title: Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors.
abstract: Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163+TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. Cancer Res; 76(23); 6851-63. ©2016 AACR.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Ireland
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Almudena
authors.initials: A
authors.lastname: Santos
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Muhammad S
authors.initials: MS
authors.lastname: Ahmed
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rainer
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Sebastian R
authors.initials: SR
authors.lastname: Nielsen
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Valeria
authors.initials: V
authors.lastname: Quaranta
authors.affiliation: Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Weyer-Czernilofsky
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.|Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
authors.forename: Danielle D
authors.initials: DD
authors.lastname: Engle
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Perez-Mancera
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Coupland
authors.affiliation: Department of Medical Physics and Clinical Engineering, Royal Liverpool University Hospital, Liverpool, United Kingdom.
authors.forename: Azzam
authors.initials: A
authors.lastname: Taktak
authors.affiliation: Medicine and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.|Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bogenrieder
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.|Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.|Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Campbell
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schmid
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mielgo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D013002:Somatomedins / Q000235:genetics*
chemical_list: D013002:Somatomedins