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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 11 of 18

[119]
brain , although the process is not fully understood in the context of breast to brain metastasis. Decreases
in zonula occludens (ZO)-expression and interactions of VLA1 and LFA1 with VCAM and ICAM have
[119]
been described in other types of tissue injury or inflammation .

The role of neutrophils in the pre-metastatic niche has not been fully explored. Neutrophils are innate
immune cells that maintain tissue homeostasis by adjusting their function in response to various
stimuli [121,122] . Although initially thought to not play an active role in cancer development, through the use of
preclinical models, it has been demonstrated that different subpopulations of neutrophils modulate cancer
[123]
metastasis . High numbers of neutrophils, compared to lymphocytes in peripheral blood, have been
associated with poor prognosis for patients with primary brain tumors or metastases to the brain , and in
[124]
the microenvironment of a tumor they have been shown to support tumor growth, partly as a result of their
[124]
[125]
polarization by IL-17 γδ T cells . It has been reported that they are attracted via G-CSF or by CXCL8
+
[73]
secreted by microglia around brain metastases and infiltrate the sites of metastasis prior to the tumor
cells, to create an immunosuppressive, tumor promoting milieu through upregulation of Arg1 and other
immunosuppressive factors. The neutrophil-like CD11b Gr1 myeloid cells promote the formation of a pre-
+
+
metastatic niche within the brain through secretion of proinflammatory cytokines, such as S100A8, S100A9,
and SAA3 [126,127] . Activated neutrophils release S100A8 and S100A9, which form heterodimers to support this
mechanism across systems . Once the initial metastatic niche has been formed, additional
[128]
immunosuppressive neutrophils are recruited through the function of phosphorylated EZH2 .
[124]
Although it is not entirely understood why the inflammatory cascades are triggered in the CNS upon the
circulation of cancer cells in the blood stream and their extravasation into the brain, it has been reported
recently that the fact that the circulating cancer cells must first arrest in brain microvessels prior to
colonizing the brain leads to local platelet activation and the formation of microthrombi, which could
initiate tissue inflammatory processes .
[129]
Metastatic cancer stem cells and their interaction with the CNS niches: to allow for the seeding of metastatic
cancer cell, a small population of cancer stem cells support the initial expansion of the cells at the secondary
site. Periostin, present in the stroma of the primary breast tumor, is induced by infiltrating cancer cells in
[130]
the secondary target organ to initiate colonization . Part of the colonization process involves shifting of
energy generation towards the infiltrating cells. For example, cancer cell-secreted circulating miR-122
[131]
suppresses CNS-resident cell glucose uptake by downregulating the glycolytic enzyme pyruvate kinase .

THE INFLUENCE OF EXOSOMES AND EXOSOME CARGO
Exosomes are vesicles ranging in size from 30-100 nm. Released from donor cells via exocytosis, they
contain functional biomolecules such as proteins, lipids, RNA, and DNA. Through endocytosis, exosomes
enter recipient cells, and the contained biomolecules are released [132-139] . Tumor derived exosomes have the
ability to direct metastasis formation in specific organs based on the exosomal integrins (ITG) present.
These integrins bind in a tissue-specific fashion, which initiates the formation of the pre-metastatic niche.
Breast cancer derived exosomes that had preferential localization to the liver, lungs, or brain were found to
express unique integrins depending on their fate. The liver-tropic exosomes expressed ITGβ , lung-tropic
5
exosomes expressed ITGα , and brain-tropic exosomes expressed ITGβ . ITGs bind a number of ECM
3
6
molecules and common signaling proteins. The expressed integrins bind neighboring cells, such as Kupffer
cells in the liver and epithelial cells in the lungs, at the sites of future metastasis which allows for exosome
uptake. It was shown that the liver- and lung-tropic exosomes were able to increase the rate of metastases to
[64]
the respective organs; however, this study was not extended to examine the brain-tropic exosomes . The
ability of exosomes to drive metastasis in a site-specific manner suggests that they may contain cargo that