Abstract
Primary tumours, particularly from major solid organs, are able to disseminate into the blood and lymphatic system and spread to distant sites. These secondary metastases to other major organs are the most lethal aspect of cancer, accounting for the majority of cancer deaths. The brain is a frequent site of metastasis, and brain metastases are often fatal due to the critical role of the nervous system and the limited options for treatment, including surgery. This creates a need to further understand the complex cell and molecular biology associated with the establishment of brain metastasis, including the changes to the environment of the brain to enable the arrival and growth of tumour cells. Local changes in the vascular network, immune system and stromal components all have the potential to recruit and foster metastatic tumour cells. This review summarises our current understanding of brain vascular microenvironments, fluid circulation and drainage in the context of brain metastases, as well as commenting on current cutting-edge experimental approaches used to investigate changes in vascular environments and alterations in specialised subsets of blood and lymphatic vessel cells during cancer spread to the brain.
Highlights
In the case of solid tumours, the most lethal attribute of cancer is the ability of tumour cells to escape the primary tumour and metastasise via blood and lymphatic vessels to distant organs
It has been speculated that the frequency of brain metastasis diagnoses has steadily risen over time due both to ongoing improvements in imaging and detection technologies that allow for greater detection rates of brain metastases in asymptomatic patients, and improvements in systematic disease treatments that prolong survival and allow more time for brain lesions to develop [3,4]
We describe the current understanding of the cellular components of the metastatic tumour microenvironment in the brain, with a specific emphasis on tumour–vasculature interactions during the early events of tumour cell seeding in the brain and the formation of established metastatic lesions
Summary
Cancer arises when acquired or inherited mutations in the cells of the body result in uncontrolled cellular proliferation. Endothelial cells are adhered to each other via tight junctions and are surrounded by the endothelial basement membrane (BM) Perivascular supporting cells such as pericytes and vascular smooth muscle cells, collectively referred to as mural cells, together with astrocytic foot-processes further encapsulate the endothelial cells, anchored through an astrocytic basement membrane. This multi-layered barrier of cells and basement membrane only allows molecules of molecular weight less than 400–500 Da to passively diffuse into the parenchyma, working in synergy to regulate molecular and cellular trafficking across the brain vasculature, and maintaining homeostasis of the central nervous system (CNS) [7]. We comment on current cutting-edge experimental approaches used to support our understanding of the tumour–vascular interactions in brain metastasis
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