic KRAS to induce pancreatic cancer precursors.…”

“…[10][11][12][13][14][15] Mature tissue homeostasis at these sites appears to be a consequence of Hh-mediated stem or progenitor cell self-renewal within the organspecific stem cell niche. In addition to this observed role in "baseline" states, more recent work suggests that the Hh pathway also plays a critical role in regenerative responses to tissue injury.…”

Shh/BMP‐4 signaling pathway is essential for intestinal epithelial development during Xenopus larval‐to‐adult remodeling

“…Also in the human adult intestine, Shh expression is restricted to the region corresponding to stem cells (van den Brink et al, 2002;de Santa Barbara et al, 2003) and upregulated in the neoplastic or inflammatory intestine when the stem cells compensate for the epithelial damage (Berman et al, 2003;Nielsen et al, 2004). Therefore, it seems likely that the stem cells may make their niche adequate for the new epithelial formation by expressing Shh, which in turn ) and Chordin proteins to the medium changes the proliferating activity of intestinal tissues cultured for 5 days.…”