Role of claudins in tumorigenesis
Introduction
Claudins (CLDNs) are a family of ∼17–27 kDa integral membrane tight junction (TJ) proteins that determine the size of molecules that pass through the paracellular space in epithelial and endothelial tissues. The first claudin gene (CLDN1) was identified in a screen for murine proteins that interacted with the known integral TJ protein, occludin. This effort was spearheaded by the demonstration that occludin knockout mice formed TJs, and that therefore there were likely to be other molecules also responsible for TJ formation and function [1]. Our group cloned the human CLDN1 gene in a differential display strategy, to identify genes upregulated during the onset of cellular senescence in normal human mammary epithelial cells (HMECs) [2]. To date more than 20 claudin family members have been cloned and characterized, primarily from mouse, rat and human, with orthologues found in insect species, e.g., in drosophila, where a TJ-like complex is termed the subapical region [reviewed in [3]]. Together with other integral membrane partners, such as occludin and the junctional adhesion molecule 1 (JAM1), the tissue-specific expression of claudin proteins perform specialized epithelial or endothelial functions including maintenance of cell polarity and paracellular barrier functions. These latter topics have been covered in recent reviews [4], [5], [6].
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Specialized epithelial functions and tumor suppression
The female mammary gland is a robust system for studying the diverse functions of the tight junction complex, which must respond to hormonal signals to deploy specialized luminal functions, such as milk secretion [7]. We hypothesize that the homotypic or heterotypic interactions and cell-specific expression of the various claudins contributes to unique functions. For example, we detect CLDN1 protein at the lateral membranes of luminal glandular cells but not in the myoepithelial cells (Fig. 1).
Claudins in human cancer
To date, five individual claudin genes have been evaluated in primary human tumors (Table 1). In this tabulation we've excluded published literature on cancer cell lines or reports from microarray studies wherein validation studies were not performed. Our compilation indicates that, depending upon the type of neoplasia, claudin proteins may be diminished, elevated or mislocated in tumor cells compared to normal adjacent cells or the tissue wherein the tumor arose.
Signaling pathways involving tight junctions
Primary and second messenger signal transduction phosphorylation cascades may mediate TJ activity. This topic has previously been reviewed in this journal, where Clarke et al. hypothesized that phosphorylation of claudins occurs [43]. Because claudin strands are localized with a plaque of intracellular anchoring and signaling molecules [5], disruption of any one of these proteins in specialized tissues could have profound effects on localization, function and expression of CLDN genes and
CLDN and TJ manipulation for future drug delivery
Recent reports suggest two means by which claudin proteins might be targeted for cancer therapeutics. For those tumors that show loss of specific claudin (e.g., CLDN3 and CLDN4) expression, future gene therapy with specific claudin cDNAs that target tumor tissue is suggested.
Perspectives
Claudins play a central role in tight junction homeostasis and barrier formation. As a result, expression and proper homing of native claudins in a differentiated epithelial tissue or endothelium may be the first line of defense against invasive, circulating carcinomas, during the processes of intravasation and extravasation. We used immunohistochemical staining to detect CLDN1 in tissue microarrays, which included breast, prostate, and colon carcinomas. Unexpectedly, we found that a high
Acknowledgements
Preparation was supported in part by the University of Washington Medical Center Breast Program Tennis Tournament. We thank Brett Wallden and Mari Swift for a critical reading of the manuscript.
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