Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation

Soini, Ylermi; Takasawa, Akira; Eskelinen, M; Juvonen, Petri; Kärjä, Vesa; Hasegawa, Tadashi; Murata, Masaki; Tanaka, Satoshi; Kojima, Takashi; Sawada, Norimasa

doi:10.1136/jclinpath-2011-200400

Cited by 32 publications

(30 citation statements)

References 46 publications

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“…In previous studies, some authors described faint expression of CLDN18 in normal pancreatic tissue, whereas others negated it . Our data confirm that CLDN18.2 is not expressed at all in normal pancreatic tissue including all different cell types prevalent in pancreas as composite organ.…”

Section: Discussionsupporting

confidence: 80%

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Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms

Wöll

Schlitter

Dhaene

et al. 2013

Intl Journal of Cancer

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The majority of pancreatic neoplasms are characterized by a generally lethal progress within a short period of time after primary diagnosis and the mortality of patients is expected to increase further. Due to lack of efficient screening programs and moderate response to treatments, novel compounds for treatment are needed. We investigated the CLDN18.2 expression in affected patients as in vitro feasibility study for a potential treatment with the novel antibody IMAB362. Therefore, we analyzed the expression of CLDN18.2 in normal pancreatic tissues (N 5 24), primary lesions (N 5 202), metastases (N 5 84) and intra-individually matched samples (N 5 48) of patients with pancreatic ductal adenocarcinoma (PDAC), neuroendocrine neoplasia (NEN) and acinar cell carcinoma. A standardized method for evaluation by immunohistochemistry was developed. The specific staining was evaluated by two independent raters and analysis of staining intensities (range 0-31) and relative proportions of tumor cells were performed. One hundred three (59.2%) samples of primary PDAC were found positive. The vast majority of positive samples were characterized to highly express CLDN18.2: 54.6% (N 5 95) with staining intensities of 21. NEN were positive in 20% of cases (all 21). Metastases of pancreatic neoplasms were also frequently found positive with comparable high rates (69.4% of lymph node and 65.7% of liver metastases). The rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis. Thus, a considerable number of patients with pancreatic neoplasms would be in principle eligible for a CLDN18.2-targeting approach.Pancreatic ductal adenocarcinoma (PDAC), representing >80% of all pancreatic neoplasms, is the seventh most frequent cancer in Europe and is the fourth most frequent cause of cancer related deaths in the European Union (EU).1-3 The prevalence of pancreatic neoplasms is 1-5/10,000 in both, the EU and the United States. 4,5 In contrast to all major cancers, however, the mortality rate of PDAC is expected to increase further. 6 No effective screening programs for early detection of pancreatic neoplasms are available and patients lack specific clinical symptoms at early stages. Thus, most PDAC patients are diagnosed at an advanced stage of the disease and are not suitable for resection with curative intent. For systemic palliative treatment cytotoxic agents are administered. The majority of patients are treated with gemcitabine, whereas patients with a good performance status undergo polychemotherapy with 5-FU/irinotecan/oxaliplatin (FOLFORINOX).3,7 Chemosensitivity of PDAC is moderate 8 and targeted therapeutics are of high interest. Although various compounds have been tested, only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, received approval by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) for the treatment of patients with metastatic disease in combination with gemcitabine. The ...

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Section: Discussionsupporting

confidence: 80%

“…CLDN18 expression has also been reported for PDAC . This prompted us to consider clinical testing of IMAB362 therapeutic antibody in this high medical need disease.…”

mentioning

confidence: 98%

Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms

Wöll

Schlitter

Dhaene

et al. 2013

Intl Journal of Cancer

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“…In our study, Claudin‐18 was distributed along the entire cell membrane of most adenocarcinoma cells but was almost completely absent from non‐neoplastic epithelial cells. These findings are in agreement with previous histological studies of biopsy or surgical specimens of the bile duct or pancreas …”

Section: Discussionsupporting

confidence: 93%

Immunocytochemistry for Claudin‐18 and Maspin in biliary brushing cytology increases the accuracy of diagnosing pancreatobiliary malignancies

et al. 2016

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“…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%).…”

Section: Discussionmentioning

confidence: 99%

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

Micke

Mattsson²,

Edlund

et al. 2014

Intl Journal of Cancer

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Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n 5 355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n 5 196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho 5 0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p 5 0.03] and multivariate COX regression model (HR: 1.9; p 5 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.Non-small-cell lung cancer (NSCLC) therapy has changed dramatically as the comprehensive molecular analysis of lung cancer specimens has identified multiple, clinically relevant driver aberrations. Many of these aberrations can be targeted by specific inhibitors previously developed for the treatment of other cancer types.1,2 Indication extension of such drug

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Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation

Cited by 32 publications

References 46 publications

Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms

Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms

Immunocytochemistry for Claudin‐18 and Maspin in biliary brushing cytology increases the accuracy of diagnosing pancreatobiliary malignancies

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

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