Changes in the structure and function of ICC networks in ICC hyperplasia and gastrointestinal stromal tumors.
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.
Kwon
Joong Goo
JG
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
Hwang
Sung Jin
SJ
Hennig
Grant W
GW
Bayguinov
Yulia
Y
McCann
Conor
C
Chen
Hui
H
Rossi
Ferdinand
F
Besmer
Peter
P
Sanders
Kenton M
KM
Ward
Sean M
SM
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
D019009:Proto-Oncogene Proteins c-kit