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Destabilized adhesion in the gastric proliferative zone and c-Src kinase activation mark the development of early diffuse gastric cancer

Cited 86 time in Web of Science Cited 89 time in Scopus
Authors
Humar, Bostjan; Fukuzawa, Ryuji; Blair, Vanessa; Dunbier, Anita; More, Helen; Charlton, Amanda; Yang, Han Kwang; Kim, Woo Ho; Reeve, Anthony E; Martin, Iain; Guilford, Parry
Issue Date
2007-03-17
Publisher
American Association for Cancer Research
Citation
Cancer Res. 2007 Mar 15;67(6):2480-9.
Keywords
Cadherins/geneticsCell Adhesion/physiologyCell Differentiation/physiologyCell Growth Processes/physiologyDisease ProgressionEnzyme ActivationGerm-Line MutationHumansProtein-Tyrosine Kinases/*metabolismProto-Oncogene Proteins/*metabolismStomach Neoplasms/*enzymology/genetics/*pathology
Abstract
The initial development of diffuse gastric cancer (DGC) is poorly understood. The study of E-cadherin (CDH1) germ line mutation carriers predisposed to DGC provides a rare opportunity to elucidate the genetic and biological events surrounding disease initiation. Samples from various stages of hereditary and sporadic DGC were investigated to determine general mechanisms underlying early DGC development. Paraffin-embedded tissues from 13 CDH1 mutation carriers and from 10 sporadic early DGC cases were analyzed. Immunofluorescence and immunohistochemistry using differentiation, proliferation, and adhesion markers showed that DGC initiation seems to occur at the proliferative zone (the upper neck) of the gastric epithelium and correlates with absent or reduced expression of junctional proteins (beta-actin, p120, Lin-7). Slow proliferation of neoplastic cells at the upper gastric neck leads to the formation of intramucosal signet-ring cell carcinoma (SRCC) displaying differentiated features. As shown by immunolabeling, invasion from SRCC lesions beyond the gastric mucosa is associated with poor differentiation, increased proliferation, activation of the c-Src system, and an epithelial-mesenchymal transition. Our results provide a molecular description of the early development of DGC and explain the relationship between the two main DGC types, poorly differentiated carcinoma and SRCC: both share their origin, but SRCC develops following cancer cell differentiation and seems relatively indolent in its intramucosal stage.
ISSN
0008-5472 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17363565

https://hdl.handle.net/10371/29710
DOI
https://doi.org/10.1158/0008-5472.CAN-06-3021
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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