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Dichotomous roles of claudins as tumor promoters or suppressors: lessons from knockout mice

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Abstract

Claudins are a family of integral tight junction proteins that regulate paracellular permeability in polarized epithelia. Overexpression or reduction of claudins can both promote and limit cancer progression, revealing complex dichotomous roles for claudins depending on cellular context. In contrast, recent studies demonstrating tumor formation in claudin knockout mouse models indicate a role for several claudin family members in suppressing tumor initiation. For example, intestine-specific claudin-7 knockout mice spontaneously develop atypical hyperplasia and intestinal adenomas, while claudin-18 knockout mice develop carcinomas in the lung and stomach. Claudin-4, -11, and -15 knockout mice show increased cell proliferation and/or hyperplasia in urothelium, Sertoli cells, and small intestinal crypts, respectively, possibly a precursor to cancer development. Pathways implicated in both cell proliferation and tumorigenesis include Yap/Taz and insulin-like growth factor-1 receptor (IGF-1R)/Akt pathways, among others. Consistent with the tumor suppressive role of claudins shown in mice, in humans, claudin-low breast cancer has been described as a distinct entity with a poor prognosis, and claudin-18-Rho GTPase activating protein 26 (CLDN18-ARHGAP26) fusion protein as a driver gene aberration in diffuse-type gastric cancer due to effects on RhoA. Paradoxically, claudins have also garnered interest as targets for therapy, as they are sometimes aberrantly expressed in cancer cells, which may or may not promote cancer progression. For example, a chimeric monoclonal antibody which targets cells expressing claudin-18.2 through antibody-dependent cell-mediated cytotoxicity has shown promise in multiple phase II studies. In this review, we focus on new findings supporting a tumor suppressive role for claudins during cancer initiation.

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Acknowledgements

This work was supported by the Hastings Foundation, research grants R35HL135747 (ZB) and HL114959 (BZ), from the National Institutes of Health and by The Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI research grant JP16K09574 (HK). Z. Borok is Hastings Professor and Edgington Chair in Medicine.

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  1. Department of Respiratory Medicine, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Hidenori Kage

  2. Division of Pulmonary, Critical Care and Sleep Medicine and Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, IRD 620, M/C 9520, Los Angeles, CA, 90089-9520, USA

    Per Flodby, Beiyun Zhou & Zea Borok

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  1. Hidenori Kage
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Kage, H., Flodby, P., Zhou, B. et al. Dichotomous roles of claudins as tumor promoters or suppressors: lessons from knockout mice. Cell. Mol. Life Sci. 76, 4663–4672 (2019). https://doi.org/10.1007/s00018-019-03238-7

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