Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer.

BACKGROUND & AIMS Sonic hedgehog (SHH) and Indian hedgehog (IHH) have cell-specific actions in some organs. Only SHH has been shown to regulate parietal cell differentiation. This study examined whether SHH, 2 other ligands IHH and Desert hedgehog, and receptors or downstream targets are expressed in normal gastric epithelium or in intestinal and diffuse-type gastric cancers. The effects of a Hedgehog (Hh) inhibitor, cyclopamine, were assessed in primary gastric epithelium cultures and gastric cancer cell lines. METHODS Reverse-transcription polymerase chain reaction and immunostaining compared expression and localization of Hh signaling molecules and phenotypic markers of pit, neck, and gland cells in situ and in cultured cells treated with cyclopamine. Bromodeoxyuridine staining assessed the effects of cyclopamine on proliferation. RESULTS Hh signaling molecules were expressed differentially in pit, neck, and gland cells. IHH co-expressed with most downstream targets in the pit. IHH, SHH, Patched (PTCH), Smoothened (SMO), and downstream targets were expressed more frequently and highly in the diffuse as compared with intestinal type cancers. In diffuse cancers, IHH was expressed in cells with an epithelial phenotype and SHH in cells with a mesenchymal phenotype. Cyclopamine reduced the number of cells with a pit phenotype but not a gland phenotype in primary cultures. Cyclopamine had particularly potent effects of inhibiting the growth of cell lines that expressed high levels of SMO. CONCLUSIONS Expression of IHH and downstream targets correlates with pit cells. IHH and SMO may be useful biomarkers of diffuse cancers that may show growth inhibition with Hh antagonists such as cyclopamine.

[1]  C. Lees,et al.  The hedgehog signalling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease. , 2005, Gastroenterology.

[2]  Xiao-li Zhang,et al.  Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. , 2005, Carcinogenesis.

[3]  F. Lordick,et al.  Recent advances in multimodal treatment for gastric cancer: a review , 2005, Gastric Cancer.

[4]  J. Merchant,et al.  Regulation and Function of the Sonic Hedgehog Signal Transduction Pathway in Isolated Gastric Parietal Cells* , 2005, Journal of Biological Chemistry.

[5]  M. German,et al.  Hedgehog signaling regulates expansion of pancreatic epithelial cells. , 2005, Developmental biology.

[6]  D. Gumucio,et al.  Epithelial hedgehog signals pattern the intestinal crypt-villus axis , 2005, Development.

[7]  M. Raderer,et al.  Palliative chemotherapy for advanced gastric cancer. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  A. Todisco,et al.  The Akt and MAPK signal-transduction pathways regulate growth factor actions in isolated gastric parietal cells. , 2004, Gastroenterology.

[9]  Masatoshi Nomura,et al.  Hedgehog Signaling Pathway is a New Therapeutic Target for Patients with Breast Cancer , 2004, Cancer Research.

[10]  M. Kusano,et al.  Gastric and intestinal phenotypic marker expression in gastric carcinomas and recurrence pattern after surgery-immunohistochemical analysis of 213 lesions- , 2004, British Journal of Cancer.

[11]  William Gaffield,et al.  Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation , 2004, Nature Genetics.

[12]  Marina Pasca di Magliano,et al.  Hedgehog signalling in cancer formation and maintenance , 2003, Nature Reviews Cancer.

[13]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

[14]  Yutaka Shimada,et al.  Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours , 2003, Nature.

[15]  F M Watt,et al.  Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Y. Yuasa.  Control of gut differentiation and intestinal-type gastric carcinogenesis , 2003, Nature Reviews Cancer.

[17]  Stephen B. Baylin,et al.  Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer , 2003, Nature.

[18]  Teruhiko Yoshida,et al.  A faithful method for PCR-mediated global mRNA amplification and its integration into microarray analysis on laser-captured cells. , 2003, Biochemical and biophysical research communications.

[19]  Jussi Taipale,et al.  Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. , 2002, Genes & development.

[20]  James M. Olson,et al.  Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade , 2002, Science.

[21]  M. Teh,et al.  FOXM1 is a downstream target of Gli1 in basal cell carcinomas. , 2002, Cancer research.

