title: Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth.
abstract: A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.
authors: Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, 14183 Huddinge, Sweden.
authors: Marco
authors: M
authors: Gerling
authors: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 69-71, AZ1105 Amsterdam, The Netherlands.
authors: Nikè V J A
authors: NV
authors: Büller
authors: Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, 14183 Huddinge, Sweden.|Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors: Leonard M
authors: LM
authors: Kirn
authors: Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, 14183 Huddinge, Sweden.
authors: Simon
authors: S
authors: Joost
authors: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17176 Stockholm, Sweden.
authors: Oliver
authors: O
authors: Frings
authors: Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, 14183 Huddinge, Sweden.|Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors: Benjamin
authors: B
authors: Englert
authors: Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, 14183 Huddinge, Sweden.
authors: Åsa
authors: Å
authors: Bergström
authors: Core Facility for Morphologic Phenotype Analysis, Clinical Research Center, Karolinska Institutet, Hälsovägen 7-9, 14183 Huddinge, Sweden.
authors: Raoul V
authors: RV
authors: Kuiper
authors: Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, 14183 Huddinge, Sweden.
authors: Leander
authors: L
authors: Blaas
authors: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 69-71, AZ1105 Amsterdam, The Netherlands.
authors: Mattheus C B
authors: MC
authors: Wielenga
authors: Department of Medicine, Solna, Karolinska Institutet, 17176 Stockholm, Sweden.|Center for Digestive Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors: Sven
authors: S
authors: Almer
authors: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors: Anja A
authors: AA
authors: Kühl
authors: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17176 Stockholm, Sweden.
authors: Erik
authors: E
authors: Fredlund
authors: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 69-71, AZ1105 Amsterdam, The Netherlands.
authors: Gijs R
authors: GR
authors: van den Brink
authors: Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, 14183 Huddinge, Sweden.
authors: Rune
authors: R
authors: Toftgård
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D047368:Tumor Burden
chemical_list: D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D016264:Dextran Sulfate; C045073:Cre recombinase; D019426:Integrases; D001397:Azoxymethane