Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer
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Keisuke Matsusaka1,2, Tetsuo Ushiku3, Masayuki Urabe2,3,4, Masaki Fukuyo2, Hiroyuki Abe1, Shumpei Ishikawa3,5, Yasuyuki Seto4, Hiroyuki Aburatani5, Takao Hamakubo6, Atsushi Kaneda2,5, Masashi Fukayama1,3
1Division of Diagnostic Pathology, The University of Tokyo Hospital, Tokyo, Japan
2Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
3Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
4Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
5Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
6Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
Atsushi Kaneda, email: [email protected]
Masashi Fukayama, email: [email protected]
Keywords: gastric cancer, intratumoral heterogeneity, nodal metastases, CDH17, CLDN18
Received: April 22, 2016 Accepted: August 13, 2016 Published: August 26, 2016
Patients with gastric cancer typically face gastrectomies even when few or no nodal metastases are reported. Current procedures poorly predict lymphatic metastases; thus, evaluation of target molecules expressed on cancer cell membranes is necessary for in vivo detection. However, marker development is limited by the intratumoral heterogeneity of gastric cancer cells. In this study, multiple gene expression arrays of 42 systemic normal tissue samples and 56 gastric cancer samples were used to investigate two adhesion molecules, cadherin 17 (CDH17) and claudin 18 (CLDN18), which are intestinal and gastric markers, respectively. Expression of CDH17 and CLDN18 was partially redundant, but overlapped in 50 of 56 cases (89.3%). Tissue microarrays constructed using primary lesions and nodal metastases of 106 advanced gastric cancers revealed CDH17 and CLDN18 expression in 98 positive cases of 106 (92%). Hierarchical clustering classified gastric cancers into three subgroups, CDH17(++)/CLDN18(+/-), CDH17(++)/CLDN18(++) or CDH17(+)/CLDN18(+), and CDH17(-)/CLDN18(++/+/-). Whole tissue sections displayed strong, homogeneous staining for CDH17 and CLDN18. Together, these results indicate that CDH17 and CLDN18 are useful target molecules; moreover, their coupling can aid in the comprehensive detection and localization of gastric cancer metastases in vivo to overcome challenges associated with intratumoral heterogeneity.
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