Claudin 7 as a possible novel molecular target for the treatment of pancreatic cancer

Background/objectives

Pancreatic cancer consists of various subpopulations of cells, some of which have aggressive proliferative properties. The molecules responsible for the aggressive proliferation of pancreatic cancer may become molecular targets for the therapies against pancreatic cancer.

Claudins 1, 3, 4, 5 and 7 in esophageal cancer: loss of claudin 3 and 4 expression is associated with metastatic behavior

The aim of the study was to elucidate the significance of claudins in surgically treated esophageal carcinoma. The expression of claudins 1, 3, 4, 5 and 7 was studied by immunohistochemistry. Tumor proliferation was assessed with Ki67 immunostaining and apoptosis by the TUNEL method and immunostaining of fragmented caspase 3. Adenocarcinomas showed significantly more cases with moderate or strong claudin 3 (p<0.001) and claudin 5 positivity (p=0.031) compared to squamous cell carcinomas. Loss of claudin 3 expression was associated with the presence of distant metastases (p=0.039). Claudins 3, 4 and 7 had a significant association with either a high apoptotic index or a high number of caspase 3-positive cells, while claudin 5 was associated with increased proliferation. In esophageal carcinoma, claudin expression may vary along with the histology of the tumor. Claudin expression may also be associated with apoptosis or proliferation, suggesting that claudins may contribute to tumor behavior and growth.     

Usefulness of Claudin 4 in the cytological diagnosis of serosal effusions

The identification of metastatic cells in serous effusions has prognostic and therapeutic implications, thus leading to a continuous search for improvement of the existing diagnostic procedures, including immunocytochemistry. To evaluate the usefulness of an antibody recognizing the tight junction-associated protein Claudin 4 in detecting metastatic tumor cells and in the differential with reactive and neoplastic mesothelium, we stained 345 cases of benign and neoplastic serous effusions obtained from pleura, peritoneum, and pericardium. Two-hundred and twenty-eight of 230 cases (99.1%) of epithelial metastasis of different origin were strongly stained by anti-Claudin 4, whereas all cases of reactive mesothelitis (78) and malignant mesothelioma (37) were negative. With the exception of a single case of ovarian carcinoma hypercalcemic-type, all tumors originating from the anatomical sites that most frequently metastasize to the serosae, including lung (61), breast (23), female genital tract (67), gastrointestinal tract (27), and peritoneum (6), were found to be positive. Claudin 4 was also extremely useful in detecting single-tumor cells dispersed among heavy inflammatory reaction. Because of its high sensitivity (99.1%) and specificity (100%), Claudin 4 might be used as an ideal "single-shot" marker for the identification of metastatic epithelial cells in serous effusions.     

Tight junction proteins: From barrier to tumorigenesis

The tight junction is a multi-protein complex and is the apical most junctional complex in certain epithelial and endothelial cells. A great deal of attention has been devoted to the understanding of these proteins in contributing to the barrier function – that is, regulating the paracellular flux or permeability between adjacent cells. However, tight junction proteins are now recognized as having functions beyond the barrier. The focus of this review is to discuss the barrier function of the tight junction and to summarize the literature with a focus on the role of tight junction proteins in proliferation, transformation, and metastasis.     

Claudin在胃肠道肿瘤发生发展中的作用

Claudin是维持紧密连接结构和功能最重要的蛋白分子,在胃肠道肿瘤的发生发展及临床诊治中起着重要的作用.本文收集国内外近年来有关Claudin的分子结构及在胃肠道肿瘤发生发展中作用的最新文献并作综述.     

Claudin 18在胰腺癌细胞中的表达

目的:检测人胰腺癌细胞中Claudin 18的表达,为临床诊断胰腺癌提供新的标志物和治疗靶位.方法:采用RT-PCR、免疫印迹和流式细胞术分别从基因、蛋白和细胞整体水平上检测胰腺导管腺癌和胰岛细胞癌细胞表面人源性Claudin 18的mRNA转录和蛋白的表达.结果:胰腺导管腺癌PANC-1、BX-PC-3和AS-PC-1细胞均可以在mRNA、蛋白和细胞整体的不同水平表达Claudin 18;而胰岛细胞癌RINm5F细胞则不表达Claudin 18.同时,对照细胞胃印戒细胞癌KATOIII也可以大量表达Claudin 18.结论:多数胰腺导管腺癌细胞系均可以在不同水平表达Claudin 18,而胰岛细胞癌细胞系则不能表达Claudin 18,该结果与前期胰腺癌患者的免疫组化检测结果一致.     

Claudin expression in Barrett's esophagus and adenocarcinoma

Claudins (CLDNs) are key molecules in cell adhesion, polarity, and control of paracellular solute transport. Several studies suggested that changes in claudin pattern have a role in cancer development. This study aimed to detect alterations in CLDN 1, 2, 3, 4, and 7 expression patterns in Barrett's esophagus (BE) and adenocarcinoma (ACC) compared with that in foveolar epithelium (FOV), normal squamous epithelium (SQ), and squamous cell carcinoma (SQCC). One hundred twenty five surgically or endoscopically removed, paraffin-embedded cases were studied by immunohistochemistry and analyzed statistically. BE, ACC, and FOV were dissected from 30 paraffin-embedded samples for further mRNA expression analysis. CLDN 7 was the dominating type in all epithelia and carcinomas, but its expression did not differ in normal and altered tissues. CLDN 1 expression was significantly increased in SQCC compared with that in SQ. CLDNs 3 and 4 were significantly elevated both in BE and ACC compared with that in FOV. CLDN 2 expression increased significantly in ACCs compared with that in BE. This is the first report proving similarities and differences regarding claudin expression pattern in BE and ACC compared with that in FOV and SQ. Our data prove a close link in CLDN pattern between BE and ACC, adding further evidence that BE is an alteration preceding esophageal ACC.     

Tight junctions and human diseases

Tight junctions are intercellular junctions adjacent to the apical end of the lateral membrane surface. They have two functions, the barrier (or gate) function and the fence function. The barrier function of tight junctions regulates the passage of ions, water, and various macromolecules, even of cancer cells, through paracellular spaces. The barrier function is thus relevant to edema, jaundice, diarrhea, and blood-borne metastasis. On the other hand, the fence function maintains cell polarity. In other words, tight junctions work as a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell biology, in terms of loss of cell polarity. Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins, and JAMs have been recently discovered. Of these molecules, claudins are exclusively responsible for the formation of tight-junction strands and are connected with the actin cytoskeleton mediated by ZO-1. Thus, both functions of tight junctions are dependent on the integrity of the actin cytoskeleton as well as ATP. Mutations in the claudin14 and the claudin16 genes result in hereditary deafness and hereditary hypomagnesemia, respectively. Some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases. In this review, the relationship between tight junctions and human diseases is summarized.