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.
Highlights
Brain metastases constitute a significant part of intracranial tumors
Chemokines seem to be important in the brain metastasis formation of breast cancer cells as well, since the CXCR4/SDF1 signaling pathway was shown to have a decisive role in the migration of breast cancer cells through brain endothelial monolayers [99]
Different proteolytic enzymes have been implicated in brain metastasis formation and migration of tumor cells through blood-brain barrier endothelial cells
Summary
Brain metastases constitute a significant part of intracranial tumors. Only in the United States, about. 170,000 metastatic brain tumors are diagnosed annually [1], whereas primary tumors represent 17,000 new cases/year. The majority of brain metastases originate from lung cancer (40%–50%), breast cancer (15%–25%) and malignant melanoma (5%–20%) [2]. Among these tumors, melanoma is the one which metastasizes to the brain with one of the highest frequencies: brain metastases are diagnosed in 40%–50% of the cases, which, after autopsy, increase with an additional 30%–40%. Since the CNS lacks a lymphatic system, the only possibility for cancer cells to reach the brain is via the blood stream. Metastatic cells invading the CNS parenchyma, have to pass the blood-brain barrier (BBB)
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