Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer.

The Hedgehog (Hh) cascade controls cell proliferation, differentiation and patterning of tissues during embryogenesis but is largely suppressed in the adult. The Hh pathway can become reactivated in cancer. Here, we assimilate data from recent studies to understand how and when the Hh pathway is turned on to aid the neoplastic process. Hh signaling is now known to have a role in established tumors, enabling categorization of tumors based on the role Hh signaling plays in their growth. This categorization has relevance for prognosis and targeted therapeutics. In the first category, abnormal Hh signaling initiates the tumor. In the second category, Hh signaling helps maintain the tumor. In the third category, Hh signaling is implicated but its role is not yet defined.

[1]  E. Díaz,et al.  From cerebellar proliferation to tumorigenesis: New insights into the role of Mad3 , 2008, Cell cycle.

[2]  A. Diehl,et al.  The adventures of sonic hedgehog in development and repair. II. Sonic hedgehog and liver development, inflammation, and cancer. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

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

[4]  Aubie K. Shaw,et al.  Lack of demonstrable autocrine hedgehog signaling in human prostate cancer cell lines. , 2007, The Journal of urology.

[5]  D. Baker,et al.  Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation , 2001, Nature Immunology.

[6]  S. Pazzaglia,et al.  High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice , 2002, Oncogene.

[7]  M. Lewis,et al.  The hedgehog signaling network, mammary stem cells, and breast cancer: connections and controversies. , 2006, Ernst Schering Foundation symposium proceedings.

[8]  C. Plopper,et al.  Immunohistochemical demonstration of cytochrome P-450 monooxygenase in Clara cells throughout the tracheobronchial airways of the rabbit. , 1987, Experimental lung research.

[9]  David Allard,et al.  Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer , 2009, Science.

[10]  D. Melton,et al.  Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Hebrok,et al.  Hedgehog/Ras interactions regulate early stages of pancreatic cancer. , 2006, Genes & development.

[12]  E. Montgomery,et al.  Epidermal growth factor receptor and hedgehog signaling pathways are active in esophageal cancer cells from rat reflux model. , 2006, The Journal of surgical research.

[13]  C. Tabin,et al.  Wnt signaling during development of the gastrointestinal tract. , 2003, Developmental biology.

[14]  M. Lewis,et al.  Hedgehog Signaling in Mouse Mammary Gland Development and Neoplasia , 2004, Journal of Mammary Gland Biology and Neoplasia.

[15]  R. Myers,et al.  Human Homolog of patched, a Candidate Gene for the Basal Cell Nevus Syndrome , 1996, Science.

[16]  C. Rudin,et al.  Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma , 2009, Science.

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

[18]  P. Sorensen,et al.  Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: An Intergroup Rhabdomyosarcoma Study , 2000, Genes, chromosomes & cancer.

[19]  M. Saitoh,et al.  Human hair cycle. , 1970, The Journal of investigative dermatology.

[20]  T. Greiner,et al.  Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma , 2008, Molecular Cancer Therapeutics.

[21]  H. Edlund,et al.  Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas , 1997, Current Biology.

[22]  B. Hogan,et al.  Evidence for the involvement of the Gli gene family in embryonic mouse lung development. , 1997, Developmental biology.

[23]  G. Page,et al.  Hedgehog signaling and response to cyclopamine differs in epithelial and stromal cells in benign breast and breast cancer , 2006, Cancer biology & therapy.

[24]  V. Grachtchouk,et al.  Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/β-catenin signaling , 2008, Nature Genetics.

[25]  A. Kligman The human hair cycle. , 1959, The Journal of investigative dermatology.

[26]  J. Kessler,et al.  Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma , 2005, Development.

[27]  R. Crystal,et al.  Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog. , 1999, The Journal of clinical investigation.

[28]  M. Scott,et al.  Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. , 1997, Cancer research.

[29]  Qian Wang,et al.  Activation of the hedgehog pathway in human hepatocellular carcinomas. , 2006, Carcinogenesis.

[30]  S. Tsunoda,et al.  Gli-1 Expression Is Associated with Lymph Node Metastasis and Tumor Progression in Esophageal Squamous Cell Carcinoma , 2007, Oncology.

[31]  Anton Berns,et al.  Cancer: Two in one , 2005, Nature.

[32]  H. Kerl,et al.  Epidemiology and aetiology of basal cell carcinoma , 2007, The British journal of dermatology.

[33]  J. Blake,et al.  Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma? , 2003, Histology and histopathology.

