title: Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages.
abstract: Smoking is an established risk factor for pancreatic cancer (PC), but late diagnosis limits the evaluation of its mechanistic role in the progression of PC. We used a well-established genetically engineered mouse model (LSL-K-ras(G12D)) of PC to elucidate the role of smoking during initiation and development of pancreatic intraepithelial neoplasia (PanIN). The 10-week-old floxed mice (K-ras(G12D); Pdx-1cre) and their control unfloxed (LSL-K-ras(G12D)) littermates were exposed to cigarette smoke (total suspended particles: 150 mg/m(3)) for 20 weeks. Smoke exposure significantly accelerated the development of PanIN lesions in the floxed mice, which correlated with tenfold increase in the expression of cytokeratin19. The systemic accumulation of myeloid-derived suppressor cells (MDSCs) decreased significantly in floxed mice compared with unfloxed controls (P<0.01) after the smoke exposure with the concurrent increase in the macrophage (P<0.05) and dendritic cell (DCs) (P<0.01) population. Further, smoking-induced inflammation (IFN-γ, CXCL2; P<0.05) was accompanied by enhanced activation of pancreatic stellate cells and elevated levels of serum retinoic acid-binding protein 4, indicating increased bioavailability of retinoic acid which contributes to differentiation of MDSCs to tumor-associated macrophages (TAMs) and DCs. TAMs predominantly contribute to the increased expression of heparin-binding epidermal growth factor-like growth factor (EGFR ligand) in pre-neoplastic lesions in smoke-exposed floxed mice that facilitate acinar-to-ductal metaplasia (ADM). Further, smoke exposure also resulted in partial suppression of the immune system early during PC progression. Overall, the present study provides a novel mechanism of smoking-induced increase in ADM in the presence of constitutively active K-ras mutation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA [2] Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Torres
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Johansson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: N
authors.initials: N
authors.lastname: Momi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Baine
authors.affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Gilling
authors.affiliation: Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Division of Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Wyatt
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA [2] Fred and Pamela Buffett Cancer Center, University of Nebraska Medical center, Omaha, NE, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Joshi
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA [2] Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA [3] Fred and Pamela Buffett Cancer Center, University of Nebraska Medical center, Omaha, NE, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D061354:Acinar Cells / Q000473:pathology; D000818:Animals; D002278:Carcinoma in Situ / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology; D018450:Disease Progression; D011905:Genes, ras / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor / Q000096:biosynthesis*; D007249:Inflammation / Q000139:chemically induced; D007371:Interferon-gamma / Q000096:biosynthesis; D053539:Keratin-19 / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008679:Metaplasia / Q000139:chemically induced; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology*; D010183:Pancreatic Ducts / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects*; D014212:Tretinoin / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D053539:Keratin-19; D018168:Receptors, Retinoic Acid; D012906:Smoke; D014212:Tretinoin; D007371:Interferon-gamma