title: Nicotine Reduces Survival via Augmentation of Paracrine HGF-MET Signaling in the Pancreatic Cancer Microenvironment.
abstract: OBJECTIVE
  The relationship between smoking and pancreatic cancer biology, particularly in the context of the heterogeneous microenvironment, remains incompletely defined. We hypothesized that nicotine exposure would lead to the augmentation of paracrine growth factor signaling between tumor-associated stroma (TAS) and pancreatic cancer cells, ultimately resulting in accelerated tumor growth and metastasis.
  
  
  METHODS
  The effect of tobacco use on overall survival was analyzed using a prospectively maintained database of surgically resected patients with pancreatic cancer. Nicotine exposure was evaluated in vitro using primary patient-derived TAS and pancreatic cancer cells independently and in coculture. Nicotine administration was then assessed in vivo using a patient-derived pancreatic cancer xenograft model.
  
  
  RESULTS
  Continued smoking was associated with reduced overall survival after surgical resection. In culture, nicotine-stimulated hepatocyte growth factor (HGF) secretion in primary patient-derived TAS and nicotine stimulation was required for persistent pancreatic cancer cell c-Met activation in a coculture model. c-Met activation in this manner led to the induction of inhibitor of differentiation-1 (Id1) in pancreatic cancer cells, previously established as a mediator of growth, invasion and chemoresistance. HGF-induced Id1 expression was abrogated by both epigenetic and pharmacologic c-Met inhibition. In patient-derived pancreatic cancer xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression by qRT-PCR and phospho-Met levels by ELISA. Similarly, elevated levels of phospho-Met in surgically resected pancreatic cancer specimens correlated with reduced overall survival.
  
  
  CONCLUSIONS
  Taken together, these data demonstrate a novel, microenvironment-dependent paracrine signaling mechanism by which nicotine exposure promotes the growth and metastasis of pancreatic cancer.
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Daniel
authors.initials: D
authors.lastname: Delitto
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Dongyu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Black
authors.affiliation: Department of Periodontology and Oral Biology, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Knowlton
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Vlada
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida. North Florida/South Georgia Veterans Health System, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: George A
authors.initials: GA
authors.lastname: Sarosi
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Behrns
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida. North Florida/South Georgia Veterans Health System, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Thomas
authors.affiliation: Department of Biostatistics and Children's Oncology Group, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, Colleges of Medicine, Dentistry and Public Health and Health Professions, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: George
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hughes
authors.affiliation: Department of Periodontology and Oral Biology, University of Florida Health Science Center, Gainesville, Florida.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Wallet
authors.affiliation: Department of Surgery, University of Florida Health Science Center, Gainesville, Florida. jose.trevino@surgery.ufl.edu.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Trevino
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D019899:Paracrine Communication / Q000187:drug effects*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012907:Smoking / Q000009:adverse effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C066855:HGF protein, human; D051798:Inhibitor of Differentiation Protein 1; D003841:Deoxycytidine; D017228:Hepatocyte Growth Factor; D009538:Nicotine; D019859:Proto-Oncogene Proteins c-met; D000093542:Gemcitabine