title: Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment.
abstract: Hedgehog (Hh) signalling controls many aspects of development. It also regulates cell growth and differentiation in adult tissues and is activated in a number of human malignancies. Hh and Wnt signalling frequently act together in controlling cell growth and tissue morphogenesis. Despite the fact that the majority of colorectal tumours have a constitutively activated canonical Wnt pathway, few previous studies have investigated the expression of Hh signalling components in colorectal tumours. We describe here epithelial cell lines derived from both nonmalignant colorectal adenomas and colorectal adenocarcinomas that express both Sonic and Indian Hh. Interestingly, these cells also express the Hh receptor Patched and the downstream signalling components Smoothened and Gli1, suggesting autocrine Hh signalling in these cells. To test whether autocrine Hh signalling contributes to cell survival, we treated colorectal tumour cells with cyclopamine, a known inhibitor of Hh signalling. Cyclopamine treatment induced apoptosis in both adenoma- and carcinoma-derived cell lines, which could be partially rescued by further stimulation of Hh signalling. These data suggest that autocrine Hh signalling can increase aberrant cell survival in colorectal tumour cells and may be a novel target for colon cancer therapy using drugs such as cyclopamine.
authors.affiliation: Cancer Research UK Colorectal Tumour Biology Research Group, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Qualtrough
authors.forename: Andrea
authors.initials: A
authors.lastname: Buda
authors.forename: William
authors.initials: W
authors.lastname: Gaffield
authors.forename: Ann C
authors.initials: AC
authors.lastname: Williams
authors.forename: Christos
authors.initials: C
authors.lastname: Paraskeva
mesh_terms: D000236:Adenoma; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D017931:DNA Primers; D053823:Hedgehog Proteins; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012004:Rectal Neoplasms / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014704:Veratrum Alkaloids / Q000494:pharmacology*; D051153:Wnt Proteins
chemical_list: D017931:DNA Primers; D053823:Hedgehog Proteins; D011518:Proto-Oncogene Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D051153:Wnt Proteins; C000541:cyclopamine