Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models Journal Article


Author: Antonescu, C. R.
Article Title: Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models
Abstract: Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in Oncology. Most GISTs are KIT-expressing and KIT-signaling driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding for a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light onto the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; and activating KIT mutations have been identified in tumors affecting most of these cell lineages. The observation that KIT mutations may be inherited, as seen in familial GIST syndrome, was used to develop murine models harboring a germline gain-of-function mutation, as a model for studying of KIT oncogenic mechanisms. These murine models of human GIST promise to become powerful preclinical tools in elucidating oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention. As true animal models of human cancer, they provide superior information compared with the more commonly used xenografts and transgenic mouse models. This review summarizes the recent knowledge on the central role of KIT oncogenic activation and subsequent signal transduction in the pathogenesis of GIST. In addition, we provide an updated discussion on familial GIST syndrome in relationship to genotype-phenotype characteristics. A succinct description of the available murine models of human GIST is presented and their applicability in further understanding of the KIT oncogenic signaling, drug screening, and mechanisms of drug resistance is discussed. © 2006 Elsevier Inc. All rights reserved.
Keywords: signal transduction; gene mutation; clinical feature; pathogenesis; nonhuman; animals; mice; gastrointestinal stromal tumor; pdgfra; imatinib; stem cell factor receptor; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; receptor, platelet-derived growth factor alpha; drug screening; platelet derived growth factor receptor; protein tyrosine kinase; carcinogenesis; transgenic mouse; genetic transduction; cancer resistance; gene activation; drug mechanism; receptor tyrosine kinase; molecular structure; tumor model; kit; disease models, animal; gist; oncogene c kit; genotype phenotype correlation; lower gastrointestinal tract
Journal Title: Seminars in Diagnostic Pathology
Volume: 23
Issue: 2
ISSN: 0740-2570
Publisher: Elsevier Inc.  
Date Published: 2006-05-01
Start Page: 63
End Page: 69
Language: English
DOI: 10.1053/j.semdp.2006.08.003
PUBMED: 17193819
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 18" - "Export Date: 4 June 2012" - "CODEN: SDPAE" - "Source: Scopus"
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  1. Cristina R Antonescu
    741 Antonescu