CDH17, GPA33 and MS4A12: Three Intestine-Specific Cell Surface Proteins as Potential Diagnostic Tools or Therapeutic Targets.
Nicole C Panarelli, Rhonda K Yantiss, Rita Chiu, Lloyd J Old, Yao-Tseng Chen. Weill Cornell Medical College, New York, NY; Ludwig Institute for Cancer Research, New York, NY
Background: Lineage-specific cell surface proteins are useful diagnostic tools and represent potential targets for monoclonal antibody therapy in cancer treatement. We identified three transmembrane proteins: CDH17, a member of the cadherin superfamily; GPA33, a cell surface differentiation antigen that belongs to the immunoglobulin superfamily; and MS4A12, a transmembrane calcium-channel protein with sequence homology to CD20, via a literature review and in-silico analysis for genes with intestine-restricted expression. The purpose of this study was to examine expression of these markers in cancers and normal tissues from the gastrointestinal (GI) tract in order to assess their potential as diagnostic markers and immunotherapeutic targets.
Design: Immunostains for CDH17, GPA33 and MS4A12 were performed using tissue microarrays (TMA) of 247 GI cancers, including esophageal adenocarcinoma (n=40), squamous cell carcinoma (n=19), diffuse-type (n=33) and intestinal-type (n=14) gastric adenocarcinoma, and colonic adenocarcinoma (n=141). A TMA of normal tissues from various organs was also tested. Membranous staining for each marker was interpreted as positive.
Results: Benign colonic and small-intestinal epithelium showed apical and basolateral membranous staining for CDH17 and GPA33, whereas MS4A12 showed apical membranous staining in normal colon but not in small intestine. All other normal tissues were negative for all three proteins. Colon cancers showed frequent expression of CDH17 (100%) and GPA33 (93%), but infrequently expressed MS4A12 (16%). CDH17 was more commonly expressed in adenocarcinomas of the esophagus (78%) and diffuse-type (91%) and intestinal-type (86%) gastric cancers than GPA33 (34%, 50%, 36%, respectively), and all GPA33-positive cases were CDH17-positive. MS4A12 was negative in all non-colonic adenocarcinomas, and esophageal squamous cell carcinomas were negative for all three markers.
Conclusions: CDH17 is a sensitive marker for adenocarcinoma of the GI tract, whereas GPA33 is preferentially expressed in colorectal cancer. These two markers could supplement existing stains, such as CDX2 in demonstrating intestinal differentiation in cancer. Their expression in >90% of colorectal cancers and in many adenocarcinomas of the upper GI tract suggests their potential as therapeutic targets. In comparison, MS4A12 is of limited diagnostic or therapeutic potential due to its low frequency of expression in cancer.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 44, Wednesday Morning