[22]  K. Sugimachi,et al.  Relationship between biologic behavior and phenotypic expression in intramucosal gastric carcinomas. , 2002, Human pathology.

[23]  David Hogg,et al.  Mutations in SUFU predispose to medulloblastoma , 2002, Nature Genetics.

[24]  D. Parkin,et al.  Global cancer statistics in the year 2000. , 2001, The Lancet. Oncology.

[25]  M. Kusano,et al.  Gastric and Intestinal Phenotypic Marker Expression in Gastric Carcinomas and Its Prognostic Significance: Immunohistochemical Analysis of 136 Lesions , 2001, Oncology.

[26]  S. Deventer,et al.  Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. , 2001, Gastroenterology.

[27]  D. Melton,et al.  Regulation of pancreas development by hedgehog signaling. , 2000, Development.

[28]  D. Melton,et al.  Hedgehog signals regulate multiple aspects of gastrointestinal development. , 2000, Development.

[29]  C. Sugnet,et al.  Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1. , 1999, Development.

[30]  Y. Ajioka,et al.  The common 18‐base pair deletion at codons 418–423 of the E‐cadherin gene in differentiated‐type adenocarcinomas and intramucosal precancerous lesions of the stomach with the features of gastric foveolar epithelium , 1999, The Journal of pathology.

[31]  W Gaffield,et al.  Essential role for Sonic hedgehog during hair follicle morphogenesis. , 1999, Developmental biology.

[32]  S. Ming.  Cellular and molecular pathology of gastric carcinoma and precursor lesions: A critical review , 1998, Gastric Cancer.

[33]  H. Westphal,et al.  Sonic hedgehog is essential to foregut development , 1998, Nature Genetics.

[34]  M. Post,et al.  Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus , 1998, Nature Genetics.

[35]  P. Beachy,et al.  Teratogen-mediated inhibition of target tissue response to Shh signaling. , 1998, Science.

[36]  Q. Gu,et al.  Activating Smoothened mutations in sporadic basal-cell carcinoma , 1998, Nature.

[37]  S. Blair,et al.  Smoothened-mediated Hedgehog signalling is required for the maintenance of the anterior-posterior lineage restriction in the developing wing of Drosophila. , 1997, Development.

[38]  Konrad Basler,et al.  Control of compartmental affinity boundaries by Hedgehog , 1997, Nature.

[39]  M. Tsai,et al.  Identification of a novel sonic hedgehog response element in the chicken ovalbumin upstream promoter-transcription factor II promoter. , 1997, Molecular endocrinology.

[40]  B. Hogan,et al.  Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. , 1997, Development.

[41]  P. Beachy,et al.  Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function , 1996, Nature.

[42]  C. Tabin,et al.  Regulation of patched by sonic hedgehog in the developing neural tube. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Clifford J. Tabin,et al.  Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein , 1996, Science.

[44]  M Garrido,et al.  MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach. , 1995, Gastroenterology.

[45]  G. Niehans,et al.  Expression cloning of gastric mucin complementary DNA and localization of mucin gene expression. , 1995, Gastroenterology.

[46]  S. Cohen,et al.  Cell interaction between compartments establishes the proximal-distal axis of Drosophila legs , 1994, Nature.

[47]  Konrad Basler,et al.  Compartment boundaries and the control of Drosopfiffa limb pattern by hedgehog protein , 1994, Nature.

[48]  P. Ingham,et al.  Genetic analysis of hedgehog signalling in the Drosophila embryo. , 1993, Development (Cambridge, England). Supplement.

[49]  C. P. Leblond,et al.  Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cell , 1993, The Anatomical record.

[50]  M. Tatematsu,et al.  Gastric and Intestinal Phenotypic Expression of Human Stomach Cancers as Revealed by Pepsinogen lmmunohistochemistry and Mucin Histochemistry , 1990, Acta pathologica japonica.

[51]  J. Mohler.  Requirements for hedgehog, a segmental polarity gene, in patterning larval and adult cuticle of Drosophila. , 1988, Genetics.

[52]  C. Nüsslein-Volhard,et al.  Mutations affecting segment number and polarity in Drosophila , 1980, Nature.

[53]  P. Laurén,et al.  THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. , 1965, Acta pathologica et microbiologica Scandinavica.