Role of claudins in tumorigenesis

https://doi.org/10.1016/j.addr.2005.01.006Get rights and content

Abstract

The family of more than 20 claudin (CLDN) proteins comprises one of the major structural elements within the apical tight junction apparatus, a dynamic cellular nexus for maintenance of a luminal barrier, paracellular transport, and signal transduction. Loss of normal tight junction functions constitutes a hallmark of human carcinomas. CLDN1 may support tumor suppressive functions in tissues such as the brain, where dramatic loss of expression has been demonstrated in glioblastoma multiforme. The role(s) for CLDNs 3 and 4 in tumorigenesis is less clear. CLDN4 appears to be over-expressed in ovarian and pancreatic carcinomas, and this raises the possibility that a unique, potentially non-toxic cancer cell target may be developed through the design of enterotoxin analogues. Future goals include understanding the biochemical and physiological mechanisms that are perturbed as a consequence of CLDN alterations in the progression of solid tumors.

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].

Section snippets

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.

References (58)

  • H. Chiba et al.

    Hepatocyte nuclear factor (HNF)-4alpha triggers formation of functional tight junctions and establishment of polarized epithelial morphology in F9 embryonal carcinoma cells

    Exp. Cell Res.

    (2003)
  • J. Mankertz et al.

    Functional crosstalk between Wnt signaling and Cdx-related transcriptional activation in the regulation of the claudin-2 promoter activity

    Biochem. Biophys. Res. Commun.

    (2004)
  • K. Hemavathy et al.

    Snail/slug family of repressors: slowly going into the fast lane of development and cancer

    Gene

    (2000)
  • H. Clarke et al.

    Modification of tight junction function by protein kinase C isoforms

    Adv. Drug Deliv. Rev.

    (2000)
  • S.V. Walsh et al.

    Modulation of tight junction structure and function by cytokines

    Adv. Drug Deliv. Rev.

    (2000)
  • T. Ishizaki et al.

    Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood–brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways

    Exp. Cell Res.

    (2003)
  • M. Fujibe et al.

    Thr(203) of claudin-1, a putative phosphorylation site for MAP kinase, is required to promote the barrier function of tight junctions

    Exp. Cell Res.

    (2004)
  • J. Weiske et al.

    The fate of desmosomal proteins in apoptotic cells

    J. Biol. Chem.

    (2001)
  • P. Michl et al.

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

    Gastroenterology

    (2001)
  • S.L. Kominsky et al.

    Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4

    Am. J. Pathol.

    (2004)
  • M. Furuse et al.

    Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin

    J. Cell Biol.

    (1998)
  • E. Knust et al.

    Composition and formation of intercellular junctions in epithelial cells

    Science

    (2002)
  • K. Matter et al.

    Signalling to and from tight junctions

    Nat. Rev., Mol. Cell Biol.

    (2003)
  • M. Itoh et al.

    The organization of tight junctions in epithelia: implications for mammary gland biology and breast tumorigenesis

    J. Mammary Gland Biol. Neoplasia

    (2003)
  • T. Hoevel et al.

    Reexpression of the TJ protein CLDN1 induces apoptosis in breast tumor spheroids

    Int. J. Cancer

    (2004)
  • J.M. Mullin

    Potential interplay between luminal growth factors and increased tight junction permeability in epithelial carcinogenesis

    J. Exp. Zool.

    (1997)
  • J.M. Mullin

    Epithelial barriers, compartmentation, and cancer

    Sci. STKE

    (2004)
  • A.E. Al Moustafa et al.

    Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells

    Oncogene

    (2002)
  • A. Cano et al.

    The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression

    Nat. Cell Biol.

    (2000)
  • Cited by (199)

    • Advances in targeted therapy for pancreatic cancer

      2023, Biomedicine and Pharmacotherapy
    • Target specific tight junction modulators

      2021, Advanced Drug Delivery Reviews
    • Claudin 18.2 as a novel therapeutic target

      2024, Nature Reviews Clinical Oncology
    View all citing articles on Scopus
    View full text