Context-Dependent Roles of Claudins in Tumorigenesis

Abstract

The barrier and fence functions of the claudin protein family are fundamental to tissue integrity and human health. Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation. Studies have uncovered that claudins engage in nearly all aspects of tumor biology and steps of tumor development, suggesting their promise as targets for treatment or biomarkers for diagnosis and prognosis. However, claudins can be either tumor promoters or tumor suppressors depending on the context, which emphasizes the importance of taking various factors, including organ type, environmental context and genetic confounders, into account when studying the biological functions and targeting of claudins in cancer. This review discusses the complicated roles and intrinsic and extrinsic determinants of the context-specific effects of claudins in cancer.

Keywords: cancer; claudin; metastasis; tight junction; tumor heterogeneity; tumorigenesis.

Figure 1

Antitumor role of claudins. The definitive mechanisms through which claudins suppress tumorigenesis have not been well established. Three possible mechanisms have been proposed: (A) When assembled into TJs, claudins prevent the passing of microorganisms, toxins and growth factors (GFs) through the paracellular space; otherwise, inflammation will occur, which is the most common predisposition for cancer, and GFs promote neoplastic transformation and growth by binding to their receptors on the basolateral membrane. (B) In TJ complexes, claudins bind and retain many other key elements of signaling pathways in the submembrane compartment to directly inhibit their activation or indirectly inhibit their activation through other scaffolding proteins (mainly ZOs). Of these molecules, YAP/TAZ, β-catenin, and PDK1 are all well-known oncogenic drivers. (C) Claudins in the basolateral membrane colocalize and form a protein complex with integrins to maintain epithelial cell attachment and suppress cell proliferation.

Figure 2

Protumor role of claudins. The mechanisms underlying tumorigenesis due to claudins have also not been well established. Studies mainly support the hypothesis that claudins activate various signaling pathways or proteases to promote tumorigenesis directly and indirectly. One direct pathway involves association with other molecules, such as epithelial cell adhesion molecule (EpCAM), membrane type-matrix metalloproteinases (MT-MMPs), disintegrin and metalloproteinase 10 (ADAM10) and integrins, which activate claudins to participate in signal transduction, extracellular matrix (ECM) degradation and receptor cleavage. Another direct way involves association with transcription factors (TFs) such as YAP/TAZ and β-catenin to induce the nuclear accumulation of these TFs, although the exact mechanisms through which claudins induce gene transcription are not clear. An indirect way in which claudins activate oncogenic pathways is proposed to require two kinds of molecules. One kind is proteases such as MMPs, which cleave the ECM to release GFs to activate the RTK/PI3K, MAPK, TGF-β/SMAD, and JAK/STAT pathways. Another indirect way is through protein kinases, such as SFK, ABL and Tyk2, which can phosphorylate downstream molecules involved in oncogenic pathways, although the mechanisms through which claudins activate these kinases are not clear. In addition, these signaling pathways are extensively interconnected at various levels, which integrate signaling from claudins to promote tumorigenesis. Although there have been studies that reported the effect of claudins on some of the molecules shown, the exact mechanisms involved are not known (represented by dashed line arrows in the figure).

Figure 3

Claudins involved in the cancer invasion and metastasis cascade. (A) In primary tumors, disruption of claudin strands in tight junctions (TJs) is necessary for detachment of cancer cells. Some claudins upregulate metalloproteinases (MMPs) and induce epithelial-mesenchymal transition (EMT), which leads to basement membrane degradation, breaching, migration and local invasion. (B) Although cancer cells mainly enter the circulation through the lymphatic system, in some conditions, they can also intravasate into blood vessels through disruption of TJs between endothelial cells. (C) Claudins facilitate collective migration, which promotes the mutual survival of cancer cells, and claudin dysregulation has also been shown to confer tumor cell resistance to anoikis. (D) Claudins on endothelial cells have protective roles against metastasis through barrier function and blood-based interactions with claudins on cancer cells, disruption of which facilitates the extravasation of cancer cells into secondary tissues. (E) Establishment of macroscopic metastasis in distant tissues largely depends on the clone forming ability and mesenchymal-epithelial transition (MET) of disseminated tumor cells (DTCs). As chief molecules expressed in epithelial cells that have been demonstrated to maintain the cancer stem cell (CSC) phenotype, claudins inevitably participate in MET and metastatic colonization, although the mechanisms remain to be characterized in detail.

Figure 4

Factors that influence the expression and role of claudins in tumorigenesis at several levels. Intrinsic factors (molecular structures and physiology roles) and extrinsic factors (cell of origin, genetic background, tumor heterogeneity, cancer evolution, TME and environmental factors, experimental conditions and detection methods) determine the divergent expression patterns and roles in cancer.