A Blazing Landscape: Neuroinflammation Shapes Brain Metastasis

Abstract

Brain metastases are more common than primary CNS tumors, and confer grave prognosis on patients, as existing treatments have very limited efficacy. The tumor microenvironment has a central role in facilitating tumorigenesis and metastasis. In recent years, there has been much progress in our understanding of the functional role of the brain metastatic microenvironment. In this review we discuss the latest advances in brain metastasis research, with special emphasis on the role of the brain microenvironment and neuroinflammation, integrating insights from comparable findings in neuropathologies and primary CNS tumors. In addition, we overview findings on the formation of a hospitable metastatic niche, and point out the major gaps in knowledge towards developing new therapeutics that will co-target the stromal compartment, in an effort to improve the treatment and prevention of brain metastases.

Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain

“…Although the use of immune checkpoint inhibitors targeting PD-1 and/or CTLA-4 has nowadays become an established therapy in melanoma, it is still critical to transfer our knowledge from extracranial sites to intracranial melanoma lesions with respect to the unique "immune-specialized" microenvironment of the brain (54,55). After extravasation of tumor cells into the brain parenchyma they enter a fundamentally different tissue environment with respect to the metabolic situation, the cellular compositions, the brain-specific extracellular matrix proteins and the immunoreactive heterogenous cell population with regard to the primary site of their origin (56).…”

Neurofilament Light Chain as A Biomarker for Brain Metastases

“…While the specific nature of NfL liberation after neuronal damage is unknown, elevations have been observed in a variety of mechanisms from trauma [ 9 , 13 ], degenerative processes [ 7 , 10 , 14 ], ischemia/anoxia [ 11 , 15 ], human immunodeficiency viruses-infections [ 16 ] and hematoma compression [ 17 ]. Hence, a release of NfL would be expected as a consequence of the neuronal damage caused by the infiltration of the brain metastasis in the brain parenchyma [ 18 ] and/or brain compression caused by the metastasis. In line with this, a recent study found elevated NfL levels in seven cancer patients with brain metastasis compared with healthy controls [ 19 ], which supports our findings.…”

High Mobility Group Box 1 in Human Cancer

“…Brain metastases are recognized as “one of the deadliest forms of tumor metastasis” [ 159 ], occurring most commonly in advanced malignancies that are associated with an intense systemic inflammatory response. These include breast and lung cancers, as well as melanoma [ 159 , 160 , 161 , 162 ].…”