Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk

Abstract

The ability of epithelial cells to organize through cell-cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.

Keywords: claudin; metastasis; signaling molecules; tight junction; tumor.

Figure 1

Epithelial intercellular junctions. Schematic drawing of the epithelial junction in vertebrate cell. The tight junctions, adherens junctions and gap junctions are located in the apical most region of the cell while the desmosomes are located toward the basal regions.

Figure 2

Schematic/proposed signaling model in a cell during tumor formation. Aberrant change in signaling pathways result in the resistance of the normal cellular apoptosis and/or senescence in a cell which is destined to be a tumor cell. The anti-apoptotic proteins belonging to the bcl2 family are upregulated. The tight junction complex changes its course of normal function of selective permeability to unrestricted flow to various unintended solutes/growth/cytokine factors which may be responsible in up regulation of survival signaling pathways. The expression and/or phosphorylation of growth factor/cytokine receptors which promote cell growth are enhanced. The PI3-K/Akt pathway, which is a survival pathway, becomes activated along with the RAS-RAF-ERK pathway and Wnt/beta-catenin pathway which result in the up regulation of several growth response genes.

Figure 3

Schematic/proposed signaling model of role and regulation of claudins in a cell during invasive or metastatic stage. Deregulated claudin expression and delocalization occurs as a consequence of epigenetic factors, growth factors and cytokines, inducing loss of “gate and barrier” function and thereby promoting inflammation, EMT and disease progression. Once the cell is destined to be a tumor cell, it further becomes more aggressive. During this stage, the well-regulated junctional molecules between cells become more and more permissible to various factors responsible for the up regulation of the survival, rapid growth and proliferative signaling pathways. Also, the inhibitor for apoptosis (IAP) proteins, which are critical for inhibiting cancer cell death and promoting their survival, are also upregulated. Further, along with the PI3-K/Akt and RAS-RAF-ERK pathways, NOTCH pathway is also upregulated which further enhances the growth potential of the cancer cell. Further, tight junctional protein, such as claudin-1 is associated with beta-catenin and help in the enhanced translocation of beta catenin into the nucleus. At this stage both the NOTCH and the Wnt pathway act in co-ordination to enhance the metastatic potential of the cancer cell.

Figure 4

Schematic presentation of healthy and leaky gut. Epithelial tight junctions are intact in a healthy gut and selectively lets some molecules in and out of the intestinal epithelium by functioning as a seal between the neighboring gut cells, hence maintaining homeostasis. Factors such as proinflammatory mediators, microbial gut imbalance, infections, some foods, exposure to chemicals, toxins, or stress may disrupt epithelial tight junctions and increase the intestinal permeability, as well as possibly damage the intestinal barrier by forming tissue lesions and punctures that could lead to a leaky intestinal epithelium. This whole sequence of events may lead to the translocation of undesired luminal gut content (microorganisms, toxins, undigested food particles) into the host tissues activating an immunological response.

Figure 5

Schematic representation of claudin interaction with adhesion molecules and signaling proteins. Claudins and claudin containing complexes influence diverse signaling processes within cancer cells that results in altered migration, invasion and metastasis. Claudins either interact directly with other adhesion molecules or recruit signaling proteins to execute their diverse array of functions.