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Changes in the structure and function of ICC networks in ICC hyperplasia and gastrointestinal stromal tumors.
Gastroenterology. 2009 Feb; 136(2):630-9.G

Abstract

BACKGROUND & AIMS

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+Show Affiliations

Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19032955

Citation

Kwon, Joong Goo, et al. "Changes in the Structure and Function of ICC Networks in ICC Hyperplasia and Gastrointestinal Stromal Tumors." Gastroenterology, vol. 136, no. 2, 2009, pp. 630-9.
Kwon JG, Hwang SJ, Hennig GW, et al. Changes in the structure and function of ICC networks in ICC hyperplasia and gastrointestinal stromal tumors. Gastroenterology. 2009;136(2):630-9.
Kwon, J. G., Hwang, S. J., Hennig, G. W., Bayguinov, Y., McCann, C., Chen, H., Rossi, F., Besmer, P., Sanders, K. M., & Ward, S. M. (2009). Changes in the structure and function of ICC networks in ICC hyperplasia and gastrointestinal stromal tumors. Gastroenterology, 136(2), 630-9. https://doi.org/10.1053/j.gastro.2008.10.031
Kwon JG, et al. Changes in the Structure and Function of ICC Networks in ICC Hyperplasia and Gastrointestinal Stromal Tumors. Gastroenterology. 2009;136(2):630-9. PubMed PMID: 19032955.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Changes in the structure and function of ICC networks in ICC hyperplasia and gastrointestinal stromal tumors. AU - Kwon,Joong Goo, AU - Hwang,Sung Jin, AU - Hennig,Grant W, AU - Bayguinov,Yulia, AU - McCann,Conor, AU - Chen,Hui, AU - Rossi,Ferdinand, AU - Besmer,Peter, AU - Sanders,Kenton M, AU - Ward,Sean M, Y1 - 2008/11/01/ PY - 2008/08/13/received PY - 2008/09/26/revised PY - 2008/10/16/accepted PY - 2008/11/27/pubmed PY - 2009/3/3/medline PY - 2008/11/27/entrez SP - 630 EP - 9 JF - Gastroenterology JO - Gastroenterology VL - 136 IS - 2 N2 - BACKGROUND & AIMS: 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/19032955/Changes_in_the_structure_and_function_of_ICC_networks_in_ICC_hyperplasia_and_gastrointestinal_stromal_tumors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(08)01866-0 DB - PRIME DP - Unbound Medicine ER -