title: ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer.
abstract: OBJECTIVE
  Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet. The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein-coupled receptors, including CXCR4. Here we investigated CXCR4-ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis.
  
  
  METHODS
  We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4-ADAM17 crosstalk in colon cancer cells. We compared the expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed Western diet versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc-mutant Min mice, we investigated the effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess the effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa.
  
  
  RESULTS
  CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, Western diet increased CXCL12 in stromal cells and TGFα in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (P < 0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (P < 0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (P < 0.05). Finally, ADAM17 was upregulated >2.5-fold in human malignant colonocytes.
  
  
  CONCLUSIONS
  ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet→CXCL12→CXCR4→ADAM17→TGFα→EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies. Clin Cancer Res; 23(2); 549-61. ©2016 AACR.
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Reba
authors.initials: R
authors.lastname: Mustafi
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Urszula
authors.initials: U
authors.lastname: Dougherty
authors.affiliation: Department of Radiology, University of Chicago, Chicago IL 60637.
authors.forename: Devkumar
authors.initials: D
authors.lastname: Mustafi
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Fatma
authors.initials: F
authors.lastname: Ayaloglu-Butun
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fletcher
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Sarbani
authors.initials: S
authors.lastname: Adhikari
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Farhana
authors.initials: F
authors.lastname: Sadiq
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Katherine
authors.initials: K
authors.lastname: Meckel
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Haider I
authors.initials: HI
authors.lastname: Haider
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Abdurahman
authors.initials: A
authors.lastname: Khalil
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Joel
authors.initials: J
authors.lastname: Pekow
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Vani
authors.initials: V
authors.lastname: Konda
authors.affiliation: Department of Pathology, University of Chicago, Chicago IL 60637.
authors.forename: Loren
authors.initials: L
authors.lastname: Joseph
authors.affiliation: Department of Pathology, University of Chicago, Chicago IL 60637.
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.affiliation: Department of Surgery, University of Chicago, Chicago IL 60637.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fichera
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D054426:Chemokine CXCL2 / Q000235:genetics*; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D066273:Diet, Western / Q000009:adverse effects; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D008024:Ligands; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage; D019718:Receptors, CXCR4 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013141:Spiro Compounds / Q000008:administration & dosage; D016211:Transforming Growth Factor alpha / Q000235:genetics
chemical_list: C499706:CXCL2 protein, human; C527276:CXCR4 protein, human; D054426:Chemokine CXCL2; C513090:INCB3619; D008024:Ligands; D010880:Piperidines; D019718:Receptors, CXCR4; D013141:Spiro Compounds; C587886:TGFA protein, human; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human