CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target

• Published in: The American journal of surgical pathology Vol. 29; no. 3; p. 390
• Main Authors: Hansel, Donna E, Dhara, Surajit, Huang, RuChih C, Ashfaq, Raheela, Deasel, Mari, Shimada, Yutaka, Bernstein, Harold S, Harmon, John, Brock, Malcolm, Forastiere, Arlene, Washington, M Kay, Maitra, Anirban, Montgomery, Elizabeth
• Format: Journal Article
• Language: English
• Published: United States 01.03.2005
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Adenocarcinoma - pathology; Barrett Esophagus - metabolism; Barrett Esophagus - pathology; CDC2 Protein Kinase - genetics; CDC2 Protein Kinase - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Progression; Dose-Response Relationship, Drug; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - enzymology; Esophageal Neoplasms - pathology; Esophagus - anatomy & histology; Esophagus - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Masoprocol - analogs & derivatives; Masoprocol - pharmacology; Precancerous Conditions - enzymology; Precancerous Conditions - pathology; RNA, Messenger - metabolism; RNA, Neoplasm - analysis; Tissue Array Analysis
• ISSN: 0147-5185
• DOI: 10.1097/00000478-200503000-00014

Esophageal adenocarcinoma arises through well-defined precursor lesions (Barrett esophagus), although only a subset of these lesions advances to invasive adenocarcinoma. The lack of markers predicting progression in Barrett esophagus, typical presentation at advanced stage, and limitations of conventional chemotherapy result in >90% mortality for Barrett-associated adenocarcinomas. To identify potential prognostic markers and therapeutic targets, we compared gene expression profiles from Barrett-associated esophageal adenocarcinoma cell lines (BIC1, SEG1, KYAE, OE33) and normal esophageal epithelial scrapings utilizing the Affymetrix U133_A gene expression platform. We identified 560 transcripts with >3-fold up-regulation in the adenocarcinoma cell lines compared with normal epithelium. Utilizing tissue microarrays composed of normal esophageal squamous mucosa (n = 20), Barrett esophagus (n = 10), low-grade dysplasia (n = 14), high-grade dysplasia (n = 27), adenocarcinoma (n = 59), and node metastases (n = 27), we confirmed differential up-regulation of three proteins (Cdc2/Cdk1, Cdc5, and Igfbp3) in adenocarcinomas and Barrett lesions. Protein expression mirrored histologic progression; thus, 87% of low-grade dysplasias had at least focal surface Cdc2/Cdk1 and 20% had >5% surface staining; 96% of high-grade dysplasias expressed abundant surface Cdc2/Cdk1, while invasive adenocarcinoma and metastases demonstrated ubiquitous expression. Esophageal adenocarcinoma cell lines treated with the novel CDC2/CDK1 transcriptional inhibitor, tetra-O-methyl nordihydroguaiaretic acid (EM-1421, formerly named M4N) demonstrated a dose-dependent reduction in cell proliferation, paralleling down-regulation of CDC2/CDK1 transcript and protein levels. These findings suggest a role for CDC2/CDK1 in esophageal adenocarcinogenesis, both as a potential histopathologic marker of dysplasia and a putative treatment target.