title: Changes in the structure and function of ICC networks in ICC hyperplasia and gastrointestinal stromal tumors.
abstract: OBJECTIVE
  Gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase c-kit. Approximately 90% of GISTs have gain-of-function mutations in the Kit gene, which leads to its constitutive activation and drives malignant behavior of GISTs. Interstitial cells of Cajal (ICC) express c-kit; however, it is unknown whether uncontrolled hyperplasia of ICC is responsible for GISTs. Here, we sought to determine whether gain-of-function mutations in Kit lead to hyperplasia of all classes of ICC, whether ICC hyperplasia begins before birth, and whether functional defects occur in ICC hyperplasia or the development of GISTs.
  
  
  METHODS
  Heterozygous mutant Kit(V558Delta)/+ mice that develop symptoms of human familial GISTs and prematurely die from pathology of the gastrointestinal tract were utilized and compared with wild-type controls. C-kit-immunohistochemistry and intracellular electrical recording of spontaneous and nerve-evoked activity were applied to examine the density and functionality of ICC in these mutants.
  
  
  RESULTS
  There was considerable hyperplasia in all classes of ICC throughout the GI tract of Kit(V558Delta)/+ mice, except for ICC in the deep muscular plexus of the intestine. Spontaneous electrical activity and postjunctional neural responses in hyperplastic ICC tissues appeared normal but were up-regulated in the cecum, where GISTs were commonly found.
  
  
  CONCLUSIONS
  Kit gain-of-function leads to hyperplasia of most classes of ICC throughout the GI tract. ICC retain normal pacemaker function and enteric neural responses well after development of hyperplasia.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
authors.forename: Joong Goo
authors.initials: JG
authors.lastname: Kwon
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Grant W
authors.initials: GW
authors.lastname: Hennig
authors.forename: Yulia
authors.initials: Y
authors.lastname: Bayguinov
authors.forename: Conor
authors.initials: C
authors.lastname: McCann
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Kenton M
authors.initials: KM
authors.lastname: Sanders
authors.forename: Sean M
authors.initials: SM
authors.lastname: Ward
mesh_terms: D000818:Animals; D002432:Cecum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D017615:Enteric Nervous System / Q000503:physiopathology; D005333:Fetus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005748:Gastric Fundus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007082:Ileum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007583:Jejunum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011706:Pyloric Antrum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D019009:Proto-Oncogene Proteins c-kit