title: Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment.
abstract: Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation, and PDAC development. Mice with acinar cell-specific expression of KrasG12Dwere crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN), and PDAC. We also used a syngeneic orthotopic PDAC mouse model to study tumor growth in the presence or absence of Lcn2 expression. In addition, to understand the mechanistic role of how LCN2 could be mediating PDAC, we studied LCN2 and its specific receptor solute carrier family 22 member 17 (SLC22A17) in human pancreatic cancer stellate cells (PSC), key mediators of the PDAC stroma. Depletion of Lcn2 diminished extracellular matrix deposition, immune cell infiltration, PanIN formation, and tumor growth. Notably, it also increased survival in both obesity-driven and syngeneic orthotopic PDAC mouse models. LCN2 modulated the secretion of proinflammatory cytokines in PSC of the PDAC tumor microenvironment, whereas downregulation of LCN2-specific receptor SLC22A17 blocked these effects. Our results reveal how LCN2 acts in the tumor microenvironment links obesity, inflammation, and PDAC development.Cancer Res; 77(10); 2647-60. ©2017 AACR.
authors.affiliation: Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sobeyda B
authors.initials: SB
authors.lastname: Gomez-Chou
authors.affiliation: Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas.|Department of Gastroenterology and Internal Medicine, University of Bialystok, Bialystok, Poland.
authors.forename: Agnieszka Katarzyna
authors.initials: AK
authors.lastname: Swidnicka-Siergiejko
authors.affiliation: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Niharika
authors.initials: N
authors.lastname: Badi
authors.affiliation: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Myrriah
authors.initials: M
authors.lastname: Chavez-Tomar
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.affiliation: Department of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Farren
authors.affiliation: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mace
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Carl
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Defeng
authors.initials: D
authors.lastname: Deng
authors.affiliation: Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Hwang
authors.affiliation: Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Liran
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Todd
authors.initials: T
authors.lastname: Moore
authors.affiliation: Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Deyali
authors.initials: D
authors.lastname: Chatterjee
authors.affiliation: Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.|Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Arlinghaus
authors.affiliation: Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas. zobeida.cruz-monserrate@osumc.edu clogsdon@mdanderson.org.|Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.affiliation: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio. zobeida.cruz-monserrate@osumc.edu clogsdon@mdanderson.org.|Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Zobeida
authors.initials: Z
authors.lastname: Cruz-Monserrate
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D000071068:Lipocalin-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D000071068:Lipocalin-2; D034741:RNA, Small Interfering