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Malone et al. J Cancer Metastasis Treat 2021;7:40 https://dx.doi.org/10.20517/2394-4722.2021.37 Page 7 of 18

OUTGROWTH
The metabolically-flexible breast cancer cells that colonize the brain have the ability to utilize glutamine as
energy source, upregulate factors like the glucose regulated protein 94 (GRP94), and regulate the process of
autophagy. The events allow the cells to grow and form the metastatic lesion at target site of the brain. This
[53]
regulation of autophagy has been recognized as an attractive strategy to target BCBM . Amplification of
epidermal growth factor receptor (EGFR) in the cancer cells is associated with loss of PTEN, which both
[62]
promotes survival and regulates c-Myc to facilitate metabolic reprogramming . A critical factor for the
colonizing cancer cells is their ability to modify their exposure to immune attack by changing the expression
of MHC I, of the ligands of NK cells and effector T cells, as well as the cGAS-Sting and cytosolic DNA-
sensing pathways, and damage-associated RNAs as ligands for pattern-recognition receptors. Modifying the
presumptive tumor microenvironment to support the infiltrating tumor cells becomes a necessary step for
[63]
the outgrowth of the breast cancer cells in the brain .

DEFINING THE PRE-METASTATIC NICHE
To successfully form secondary tumors in organs distant from the primary neoplasm, tumor cells require a
permissive environment to seed and grow. The pre-metastatic niche is defined as a supportive environment
in a tissue prior to tumor spread. The formation of a pre-metastatic niche was first described when
hematopoietic progenitor cells expressing vascular endothelial growth factor receptor 1 (VEGFR1) localized
and clustered at pre-metastatic sites prior to the arrival or detection of tumor cells [64-66] . Appropriate
expression of matrix metalloproteases and deposition of fibronectin are thought to contribute to the
permissive environment of the pre-metastatic niche .
[66]

In addition to the bone marrow-derived progenitor cells, tumor cell-derived factors also play a role in the
preparation of the pre-metastatic niche in a distant organ. These factors secreted by the tumor cells include
both soluble factors, such as cytokines, and extracellular vesicles (EV) that interact with and influence cells
within the pre-metastatic niche. Through these interactions, the secreted factors are involved in the
processes of cell activation, extracellular matrix remodeling, and overall priming of the pre-metastatic
niche [5,67-70] . Analysis of the secretome of a tumor can be useful to define these interactions and for
therapeutic purposes as it can provide biomarkers for tumor progression and potential targets to inhibit the
[71]
interactions between the secreted macromolecules and resident cells of the pre-metastatic niche .
RESIDENT CELL CONTRIBUTIONS TO THE ESTABLISHMENT OF THE BRAIN
PREMETASTATIC NICHE
Within the brain microenvironment microglia, astrocytes, pericytes, neurons, and endothelial cells all
interact through a network of cell signaling that results in changes in both gene expression and secretome
[Figure 2]. Crosstalk between these CNS-residing cells and circulating tumor cells can result in the
establishment of a more favorable environment for metastatic colonization [Figure 3] . All cells within the
[72]
microenvironment collaborate to prime the premetastatic niche. Recent analyses of the eventual
microenvironment around brain tumors have indicated that the resident CNS cells respond differently to
primary brain tumors vs secondary, metastatic tumors, with the latter, and specifically the breast metastases,
characterized by significant accumulation of neutrophils .
[73]

Microglia are the resident innate immune cells located in the brain. Although they are known to become
activated by exaggerated CNS stimulation and pathological conditions, but until recently little was known
about their involvement in the formation of brain metastases [74,75] . Microglia remain in a resting state
constantly surveying the CNS parenchyma. Upon pathological stimulation they are activated and shift into
phenotypes that have been termed either M1 or M2 [76,77] . Similar to tumor associated macrophages,