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.

Frequency of Silent Brain Metastasis Before Prophylactic Cranial Irradiation in Small Cell Lung Cancer

“…Most chemotherapeutic agents cannot pass through the blood-brain barrier [7,8]. Because of that, the brain is considered the first site of recurrence in an aggressive tumor such as SCLC.…”

Antidepressant use and risk of central nervous system metastasis

“…The endothelial cells of the BBB may allow brain metastases to pass through and even help facilitate this process by aiding metastatic growth. Additionally, the cancerous cells are protected from the immune system as they attempt to pass through the BBB [105].…”

Blood-brain Barrier Remodeling during Brain Metastasis Formation

“…A growing body of evidence suggests that the majority of tumor cells arrest in capillaries of a similar diameter, indicating that physical restriction initially plays the crucial role, and the stable attachments form in the following stage (27,34). Tumor cells metastasizing to the brain usually arrest via the bloodstream (31). Because of the existence of the BBB, to migrate into the brain tissue, tumor cells need markedly more time compared with other organs (31,32).…”

“…Tumor cells metastasizing to the brain usually arrest via the bloodstream (31). Because of the existence of the BBB, to migrate into the brain tissue, tumor cells need markedly more time compared with other organs (31,32). For instance, it has been reported that ~48 h is required for lung cancer cells to extravasate into the brain, whereas extravasation into the liver takes only 6 h for the same tumor cells (33).…”

“…endothelial barrier using the paracellular or transcellular route (31). Regardless of the exact mechanism, the process of extravasation requires dynamic changes to tumor cell shape, as well as formation of specific protrusive structures that facilitate the migration (37) (29,49).…”