Claudin-4: A new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin

Michl, Patrick; Buchholz, Malte; Rolke, Monika; Kunsch, Steffen; Löhr, Matthias; McClane, Bruce A.; Tsukita, Shöichiro; Leder, Gerhard; Adler, Guido; Gress, Thomas M.

doi:10.1053/gast.2001.27124

Cited by 269 publications

(253 citation statements)

References 33 publications

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“…18 More recently, a monoclonal antibody against CLDN4 32 and C-terminal fragment of C. perfringens enterotoxin 33 has been demonstrated to have antitumor activity in pancreatic cancer. These findings and our present results suggest that CLDN4 represents a promising therapeutic target for pancreatic ductal adenocarcinomas and intraductal papillary mucinous neoplasms.…”

Section: Discussionmentioning

confidence: 99%

“…CLDN4 has been shown to be overexpressed in a variety of cancers, including ovarian carcinoma, 15 breast carcinoma, 16 prostate cancer, 17 and pancreatic ductal adenocarcinoma. [18][19][20][21][22] Importantly, CLDN4 has been reported as having an important role in the growth, invasion, and metastasis of pancreatic cancer. CLDN4 is also known to function as a high-affinity receptor for Clostridium perfringens enterotoxin (CPE) 23 and is, therefore, expected to be a therapeutic target.…”

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confidence: 99%

“…CLDN4 is also known to function as a high-affinity receptor for Clostridium perfringens enterotoxin (CPE) 23 and is, therefore, expected to be a therapeutic target. 18 CLDN4 expression was also found in a subset of intraductal papillary mucinous neoplasms, but its expression pattern during neoplastic progression of intraductal papillary mucinous neoplasms remains unknown.…”

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Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

et al. 2011

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Claudin-4, encoding a protein for tight junction formation and function, is highly overexpressed in pancreatic ductal adenocarcinoma and is also associated with invasive adenocarcinomas arising in intraductal papillary mucinous neoplasms of the pancreas. However, the expression pattern of claudin-4 during neoplastic progression of intraductal papillary mucinous neoplasms remains unknown. Using quantitative real-time reverse transcription-PCR, we analyzed claudin-4 mRNA in a panel of 14 pancreatic cancer cell lines and in formalin-fixed paraffinembedded tissues from 80 patients with intraductal papillary mucinous neoplasms of different histological grades and papillary subtypes. Increased expression of claudin-4 was confirmed in all the pancreatic cancer cell lines tested as compared with normal ductal epithelial cells and fibroblast cultures. The claudin-4 expression was significantly higher in high-grade intraductal papillary mucinous neoplasms (borderline neoplasm and carcinoma) than in low-grade intraductal papillary mucinous neoplasms (adenoma) (Po0.0001). In addition, claudin-4 mRNA levels were significantly higher in intestinal-type intraductal papillary mucinous neoplasms than in non-intestinaltype intraductal papillary mucinous neoplasms based on papillary subclassification (Po0.0001). Our findings suggest that claudin-4 expression is associated with neoplastic progression of intraductal papillary mucinous neoplasms and, especially, with a distinct pathway to intestinal differentiation.

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Section: Discussionmentioning

confidence: 99%

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Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

et al. 2011

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“…For example, we and others have shown that claudin-3 and claudin-4 are highly increased in ovarian cancer [7][8][9][10][11][12][13][14]. These claudins have also been shown to be elevated in prostate, pancreatic, uterine, and breast cancer [15][16][17]. So far, claudin-1,3,4,5,7,10,16 have been shown altered in various cancers [5].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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Claudin proteins belong to a large family of transmembrane proteins essential to the formation and maintenance of tight junctions (TJs). In ovarian cancer, TJ protein claudin-4 is frequently overexpressed and may have roles in survival and invasion, but the molecular mechanisms underlying its regulation are poorly understood. In this report, we show that claudin-4 can be phosphorylated by protein kinase C (PKC) at Thr189 and Ser194 in ovarian cancer cells and overexpression of a claudin-4 mutant protein mimicking the phosphorylated state results in the disruption of the barrier function. Furthermore, upon phorbol ester-mediated PKC activation of OVCA433 cells, TJ strength is decreased and claudin-4 localization is altered. Analyses using PKC inhibitors and siRNA suggest that PKCε, an isoform typically expressed in ovarian cancer cells, may be important in the TPAmediated claudin-4 phosphorylation and weakening of the TJs. Furthermore, immunofluorescence studies showed that claudin-4 and PKCε are co-localized at the TJs in these cells. The modulation of claudin-4 activity by PKCε may not only provide a mechanism for disrupting TJ function in ovarian cancer, but may also be important in the regulation of TJ function in normal epithelial cells.

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“…18 Little information is available on the expression of cytoplasmic tight junction proteins in human cancers, [19][20][21][22] and only one study has been published about the immunohistochemical localization of a tight junction protein (occludin (OCLN)) in lung tumors. 23 Considering the role of tight junctions in epithelial cell function, the involvement of tight junction proteins in the regulation of epithelial proliferation, and their potential usefulness as novel tools in cancer diagnosis, prognosis and treatment, 24,25 it is essential to understand in detail how tumor development correlates to changes in tight junction protein expression. To address this issue, we used immunocytochemistry and the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to examine the expression of several cytoplasmic and transmembrane proteins of tight junctions in human lung squamous cell carcinomas and adenocarcinomas.…”

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Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

et al. 2007

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We investigated the expression of tight junction proteins in human lung squamous cell carcinomas and adenocarcinomas by immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). We found a statistically significant correlation between diagnosis and positivity of tumors with either claudin (CLDN)-1 or CLDN-5. Squamous cell carcinomas and basal cells of bronchial epithelium were positive for CLDN-1 and negative for CLDN-5, whereas adenocarcinomas, normal cylindrical cells and pneumocytes were positive for CLDN-5 and negative for CLDN-1, suggesting different pathways in tumor development and progression. CLDN-4 and ZO-1 staining were detected in both types of tumors, whereas cingulin (CGN) was not detected in squamous cell carcinomas. Quantitative RT-PCR was used to evaluate changes in transcript levels for a large panel of tight junction proteins. In squamous cell carcinomas, we observed statistically significant decreases in the mRNA levels of JAM-1, occludin, CLDN-3, CLDN-4, CLDN-7, CGN, ZO-2 and ZO-3, and an increase in CLDN-1 mRNA. In adenocarcinomas, when transcript levels were compared with bronchial cells, we observed statistically significant decreases in the mRNA levels of CLDN-1, CLDN-3, CLDN-4, CLDN-7, ZO-2 and ZO-3. These results indicate that characterization of tight junction protein expression in human lung tumors can be an additional diagnostic tool and provide new insights on their histogenesis. Modern Pathology (2007) 20, 947-954;

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Claudin-4: A new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin

Cited by 269 publications

References 33 publications

Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

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