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Page 10 of 18 Malone et al. J Cancer Metastasis Treat 2021;7:40 https://dx.doi.org/10.20517/2394-4722.2021.37

heparan sulfate-associated growth factors, such as vascular endothelial growth factor A (VEGF-A) and
FGF-2 [104-106] . The contribution of neurotrophins has been linked either directly with the upregulation of
heparanase and its effects [107,108] , or by direct effects on neighboring cells in the CNS to promote a permissive
[109]
metastatic niche . Further, sub-populations of STAT3-expressing activated astrocytes can be identified
near the border of metastatic lesions within the brain that support continued metastatic growth through
[110]
suppression of the innate immune system . It remains unclear if this population is present prior to
metastatic colonization. An additional mechanism by which astrocytes interact with the metastatic cells is
through gap junctions that may form between protocadherin 7 on the metastatic cells and connexin 43 on
astrocytes. This interaction and the subsequent upregulation of survival genes, STAT1 and the NF-κB
signaling pathway, leads to the support of metastasis .
[111]

Pericytes surround the capillaries of the brain and have been described to have both signaling and barrier
roles. Hemodynamic modulation and blood brain barrier maintenance are among the most important .
[112]
The role of pericytes on primary brain tumors has been studied extensively and, in this context, elimination
of pericytes resulted in increase in vessel leakiness and blood supply . Previously, studies have shown an
[113]
inverse relationship between the number of pericytes and the likelihood of breast cancer metastasis to the
lungs [114,115] . A recent study conducted by Molnár et al. has reported that pericytes are crucial to the
[116]
development of TNBC-derived brain metastases. Pericytes directly interact with the metastatic cells by
secreting proteins of the extracellular matrix, insulin-like growth factors (IGFs), and other soluble factors
which have chemoattractant, adhesion-, and proliferation-enhancing effects. Insulin-like growth factor 2
(IGF2) is highly upregulated in pericytes and interacts with insulin-like growth factor 1 receptor (IGF1R) on
TNBC cells to promote proliferation. TNBC cells respond to the increased collagen type IV and fibronectin
secretion from pericytes by increasing intracellular focal adhesion kinase (FAK) and Src phosphorylation to
promote focal adhesion formation with the newly formed extracellular matrix. Intercellular adhesion is also
disrupted by pericytes which confers a migratory and invasive phenotype onto the metastatic TNBC
cells . Increased permeability of the blood brain barrier and experimental TNBC metastasis to the brain
[116]
was found to involve changes in pericytes, namely an increase in desmin+ pericytes, and decrease in CD13+
[117]
pericytes, as well as in extracellular laminin α2 . The impact that pericytes in the brain have on the
formation of local metastases derived from other breast cancer subtypes remains unknown as does their
effect on priming the pre-metastatic niche.

Until recently, the role that neurons had on the formation of breast-derived brain metastases had remained
largely unexplored. Zeng et al. revealed that neurons interact with metastatic cells to activate the
[118]
glutamine-stimulated N-methyl-D-aspartate receptor (NMDAR) signaling (GluN2B-mediated) in the
invading cancer cells within the brain. They demonstrated a dependence on NMDAR activation for
successful colony formation in the pre-metastatic niche, thus indicating that this signaling axis may yield
potential therapeutic targets for the prevention of metastasis .
[118]

Endothelial cells are critical for the process of extravasation of tumor cells from the CNS vasculature .
[119]
Soto et al. have demonstrated in vitro that the adhesion molecules E-selectin, vascular cell adhesion
[120]
molecule-1 (VCAM-1), activated leukocyte cellular adhesion molecule (ALCAM), intercellular adhesion
molecule-1 (ICAM-1), and very late antigen 4 (VLA-4) are upregulated on the surface of CNS endothelial
cells in the presence of TNBC cells. In parallel, expression of ligands to these adhesion molecules is
increased on the surface of TNBC cells. Inhibition of ALCAM and VLA-4 significantly decreased the
number of brain metastases, further demonstrating the importance of these adhesion molecules in the
formation of the pre-metastatic niche to allow metastatic colony formation in the CNS . Activation of
[120]
endothelial cells has also been shown to allow for the extravasation of T cells from the periphery into the