Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer

Abstract

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.

Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction

“…Some of the immunohistochemical markers have also been previously tested in malignant and premalignant stages of colorectal and gastroesophageal cancers . The combination of CDH17 and CLDN18, for example, has been confirmed as being predictive for nodal involvement and poor prognosis in gastric adenocarcinomas . CLDN18 is a dominant marker in our poor prognosis Group 1 and CDH17 is characteristic for Group 2 which shows intermediate outcome in our primary cohort, but poor prognosis in some of the validation cohort.…”

“…38,39 The combination of CDH17 and CLDN18, for example, has been confirmed as being predictive for nodal involvement and poor prognosis in gastric adenocarcinomas. 40 CLDN18 is a dominant marker in our poor prognosis Group 1 and CDH17 is characteristic for Group 2 which shows intermediate outcome in our primary cohort, but poor prognosis in some of the validation cohort. Some of our target genes have also been reported to be relevant for subtypes of pancreatic and right-sided colorectal cancer, suggesting that similar mechanisms such as exposure to small bowel content (including bile and pancreatic enzymes) might be involved in carcinogenesis of gastroenteropancreatic tumors.…”

111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis

“…Therefore, compared with HER2-targeted imaging, CDH17-targeted imaging could be useful in a larger number of patients. CDH17 is expressed in not only gastric cancer but also colon cancer and pancreatic cancer: the expression ratios of colonic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, and cholangiocarcinoma were reported to be 97.3%, 39.3%, 24.1%, and 53.3%, respectively [9,10,28]. These findings suggest that imaging with 111 In-D2101 could visualize these cancers in addition to gastric cancer.…”

“…Cadherin-17 (CDH17) is a membrane protein that mediates cell-cell adhesion and is frequently expressed in adenocarcinomas such as gastric cancer, colorectal cancer, and pancreatic cancer [9,10]. The positive ratio of CDH17 is approximately 60% in both primary and metastatic gastric cancer, suggesting that CDH17 is a promising marker of gastric cancer [11].…”

<p>Knockdown of ROS proto-oncogene 1 inhibits migration and invasion in gastric cancer cells by targeting the PI3K/Akt signaling pathway</p>

“…Gastric cancer is the fourth common malignancies and the third leading cause of cancer death worldwide. 1,2 Patients are diagnosed at the advanced stages of gastric cancer and 5-year survival rate is no more than 40% in China. [3][4][5] Surgical resection, radiation therapy, chemotherapy and combination treatments are considered as therapeutic approaches for malignancies, including gastric cancer.…”