[34]  R. Wechsler-Reya,et al.  Stem Cells and the Origin and Propagation of Brain Tumors , 2008, Journal of child neurology.

[35]  D. Krause,et al.  Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  H. Clevers,et al.  Wnt signaling in the intestinal epithelium: from endoderm to cancer. , 2005, Genes & development.

[37]  T. Curran,et al.  Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. , 2008, Cancer cell.

[38]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[39]  R. J. Mullen,et al.  Cerebellar mutant mice and chimeras revisited. , 1997, Perspectives on developmental neurobiology.

[40]  B. Brand-Saberi Genetic and epigenetic control of skeletal muscle development. , 2005, Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft.

[41]  L. Yoder Lung cancer epidemiology. , 2006, Medsurg nursing : official journal of the Academy of Medical-Surgical Nurses.

[42]  M. Lauth,et al.  Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. , 2006, Developmental cell.

[43]  M. Cohen,et al.  The hedgehog signaling network , 2003, American journal of medical genetics. Part A.

[44]  K. Garber Hedgehog drugs begin to show results. , 2008, Journal of the National Cancer Institute.

[45]  W. Bushman,et al.  Hedgehog signaling in prostate growth and benign prostate hyperplasia , 2007, Current urology reports.

[46]  F. D. de Sauvage,et al.  Paracrine Hedgehog signaling in cancer. , 2009, Cancer research.

[47]  M. Hebrok,et al.  Hedgehog signaling in pancreas development and disease , 2006, Cellular and Molecular Life Sciences CMLS.

[48]  Valerie Horsley,et al.  More than one way to skin . . . , 2008, Genes & development.

[49]  J. Rutka,et al.  Molecular Insight into Medulloblastoma and Central Nervous System Primitive Neuroectodermal Tumor Biology from Hereditary Syndromes: A Review , 2000, Neurosurgery.

[50]  Gareth A. Stewart,et al.  Sonic Hedgehog Signaling Modulates Activation of and Cytokine Production by Human Peripheral CD4+ T Cells1 , 2002, The Journal of Immunology.

[51]  A. Maitra,et al.  The hedgehog pathway and pancreatic cancer. , 2009, The New England journal of medicine.

[52]  A. Zapata,et al.  Sonic Hedgehog Is Produced by Follicular Dendritic Cells and Protects Germinal Center B Cells from Apoptosis1 , 2005, The Journal of Immunology.

[53]  A. Ruiz i Altaba,et al.  Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion , 2009, EMBO molecular medicine.

[54]  Yunqing Li,et al.  Signaling pathways in medulloblastoma , 2008, Journal of cellular physiology.

[55]  K. Ogawa,et al.  Hedgehog and epithelial‐mesenchymal transition signaling in normal and malignant epithelial cells of the esophagus , 2009, International journal of cancer.

[56]  M. Scott,et al.  Altered neural cell fates and medulloblastoma in mouse patched mutants. , 1997, Science.

[57]  Hans Clevers,et al.  Hindgut defects and transformation of the gastro‐intestinal tract in Tcf4−/−/Tcf1−/− embryos , 2004, The EMBO journal.

[58]  Hua Tian,et al.  A paracrine requirement for hedgehog signalling in cancer , 2008, Nature.

[59]  Joel Greshock,et al.  High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization , 2005, Breast Cancer Research.

[60]  A. Bale,et al.  Developmental genes and cancer: role of patched in basal cell carcinoma of the skin. , 1997, Journal of the National Cancer Institute.

[61]  J. Merchant,et al.  Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. , 2009, Gastroenterology.

[62]  P. Picci,et al.  Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma. , 2004, Histology and histopathology.

[63]  D. Mu,et al.  Genetic similarities between organogenesis and tumorigenesis of the lung , 2008, Cell cycle.

[64]  A. Berns Stem Cells for Lung Cancer? , 2005, Cell.

[65]  P. Beachy,et al.  Mending and malignancy , 2004, Nature.

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

[67]  C. Sugnet,et al.  The Gli2 transcription factor is required for normal mouse mammary gland development. , 2001, Developmental biology.

[68]  M. Scott,et al.  Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice , 1999, Nature Medicine.

[69]  J. Sicklick,et al.  Role for Hedgehog signaling in hepatic stellate cell activation and viability , 2005, Laboratory Investigation.

[70]  R. Takimoto,et al.  Adenoviral Vector‐Mediated Transfer of the Indian Hedgehog Gene Modulates Lymphomyelopoiesis In Vivo , 2008, Stem cells.

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

[72]  R. Takimoto,et al.  Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID-beta2m-/- repopulating cells. , 2004, Blood.

