Claudin Proteins in Human Cancer: Promising New Targets

The tight junction proteins claudins are abnormally regulated in several human cancers. In particular, claudin-3 and claudin4 are frequently overexpressed in several neoplasias, including ovarian, breast, pancreatic, and prostate cancers. Although the exact roles of these proteins in tumorigenesis are still being uncovered, it is clear that they represent promising targets for cancer detection, diagnosis, and therapy. (Cancer Res 2005; 65(21): 9603-6) Claudins Are Tight Junction Proteins Tight junctions, together with adherens junctions and desmosomes, form the apical junctional complex in epithelial and endothelial cellular sheets. Adherens junctions and desmosomes are responsible for the mechanical adhesion between adjacent cells, whereas tight junctions are essential for the tight sealing of the cellular sheets, thus controlling paracellular ion flux and therefore maintaining tissue homeostasis (1). Tight junctions also play a crucial role in the maintenance of cell polarity by forming a fence that prevents lateral diffusion of membrane proteins and lipids, thereby maintaining the differential composition of the apical and basolateral domains. Finally, because of the ability of tight junction proteins to recruit signaling proteins (2), tight junctions have also been hypothesized to be involved in the regulation of proliferation, differentiation, and other cellular functions. When observed by electron microscopy, tight junctions form multiple strands that seem to provide the structural basis for adhesion between adjacent cells (1). Tight junctions are composed of three major integral membrane proteins, occludin, claudins, and junctional adhesion molecules. Although the exact roles of these proteins are not completely clear, it seems that the claudins form the backbone of the tight junction strands. The claudin family of proteins is comprised of 23 members of closely related transmembrane proteins (see Fig. 1). Although the expression pattern of claudins is tissue specific, most tissues express multiple claudins, which can interact in both homotypic and heterotypic fashion to form the tight junction strands. It is believed that the exact combination of claudin proteins within a given tissue can determine the selectivity and strength of the tight junctions. Claudins are polymerized together within a given cell and can interact with the claudin of the adjacent cells to form an adhesive structure. The high degree of cellular organization typically observed in normal differentiated tissues is often lost in cancer. Tumor cells frequently exhibit abnormal tight junction function as well as decreased differentiation and cell polarity (3, 4). Loss of tight junction integrity may be particularly important in allowing the diffusion of nutrients and other factors necessary for the survival and growth of the tumor cells (5). In addition, decreased polarity and differentiation may be important for the metastatic phenotype, where individual cells must leave the primary site and enter the blood vessels to reach distant sites (6). Finally, the destruction of functional tight junctions in cancer may have a role in growth control. For example, in Drosophila , mutations in many tumor suppressor genes lead to loss of cell polarity and overproliferation of the epithelia (7). Based on the similarity between the vertebrate and Drosophila epithelia, mammalian cells are likely to require cytoarchitectural cues for cell growth control as well. Claudin Expression in Cancer The expression of occludin and claudins, the two major transmembrane proteins that contribute to formation of tight junctions, has been found to be altered in several cancers. An early study in the field showed that occludin was often downregulated in gastrointestinal tumors (8). Similarly, other studies have shown that claudins are down-regulated in various cancers. For example, claudin-1 has been found to be reduced in breast cancer (9, 10) as well as in colon cancer (11). Claudin-7 has also been found down-regulated in invasive breast cancer (12) and in head and neck cancer (13). These reports of decreased tight junction protein expression in cancer are consistent with the generally accepted idea that tumorigenesis is accompanied by a disruption of tight junctions, a process that may play an important role in the loss of cohesion, invasiveness, and lack of differentiation observed in cancer cells. In addition to the downregulation of protein levels, phosphorylation of tight junction proteins, including claudins, may affect tight junction function in cancer (14). For example, phosphorylation of claudin-1 by mitogen activated protein kinases (15) and protein kinase C (16), as well as phosphorylation of claudin-5 by cyclic AMP– dependent protein kinase (17, 18) have been reported. Also, WNK4 kinase has been shown to phosphorylate claudin-3 and claudin-4, and decrease tight junction function (19). Interestingly, phosphorylation of claudin-3 and claudin-4 in ovarian cancer cells has been shown to disrupt tight junctions (20). Paradoxically, other studies have shown that certain claudin proteins are up-regulated in cancer. In fact, the overwhelming majority of the studies published thus far report an overexpression of claudins in various cancers (see Table 1). One of the first studies reporting this fact was a serial analysis of gene expression (SAGE) study of ovarian cancer showing that CLDN3 and CLDN4 (encoding claudin-3 and claudin-4, respectively) were among the most highly up-regulated genes in this cancer (21). Several additional reports have since confirmed the high Requests for reprints: Patrice J. Morin, Laboratory of Cellular and Molecular Biology, National Institute on Aging, NIH, Box 12, 5600 Nathan Shock Drive, Baltimore, MD 21224. Phone: 410-558-8506; Fax: 410-558-8386; E-mail: [email protected]. I2005 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-05-2782 www.aacrjournals.org 9603 Cancer Res 2005; 65: (21). November 1, 2005 Review American Association for Cancer Research Copyright © 2005 on February 23, 2013 cancerres.aacrjournals.org Downloaded from DOI:10.1158/0008-5472.CAN-05-2782