This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Humar, B. Articles by Guilford, P. Search for Related Content PubMed PubMed Citation Articles by Humar, B. Articles by Guilford, P.

Destabilized Adhesion in the Gastric Proliferative Zone and c-Src Kinase Activation Mark the Development of Early Diffuse Gastric Cancer

¹ Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand; Departments of ² Surgery and ³ Pathology, University of Auckland, Auckland, New Zealand; and ⁴ Seoul National University, Seoul, South Korea

Requests for reprints: Bostjan Humar or Parry Guilford, Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand. Phone: 64-3479-7868; E-mail: bostjan.humar{at}otago.ac.nz or parry.guilford{at}otago.ac.nz.

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 (ß-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. [Cancer Res 2007;67(6):2480–9]