title: Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer.
abstract: BACKGROUND
  Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood.
  
  
  RESULTS
  Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype.
  
  
  CONCLUSIONS
  These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.
authors.affiliation: Biomedical Sciences Program, Cardiovascular Research Institute and Department of Anatomy, University of California at San Francisco, San Francisco, California, United States of America. Hassan.alaoui@yahoo.com
authors.forename: Hassan
authors.initials: H
authors.lastname: Lemjabbar-Alaoui
authors.forename: Vijay
authors.initials: V
authors.lastname: Dasari
authors.forename: Sukhvinder S
authors.initials: SS
authors.lastname: Sidhu
authors.forename: Aklilu
authors.initials: A
authors.lastname: Mengistab
authors.forename: Walter
authors.initials: W
authors.lastname: Finkbeiner
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.forename: Carol
authors.initials: C
authors.lastname: Basbaum
mesh_terms: D000818:Animals; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014704:Veratrum Alkaloids / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D012906:Smoke; D014704:Veratrum Alkaloids; D051153:Wnt Proteins; D013467:Sulindac; C000541:cyclopamine