title: Destabilized adhesion in the gastric proliferative zone and c-Src kinase activation mark the development of early diffuse gastric cancer.
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.
authors.affiliation: Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand. bostjan.humar@otago.ac.nz
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuzawa
authors.forename: Vanessa
authors.initials: V
authors.lastname: Blair
authors.forename: Anita
authors.initials: A
authors.lastname: Dunbier
authors.forename: Helen
authors.initials: H
authors.lastname: More
authors.forename: Amanda
authors.initials: A
authors.lastname: Charlton
authors.forename: Han Kwang
authors.initials: HK
authors.lastname: Yang
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Reeve
authors.forename: Iain
authors.initials: I
authors.lastname: Martin
authors.forename: Parry
authors.initials: P
authors.lastname: Guilford
mesh_terms: D015703:Antigens, CD; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D018450:Disease Progression; D004789:Enzyme Activation; D018095:Germ-Line Mutation; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D019061:src-Family Kinases
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human