Table 1.

Unique aspects of brain metastasis formation.

Unique aspect of brain metastasis formation	Description	Remarks	References
Lack of classical lymphatic vasculature in the brain parenchyma (only hematogenous dissemination of metastatic cells)	Extravasation of tumor cells through vessels of the 1. brain parenchyma or 2. choroid plexus	Molecular mechanisms of transmigration of tumor cells through fenestrated capillaries of the choroid plexus and through the blood–cerebrospinal fluid are largely uncharacterized	219
Interaction of metastatic cells with endothelial cells of the BBB	1. Metastatic cells have to overcome this tight cellular barrier; 2. The brain endothelium may support transmigration and growth of tumor cells in the CNS	Janus-faced role of the neurovascular unit
Unique immunology of the brain (partially immune privileged organ)	Immune cells may have both supporting and inhibitory effects on tumor cells	Brain metastases harbor an active inflammatory microenvironment dependent on both resident microglia and infiltrating leukocytes	220,221
Highly specific neural environment	Both cellular (e.g. astrocytes and microglial cells) and non-cellular elements (extracellular matrix, growth factors, etc.) of the brain parenchyma influence the fate of tumor cells, being either harmful or protective	Janus-faced role of the neurovascular unit