Role of the blood-brain barrier in the formation of brain metastases

Abstract

The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to transmigrate through the endothelial cell layer of brain capillaries, which forms the morphological basis of the blood-brain barrier (BBB). The BBB has a dual role in brain metastasis formation: it forms a tight barrier protecting the central nervous system from entering cancer cells, but it is also actively involved in protecting metastatic cells during extravasation and proliferation in the brain. The mechanisms of interaction of cancer cells and cerebral endothelial cells are largely uncharacterized. Here, we provide a comprehensive review on our current knowledge about the role of junctional and adhesion molecules, soluble factors, proteolytic enzymes and signaling pathways mediating the attachment of tumor cells to brain endothelial cells and the transendothelial migration of metastatic cells. Since brain metastases represent a great therapeutic challenge, it is indispensable to understand the mechanisms of the interaction of tumor cells with the BBB in order to find targets of prevention of brain metastasis formation.

Figure 1

Schematic structure of the blood-brain barrier. Cerebral endothelial cells—coming in contact with pericytes and astrocytes—form the morphological basis of the blood-brain barrier. Endothelial cells are interconnected by a continuous line of tight junctions. The insert shows the molecular structure of the junctional complex. TJ = tight junction; AJ = adherens junction.

Figure 2

Mechanisms of interaction between tumor cells and the brain endothelium. (a) Morphological aspects and upregulated genes and proteins involved in brain metastasis formation of melanoma, breast and lung cancer; (b) Molecular mechanisms. Several adhesion molecules were shown to be involved in the adhesion of tumor cells to the brain endothelium. Proteases and other soluble factors secreted by tumor cells may induce the disruption of the tight junctions.

Figure 2

Mechanisms of interaction between tumor cells and the brain endothelium. (a) Morphological aspects and upregulated genes and proteins involved in brain metastasis formation of melanoma, breast and lung cancer; (b) Molecular mechanisms. Several adhesion molecules were shown to be involved in the adhesion of tumor cells to the brain endothelium. Proteases and other soluble factors secreted by tumor cells may induce the disruption of the tight junctions.