Tight Junctions and the Tumor Microenvironment

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Abstract

Purpose of review

Tight junctions (TJs) are specialized differentiations of epithelial and endothelial cell membranes. TJs play an important role in the adhesion of cells and their interaction with each other. Most cancers originate from epithelial cells. Thus, it is of significance to examine the role of TJs in the tumor microenvironment (TME) and how they affect cancer metastasis.

Recent findings

In epithelium-derived cancers, intactness of the primary tumor mass is influenced by intercellular structures as well as cell-to-cell adhesion. Irregularities of these factors may lead to tumor dissociation and subsequent metastasis. Low expression of TJs is observed among highly metastatic cancer cells.

Summary

In this review, we summarized findings from current literature in consideration of the role of TJs in relation to the TME and cancer. Deeper understanding of the mechanisms leading to TJ dysregulation is needed to facilitate the design and conceptualization of new and better therapeutic strategies for cancer.

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Most cited references 76

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Claudin-based tight junctions are crucial for the mammalian epidermal barrier

Mikio Furuse, Masaki Hata, Kyoko Furuse … (2002)

The tight junction (TJ) and its adhesion molecules, claudins, are responsible for the barrier function of simple epithelia, but TJs have not been thought to play an important role in the barrier function of mammalian stratified epithelia, including the epidermis. Here we generated claudin-1–deficient mice and found that the animals died within 1 d of birth with wrinkled skin. Dehydration assay and transepidermal water loss measurements revealed that in these mice the epidermal barrier was severely affected, although the layered organization of keratinocytes appeared to be normal. These unexpected findings prompted us to reexamine TJs in the epidermis of wild-type mice. Close inspection by immunofluorescence microscopy with an antioccludin monoclonal antibody, a TJ-specific marker, identified continuous TJs in the stratum granulosum, where claudin-1 and -4 were concentrated. The occurrence of TJs was also confirmed by ultrathin section EM. In claudin-1–deficient mice, claudin-1 appeared to have simply been removed from these TJs, leaving occludin-positive (and also claudin-4–positive) TJs. Interestingly, in the wild-type epidermis these occludin-positive TJs efficiently prevented the diffusion of subcutaneously injected tracer (∼600 D) toward the skin surface, whereas in the claudin-1–deficient epidermis the tracer appeared to pass through these TJs. These findings provide the first evidence that continuous claudin-based TJs occur in the epidermis and that these TJs are crucial for the barrier function of the mammalian skin.

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Complex phenotype of mice lacking occludin, a component of tight junction strands.

Mitinori Saitou, Mikio Furuse, Hiroyuki Sasaki … (2000)

Occludin is an integral membrane protein with four transmembrane domains that is exclusively localized at tight junction (TJ) strands. Here, we describe the generation and analysis of mice carrying a null mutation in the occludin gene. Occludin -/- mice were born with no gross phenotype in the expected Mendelian ratios, but they showed significant postnatal growth retardation. Occludin -/- males produced no litters with wild-type females, whereas occludin -/- females produced litters normally when mated with wild-type males but did not suckle them. In occludin -/- mice, TJs themselves did not appear to be affected morphologically, and the barrier function of intestinal epithelium was normal as far as examined electrophysiologically. However, histological abnormalities were found in several tissues, i.e., chronic inflammation and hyperplasia of the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in striated duct cells of the salivary gland, and thinning of the compact bone. These phenotypes suggested that the functions of TJs as well as occludin are more complex than previously supposed.

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The tumour microenvironment as a target for chemoprevention.

Adriana Albini, Michael B. Sporn (2007)

New data indicate that primary dysfunction in the tumour microenvironment, in addition to epithelial dysfunction, can be crucial for carcinogenesis. These recent findings make a compelling case for targeting the microenvironment for cancer chemoprevention. We review new insights into the pathophysiology of the microenvironment and new approaches to control it with chemopreventive agents. The microenvironment of a cancer is an integral part of its anatomy and physiology, and functionally, one cannot totally dissociate this microenvironment from what have traditionally been called 'cancer cells'. Finally, we make suggestions for more effective clinical implementation of this knowledge in preventive strategies.

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Author and article information

Contributors

Carola Y. Förster: + 49 931 201 30065 , Foerster_C@ukw.de

Journal

Journal ID (nlm-ta): Curr Pathobiol Rep

Journal ID (iso-abbrev): Curr Pathobiol Rep

Title: Current Pathobiology Reports

Publisher: Springer US (New York )

ISSN (Electronic): 2167-485X

Publication date (Electronic): 1 July 2016

Publication date PMC-release: 1 July 2016

Publication date (Print): 2016

Volume: 4

Pages: 135-145

Affiliations

Department of Anesthesia and Critical Care, University of Wurzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany

Article

Publisher ID: 106

DOI: 10.1007/s40139-016-0106-6

PMC ID: 4978755

PubMed ID: 27547510

SO-VID: 18a69823-4f6b-4f6f-a142-d28da947fdb5

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Keywords: tight junctions,intercellular permeability,tumor microenvironment,metastasis,cancer

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Keywords: tight junctions, intercellular permeability, tumor microenvironment, metastasis, cancer

Tight Junctions and the Tumor Microenvironment

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Abstract

Purpose of review

Recent findings

Summary

Related collections

Karger: Oncology

Most cited references 76

Claudin-based tight junctions are crucial for the mammalian epidermal barrier

Complex phenotype of mice lacking occludin, a component of tight junction strands.

The tumour microenvironment as a target for chemoprevention.

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Contributors

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