Genes that Mediate Metastasis across the Blood-Brain Barrier

Abstract

Brain metastasis is an important cause of mortality in patients with cancer and represents the majority of all intracranial tumors. A key step during the metastatic journey of the cancer cell to the brain is the invasion through the blood-brain barrier (BBB). Nevertheless, the molecular mechanisms that govern this process remain unknown. The BBB has been blamed for limiting the access of therapeutic drugs to the brain, which provides a safe haven for cancer cells in the brain and confers poor prognosis for the patient. Here, we explore the genes that control the transmigration of metastatic cancer cells across the BBB, offering new targets for the development of gene and cell therapies against brain metastases.

Keywords: blood–tumor barrier; brain metastases; cancer; paracellular migration; tight junctions; transcellular migration.

Figure 1:. Anatomy and pathophysiology of the blood-brain barrier.

The metastatic cancer cell faces the BBB on its way to the brain. This barrier consists of multiple layers of different cell types that restrict the entrance of large macromolecules into the brain parenchyma. The innermost layer is formed by endothelial cells, which contain different transporters in their membranes and are connected through tight junctions. Pericytes attach to the abluminal site of the endothelial cells and are embedded in a sheet of extracellular matrix (ECM). The outermost layer consists of the end-feet of astrocytes. While the BBB restricts the entry of many molecules and cells, it is not an impenetrable barrier to transmigration of metastasizing cancer cells (1). Indeed, in this regard, it has been proposed that the brain can function as a sanctuary site for metastatic cells that effectively breach the BBB, where they are subsequently protected from the effects of chemotherapy and other agents that cannot penetrate the brain (2). Eventually, metastasizing cancer cells colonize their new microenvironment and grow into macrometastases (3).

Figure 2:. Mechanisms of transmigration across the blood-brain barrier.

Metastatic cells utilize different approaches to cross the multiple cell layers that constitute the blood-brain barrier (BBB). Passage through the paracellular route (left) includes proteolysis of junctional adhesion molecules, such as JAM-B, using proteases and serum factors or intercalation between the layers of endothelial cells and disrupting the integrity of the BBB. The transcellular pathway (right) involves strong adhesion through integrins and the formation of a channel or a pore within the endothelial cell that allows the transmigration of the invading cancer cell into the brain.

Figure 3:. Anatomy of the tight junction.

Tight junctions between endothelial cells are formed by transmembrane proteins, such as junctional adhesion molecules (JAMs), cadherins, claudins, and occludins, and by cytosolic proteins, such as catenins and zonula occludens (ZO) proteins.