Claudin-18 Is an Early-Stage Marker of Pancreatic Carcinogenesis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy. This cancer's poor prognosis and late presentation emphasize the importance of early detection; therefore, accumulating knowledge about the pathological details and the molecular alterations of early or precursor lesions of PDAC is essential. Three distinct epithelial lesions-pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCNs)-are recognized as the precursors of PDAC (Maitra et al. 2005). The multistep progression models of these precursor lesions have been clarified using morphological and molecular examinations (Maitra et al. 2005;Maitra et al. 2003).Several lines of evidence indicate that phenotypic changes of the pancreatic epithelium, especially the acquisition of gastric epithelium-like characteristics, constitute a crucial event in the early stage of pancreatic carcinogenesis (Ban et al. 2006;Prasad et al. 2005;Kim et al. 2002;Basturk et al. 2010). IPMNs with gastric foveolar epithelium-like morphology are a major subset of IPMNs (gastric-type IPMNs) (Ban et al. 2006). The foregut markers are characteristically upregulated in PanINs, including the ectopic appearance of the gastric epithelial phenotype (Prasad et al. 2005 SummaryPancreatic ductal neoplasms exhibit gastric epithelium-like characteristics. In this study, we evaluated the expression of claudin-18 (CLDN18), a gastric epithelium-associated claudin, in pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and pancreatic ductal adenocarcinomas (PDACs) using immunohistochemistry. We observed a high level of expression of CLDN18 in PanINs (31/32, 97%), IPMNs (61/65, 95%), and MCNs (4/5, 80%) using ordinary tissue section analysis. Furthermore, we observed a high level of CLDN18 expression in PDACs (109/156, 70%) using tissue microarray analysis. However, the normal pancreatic duct or the ductal metaplasia of the acinar cells was not immunoreactive. Comparative analysis of CLDN18 and phenotypic markers in IPMNs revealed that simultaneous expression of CLDN18 and intestinal markers frequently occurred, even in intestinaltype IPMNs. CLDN18 variant 2 mRNA was expressed and was similarly upregulated by phorbol 12-myristate 13-acetate (PMA) treatment in pancreatic cancer cell lines and in a gastric cancer cell line. An inhibitor of pan-PKC (GF109203X) completely suppressed this upregulation in pancreatic cancer cells. These results indicate that CLDN18, a marker for the early carcinogenetic process, is commonly expressed in precursor lesions of PDAC. Activation of the PKC pathway might be involved in CLDN18 expression associated with pancreatic carcinogenesis. (J Histochem Cytochem 59:942-952, 2011)

Claudin‐18 overexpression in intestinal‐type mucinous borderline tumour of the ovary

“…Interestingly, they showed further that CLDN18 is down‐regulated in gastric epithelium with intestinal metaplasia and in gastric cancers with an intestinal phenotype. Our group showed recently that a subset of intrahepatic cholangiocarcinomas and pancreatic ductal carcinomas show a CLDN18‐positive gastric phenotype . It is of note that up‐regulation of CLDN18 occurs in the early stage of cholangiocellular and pancreatic carcinogenesis, as shown by CLDN18 positivity in precancerous lesions such as pancreatic intraepithelial neoplasias and biliary intraepithelial neoplasias.…”

“…In normal human tissues, expression of claudin18a2 is confined to gastric epithelial cells (foveolar, endocrine, parietal and chief cells) and duodenal Paneth cells, and is not expressed in other organs, including the oesophagus, colon, pancreas and lung . CLDN18 is now considered to be a highly selective immunohistochemical marker of gastric lineage, and its expression is considered to determine the gastric phenotype in neoplastic conditions . Sanada et al .…”

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

“…A similar change of acinar cell identity extends to the loss of PTF1A and the appearance of gastric markers in early neoplastic lesions (PanINs) of pancreatic adenocarcinoma (96)(97)(98). MECOM has been proposed to play an early role in pancreatic cancer, in part by stimulating the accumulation of KRAS mRNA (48).…”

Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non‐small‐cell lung cancer

“…In normal lung tissue, the bronchial epithelium is known to express CLDN1, 3, 4 and 7, while pneumocytes express CLDN5, 18.1 (but not 18.2), weakly CLDN10 and partially CLDN4 . In contrast, during tumorigenesis, expression of CLDNs is frequently altered . In NSCLC, CLDN10 expression is preferentially observed in adenocarcinomas, whereas CLDN1 protein expression is more frequently detected in the squamous‐cell carcinoma subtype (77%) compared to adenocarcinoma (29%).…”