title: Upregulated Akt signaling adjacent to gastric cancers: implications for screening and chemoprevention.
abstract: Most gastric adenocarcinomas arise as a longterm complication of Helicobacter pylori infection of the stomach, but the high prevalence of this infection limits the cost-effectiveness of antibiotic eradication as a cancer prevention strategy. Here we have used phosphorylation-specific antibodies against the Akt kinase consensus sequence to detect downstream substrates of this oncogenic signaling pathway in normal and malignant gastric tissues. In vitro studies confirm that phosphorylation of Akt and its substrates is inducible by epithelial mitogens such as epidermal growth factor (EGF), which is implicated in the pathogenesis of H. pylori gastritis. Control clinical studies confirm far stronger Akt substrate phosphorylation in primary human breast cancers than in matched adjacent normal breast tissues; unexpectedly, however, increased Akt signaling is apparent in both primary stomach cancers and adjacent normal gastric tissues. These findings raise the possibility of a preneoplastic field defect induced in morphologically normal tissues, and suggest that immunoassays of mucosal Akt activity could guide preventive surveillance and/or intervention in patients at risk of gastric cancer. Moreover, since recent reports confirm Akt inhibition by COX-2 inhibitors, these data support the chemopreventive efficacy of such drugs for at-risk individuals.
authors.affiliation: Laboratory of Tumor Phosphoproteomics, National Cancer Centre, Singapore.
authors.forename: Kok Long
authors.initials: KL
authors.lastname: Ang
authors.forename: Diong Lang
authors.initials: DL
authors.lastname: Shi
authors.forename: Wong Wai
authors.initials: WW
authors.lastname: Keong
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Epstein
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control; D000906:Antibodies; D001943:Breast Neoplasms / Q000235:genetics; D018890:Chemoprevention; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007118:Immunoassay; D008403:Mass Screening; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000517:prevention & control; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D016861:Cyclooxygenase Inhibitors; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt