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Page 12 of 18 Malone et al. J Cancer Metastasis Treat 2021;7:40 https://dx.doi.org/10.20517/2394-4722.2021.37

helps to promote the formation of a premetastatic niche in a target organ.

[131]
A study by Fong et al. reported that breast cancer cell-secreted vesicles containing miR-122
downregulated pyruvate kinase in astrocytes and neurons, thereby decreasing their glucose uptake. The
level of ATP in the miR-122 expressing cell line was not significantly changed, suggesting that an alternate
metabolic pathway was used to meet energy needs. In the cells of the CNS microenvironment, the level of
ATP was not measured so it remains unknown if they are affected by the decrease in glucose uptake or if
they are able to overcome it by means of another metabolic pathway. It was suggested that this suppression
of glucose consumption by resident cell types increased the availability of the nutrient for the cancer cells
once they arrive. Interestingly, miR-122 antagonism reduced breast cancer metastasis to the brain (and the
[131]
lungs) in a mouse xenograft model . This study was one of the first to show modulation of metabolic
environment to support cancer cell seeding and growth in the pre-metastatic niche.

Other reports propose additional exosomal cargo that modulates the ability of breast cancer cells to
metastasize to the brain. MiR19a-enriched exosomes are secreted by astrocytes and taken up by tumor cells.
The uptake results in reduced expression of PTEN. Suppression of miR19a significantly decreased breast to
[141]
[140]
brain metastasis . In a recent study by Arnold et al. live cell imaging and microarray data revealed that
Tubulin Tyrosine Ligase Like 4 (TTLL4) expression correlated with brain metastasis by altering extracellular
vesicle homeostasis and allowing the breast cancer cells to adhere to endothelial cells and increasing the
compromise of the BBB. In some studies, the compromise of BBB was not necessary, as tumor-derived
[142]
exosomes could be transferred into the CNS parenchyma by transcytosis . Beyond aligning and adhering
to blood vessels, Lu et al. reported that lncRNA GS1-600G8.5 was responsible for compromising the BBB
[143]
by decreasing the expressing of tight junction proteins, including ZO-1, Claudin-5, and N-cadherin.
Exosomes containing cell migration-inducing and hyaluronan-binding protein (CEMIP) facilitated
metastasis specifically to the brain, as opposed to other organs. Uptake of CEMIP by parenchymal microglia
and by endothelial cells induced perivascular inflammation and local vascular remodeling .
[144]
CONCLUSION
Conditioning of the premetastatic niche is vital for metastatic colony formation. Exosomes originating from
the primary tumor have organ specific characteristics and can dictate the site of metastasis. Exosomes and
the cargo they carry may cause the initial priming of the premetastatic niche. Further crosstalk between
exosomes or circulating tumor cells with the resident cells of the target tissue around the premetastatic
niche allows for initial changes to be made to the microenvironment. M2-like activated microglia not only
release pro-tumoral cytokines, but they also decrease their innate immune function which allows circulating
tumor cells to enter the CNS. The secretion of heparanase from activated astrocytes degrades the endothelial
basement membranes which further aids metastatic cell invasion. The extracellular matrix of the
premetastatic niche is affected by pericytes which secrete factors that have chemoattractant, adhesion-, and
proliferation-enhancing effects on circulating tumor cells. Endothelial cells aid in the process of
extravasation through the upregulation of adhesion molecules on the cell surface. Exosomes carrying miR-
122 are able to interact with astrocytes and neurons of the premetastatic niche and may change local cellular
metabolism , resulting in a decrease in glucose uptake from the environment. This excess glucose can
[145]
then be utilized by invading metastatic tumor cells which require a larger amount of glucose to meet the
metabolic demands.

Metastasis is the leading cause of breast cancer related death with metastasis to the brain having the worst
prognosis. While molecular subtype and histological grade can allow for predictions on likelihood of
metastasis as well as metastatic sites to be made, secondary metastatic colonies would not be able to form