[73]  A. Joyner,et al.  Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, and Gli-3, in ectoderm- and mesoderm-derived tissues suggests multiple roles during postimplantation development. , 1994, Developmental biology.

[74]  S. Hilsenbeck,et al.  Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia , 2007, Development.

[75]  A. Rosenthal,et al.  Downregulation of Hedgehog signaling is required for organogenesis of the small intestine in Xenopus. , 2001, Developmental biology.

[76]  L. Aparicio,et al.  Prostate cancer and Hedgehog signalling pathway. , 2007 .

[77]  Monika Engelhardt,et al.  Essential role of stromally induced hedgehog signaling in B-cell malignancies , 2007, Nature Medicine.

[78]  J. Minna,et al.  Focus on lung cancer. , 2002, Cancer cell.

[79]  D. Walterhouse,et al.  Optimal Management Strategies for Rhabdomyosarcoma in Children , 2007, Paediatric drugs.

[80]  Douglas Losordo,et al.  Sonic hedgehog regulates angiogenesis and myogenesis during post‐natal skeletal muscle regeneration , 2009, Journal of cellular and molecular medicine.

[81]  Keith L Ligon,et al.  A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. , 2006, Cancer research.

[82]  R. Goldberg,et al.  Pharmacological Treatments for Basal Cell Carcinoma , 2012, Drugs.

[83]  M. Gering,et al.  Hedgehog signaling is required for adult blood stem cell formation in zebrafish embryos. , 2005, Developmental cell.

[84]  T. Shimokawa,et al.  Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists , 2007, Proceedings of the National Academy of Sciences.

[85]  M. Scott,et al.  Communicating with Hedgehogs , 2005, Nature Reviews Molecular Cell Biology.

[86]  J. Reiter,et al.  Primary cilia can both mediate and suppress Hedgehog pathway–dependent tumorigenesis , 2009, Nature Medicine.

[87]  M. Dyer,et al.  Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. , 2001, Development.

[88]  M. Peppelenbosch,et al.  Expression of hedgehog pathway components in the adult colon. , 2006, Gastroenterology.

[89]  R. Toftgård,et al.  Hedgehog beyond medulloblastoma and basal cell carcinoma. , 2010, Biochimica et biophysica acta.

[90]  D. Albertini,et al.  An oocentric view of folliculogenesis and embryogenesis. , 2007, Reproductive biomedicine online.

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

[92]  R. Govindan,et al.  Hedgehog signaling pathway and lung cancer. , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[93]  R. Lipinski,et al.  Functional compensation in Hedgehog signaling during mouse prostate development. , 2006, Developmental biology.

[94]  Y. Fujiwara,et al.  Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy , 2008, British Journal of Cancer.

[95]  Paul A. Khavari,et al.  Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog , 1997, Nature Medicine.

[96]  Raoul Tibes,et al.  Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. , 2009, The New England journal of medicine.

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

[98]  Yi Ren The hedgehog signaling pathway in the mouse ovary , 2012 .

[99]  E. Dmitrovsky,et al.  Frequent requirement of hedgehog signaling in non-small cell lung carcinoma , 2007, Oncogene.

[100]  C. Hui,et al.  Basal cell carcinomas in mice overexpressing Gli2 in skin , 2000, Nature Genetics.

[101]  Scott L Pomeroy,et al.  Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. , 2003, Developmental biology.

[102]  Lee L. Rubin,et al.  Targeting the Hedgehog pathway in cancer , 2006, Nature Reviews Drug Discovery.

[103]  J. Sicklick,et al.  Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation , 2007, Laboratory Investigation.

[104]  T. Curran,et al.  The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. , 2000, Cancer research.

[105]  A. Polednak Lung cancer incidence trends by histologic type in areas of California vs. other areas in the Surveillance, Epidemiology and End Results Program. , 2009, Cancer epidemiology.

[106]  S. Pazzaglia,et al.  Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice , 2006, Oncogene.

[107]  M. Grachtchouk,et al.  Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. , 2005, Genes & development.

[108]  M. Scott,et al.  A Mouse Model for Medulloblastoma and Basal Cell Nevus Syndrome , 2001, Journal of Neuro-Oncology.

[109]  W. Wanga Colorectal carcinoma: from tumorigenesis to treatment , 2006 .

[110]  Helen Baines,et al.  Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. , 2004, Cancer cell.

[111]  Hans Clevers,et al.  The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. , 2002, Cell.

