The role of claudin-5 in blood-brain barrier (BBB) and brain metastases (Review)

Abstract

Metastatic brain tumours are frequently observed in patients with lung, breast and malignant melanoma and a severe complication of metastatic cancers. With improved primary cancer treatments, including surgery, radiation therapy and chemotherapy, patients are now living longer following initial treatment, compared with previous treatments. Brain metastasis (BM) remains a significant clinical issue. Since BM represents a major therapeutic challenge, it is vital that the mechanisms of interaction between tumour cells and the blood‑brain barrier (BBB), as well as the method by which tumour cells establish metastatic tumours in the brain, are understood. A key step in BM is the interaction and penetration of the BBB by cancer cells. The BBB consists of endothelial cells, pericytes, astrocytes and a number of molecular structures between these cells. The BBB relies on the tight junctions (TJs) that are present between the endothelial cells of the brain capillaries to provide a closed environment for the brain. TJs comprise a number of proteins, including occludin, claudins and junctional adhesion molecules (JAMs). Among them, claudins are the key integral proteins that regulate BBB permeability. It has previously been shown that claudin‑5, not only regulates paracellular ionic selectivity, but also plays a role in the regulation of tumour cell motility, suggesting that TJs and claudin‑5 contribute to the control of BM. This study reviews the role of claudin‑5 in the regulation of BBB permeability during the brain metastatic process.

Exercise maintains blood–brain barrier integrity during early stages of brain metastasis formation

“…The claudin family of proteins has 24 members identified; mainly located in endothelial and epithelial cells, with claudin-5 being the most abundant type found in brain endothelium [6,15]. The selectivity of claudin-5 expression in brain endothelial cells suggests it plays a crucial role in BBB function [6].…”

“…The selectivity of claudin-5 expression in brain endothelial cells suggests it plays a crucial role in BBB function [6]. Indeed, it has been demonstrated that claudin-5 participates in modulating permeability to ions as well as macromolecules [21,22].…”

“…Indeed, it has been demonstrated that claudin-5 participates in modulating permeability to ions as well as macromolecules [21,22]. Several studies indicated that increased permeability of the BBB was accompanied by decreased claudin-5 expression [6]. Interestingly, it was demonstrated that Rho kinase (ROCK) could induce phosphorylation of claudin-5 (and occludin) leading to TJ disruption and promoting monocyte migration through the BBB in a model of HIV-1 encephalitis [23,24].…”

“…Particularly in the brain, where the blood-brain barrier (BBB) selectively restricts both tumor cell trafficking and therapeutic interventions, it is imperative that regulatory mechanisms underlying that selectivity be better understood [5]. Lung and breast tumors as well as melanoma are the most common sources of brain metastases [6]. However the majority of exercise and cancer data comes from breast cancer followed by gastrointestinal and then prostate [3].…”

Challenges in the Delivery of Therapies to Melanoma Brain Metastases

“…The invasion and growth of tumor cells in the brain parenchyma is facilitated by the interaction of metastatic cells with the BBB endothelial cells and surrounding ECM components (Fidler 2015; Jia et al 2014; Wilhelm et al 2013; Fidler 2011). The high percentage of MBM from advanced melanoma as compared to other solid tumors is suggestive of a possible brain tropism of metastatic melanoma (Zakrzewski et al 2011).…”