Tight Junctions and the Tumor Microenvironment

Curr Pathobiol Rep (2016) 4:135–145 DOI 10.1007/s40139-016-0106-6 LEAKY JUNCTIONS IN CANCER (CHRIS CAPALDO, SECTION EDITOR) Tight Junctions and the Tumor Microenvironment Ellaine Salvador1 • Malgorzata Burek1 • Carola Y. Förster1 Published online: 1 July 2016  The Author(s) 2016. This article is published with open access at Springerlink.com 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. Keywords Tight junctions
Intercellular permeability
Tumor microenvironment
Metastasis
Cancer Introduction Since epithelial cells line hollow organs, they are prone to damage and are much exposed to carcinogens in the environment. For this reason, they demand high renewal rate. Due to their vulnerability, about 90 % of human cancers originate from the epithelial tissues [1•]. Constant remodeling of cell-to-cell contacts takes place for renewal and replacement of old or damaged cells. In addition, this process helps to incorporate newly differentiated cells without compromising the integrity of the barrier [2]. In epithelium-derived cancers, intactness of the primary tumor mass is influenced by intercellular structures as well as cell-to-cell adhesion [3]. These factors should be maintained since irregularities may lead to tumor dissociation and subsequent metastasis [4]. Tight junctions (TJs) are among those that preserve cell adhesiveness in this tumor mass. Therefore, alterations in the TJs present could result to split of the tumor mass [5]. In addition, TJs also suppress cell proliferation [6]. Owing to these facts, research has focused greatly in drawing the link between TJs and the tumor microenvironment (TME). In this review, we surveyed current literature in consideration of the role of TJs in relation to the TME and cancer. This article is part of the Topical collection on Leaky Junctions in Cancer. Characteristics of Tight Junctions & Carola Y. Förster Tight junctions (TJs) are specialized differentiations of epithelial cell membranes [5]. They form a continuous intercellular barrier between epithelial cells and separate tissue spaces which regulate selective transport across the epithelium [7•]. 1 Department of Anesthesia and Critical Care, University of Wurzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany 123 136 TJs serve various functions. Foremost, they seal intercellular spaces and separate the apical and basolateral fluid compartments of epithelia and endothelia. They regulate epithelial and endothelial cell permeability and act as points of contact between the plasma membranes of neighboring cells, occluding the extracellular space. They also act as cell-to-cell adhesion molecules. They play a role in cell adhesion and paracellular barrier functions and form an intercellular barrier and an intramembrane diffusion fence [5]. The diffusion of solutes is regulated by TJs through size and charge selectivity and differs depending on epithelial cell type. TJs are impermeable to most macromolecules but are permeable to inorganic ions. As such, TJs, together with adherens junctions and desmosomes, maintain the integrity of the epithelial cell layer and protect multicellular organisms from the external environment [5]. In addition, they play a role in cell polarity, differentiation, growth and proliferation through their involvement in cell signaling processes. They are suggested to be involved in the regulation of cell proliferation by controlling epithelial cell microenvironment [8]. Due to this, they are able to suppress malignant phenotype of cells during tumorigenesis. Furthermore, they function as cell migration barrier. Their functions are shown to be regulated by phosphorylation. A link between barrier disruption due to TJ dysfunction and disease has long been established [9]. The main cause of lethality among cancer patients is metastasis [10]. Metastasis takes place with various prerequisites. Primarily, cancer cells need to be able to surmount the barriers, mostly epithelial and endothelial tissues consisting of cells bound together by tight junctions (TJs). Dissociated cells provide easy access to metastasizing cancer cells. Therefore, the intactness of TJs helps prevent cell dissociation [11, 12]. Tight Junctional Components Transmembrane proteins occludin, claudins, junctional adhesion molecules (JAMs), and tricellulin as well as intracellular scaffold proteins like zonula occludens (ZO) and cingulin comprise the molecular make-up of tight junctions (TJs). Transmembrane Proteins Occludin The first discovered molecular component of the TJs is occludin [13]. Although it was first suggested to form the structural unit of the TJs, it has later been found out that embryonic stem cells lacking occludin are still capable of 123 Curr Pathobiol Rep (2016) 4:135–145 forming TJ structures which shows that occludin is not indispensable for TJ structural assembly. To demonstrate this, occludin null mice were born without any signs of abnormal phenotype but later showed growth retardation. The TJs appear morphologically unaltered but histological abnormalities were observed in several tissues [14]. In addition, occludin knock-out mice manifest atrophic gastritis, testicular atrophy, male infertility, salivary gland dysfunction, osteoporosis, and brain calcifications [14, 15]. Apical-basal polarity is used to sense cell–cell contacts on epithelial surfaces. It has been observed that hippo pathway elements co-localize with occludin, creating a possible sensor system in pancreatic epithelial cells which may regulate their proliferation [16•]. It has been reported that epigenetic silencing of occludin could promote tumorigenic and metastatic properties of cancer cells [17]. For example, occludin was shown to inhibit Raf-1 signaling which induces tumor growth [18]. A low level of occludin expression results to an increased progression and metastatic potential in breast, ovarian, endometrial, and liver carcinoma [19–22]. The increased metastatic potential, however, might not (...truncated)