[112]  S. Levanat,et al.  The Patched gene is epigenetically regulated in ovarian dermoids and fibromas, but not in basocellular carcinomas. , 2007, International journal of molecular medicine.

[113]  E. Epstein Basal cell carcinomas: attack of the hedgehog , 2008, Nature Reviews Cancer.

[114]  J. Grootegoed,et al.  Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells. , 2005, Endocrinology.

[115]  M. Scott,et al.  Basal cell carcinomas in mice overexpressing sonic hedgehog. , 1997, Science.

[116]  J. Ajani,et al.  Hedgehog: an Attribute to Tumor Regrowth after Chemoradiotherapy and a Target to Improve Radiation Response , 2006, Clinical Cancer Research.

[117]  J. Sicklick,et al.  Hedgehog signaling maintains resident hepatic progenitors throughout life. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[118]  M. Scott,et al.  Control of Neuronal Precursor Proliferation in the Cerebellum by Sonic Hedgehog , 1999, Neuron.

[119]  Michael Dean,et al.  Is human patched the gatekeeper of common skin cancers? , 1996, Nature Genetics.

[120]  R. Paus,et al.  Sonic hedgehog signaling is essential for hair development , 1998, Current Biology.

[121]  Andrew J. Brown,et al.  Autonomous Hedgehog signalling is undetectable in PC-3 prostate cancer cells. , 2008, Biochemical and biophysical research communications.

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

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

[124]  S. McCall,et al.  Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis , 2007, Hepatology.

[125]  Xiao-li Zhang,et al.  Hedgehog signaling is activated in subsets of esophageal cancers , 2006, International journal of cancer.

[126]  U. Heinzmann,et al.  Molecular characterization of Patched‐associated rhabdomyosarcoma , 2003, The Journal of pathology.

[127]  K. Janssen,et al.  Epithelial morphogenesis and intestinal cancer: new insights in signaling mechanisms. , 2008, Advances in cancer research.

[128]  L. Kindblom,et al.  Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development , 2006, The Journal of pathology.

[129]  T. Curran,et al.  Loss of suppressor-of-fused function promotes tumorigenesis , 2007, Oncogene.

[130]  Ryosuke Osada,et al.  Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis , 2007, Cancer science.

[131]  B. Wainwright,et al.  Patched1 functions as a gatekeeper by promoting cell cycle progression. , 2006, Cancer research.

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

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

[134]  J. Biegel,et al.  Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma , 2000, Genes, chromosomes & cancer.

[135]  G. R. van den Brink,et al.  The morphogenetic code and colon cancer development. , 2007, Cancer cell.

[136]  A. Kligman Full Length ReportThe Human Hair Cycle1 , 1959 .

[137]  Margaret J. Dallman,et al.  Sonic Hedgehog Promotes Cell Cycle Progression in Activated Peripheral CD4+ T Lymphocytes1 , 2002, The Journal of Immunology.

[138]  R. Peterson,et al.  Growth, morphogenesis, and differentiation during mouse prostate development in situ, in renal grafts, and in vitro , 2005, The Prostate.

[139]  J. Habener,et al.  Hedgehog signaling regulation of insulin production by pancreatic beta-cells. , 2000, Diabetes.

[140]  V. Velcheti Hedgehog signaling is a potent regulator of angiogenesis in small cell lung cancer. , 2007, Medical hypotheses.

[141]  J. Engelhardt Stem cell niches in the mouse airway. , 2001, American journal of respiratory cell and molecular biology.

[142]  D. Albertini,et al.  Oogenesis: Prospects and challenges for the future , 2008, Journal of cellular physiology.

[143]  R. Lindemann Stroma-initiated hedgehog signaling takes center stage in B-cell lymphoma. , 2008, Cancer research.

[144]  Jussi Taipale,et al.  Hedgehog: functions and mechanisms. , 2008, Genes & development.

[145]  S. Pazzaglia,et al.  Two-hit model for progression of medulloblastoma preneoplasia in Patched heterozygous mice , 2006, Oncogene.

[146]  Michael Dean,et al.  Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome , 1996, Cell.

[147]  L. Medeiros,et al.  Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. , 2009, Cancer research.

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

[149]  T. Okumura,et al.  Hedgehog Promotes Neovascularization in Pancreatic Cancers by Regulating Ang-1 and IGF-1 Expression in Bone-Marrow Derived Pro-Angiogenic Cells , 2010, PloS one.

[150]  C. Osipo,et al.  Hedgehog signaling in hepatocellular carcinoma novel therapeutic strategy targeting hedgeHog signaling in HCC , 2006, Cancer biology & therapy.