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that miRNAs genomic locations are frequently associated are extensively studied as potential biomarkers in different
to genomic regions involved in cancer. It has been cancer types. [34]
calculated that about 50% of known miRNAs are located
inside or close to fragile sites in minimal regions of loss Exosomes are 40-100 nm vesicles secreted by a wide range
[35]
of heterozygocity, regions of amplifications and common of mammalian cell types, including cancer cells. miRNAs
breakpoints associated with cancer. [25,26] shuttled by exosomes involved in cancer metastases have
been found to be implicated in angiogenesis and tumor
These studies indicate that miRNAs represent key players in niche formation. [36,37]
cancer development and moreover, accumulating evidence
demonstrates that miRNAs can also influence multiple steps Recently, an interesting study reported a new and
of metastasis such as EMT, tumor cell migration, invasion unexpected mechanism by which a miRNA contributes to
and colonization. [27] metastatic spread in the brain; the miR-181c contained in
cancer-derived extra-cellular vescicles, carrying proteins
The miR-200 family (miR-200a, miR-200b, miR-200c, and miRNAs, promotes the destruction of blood brain
miR-141 and miR-429) and miR-205 were the first group barrier (BBB) through delocalization of actin fibres via the
of miRNAs found downregulated in various tumors that downregulation of 3-phosphoinositide-dependent protein
underwent EMT progression. Members of the miR-200 kinase-1 in vitro and in vivo. The breakdown of BBB
[38]
family inhibit the EMT process by positively regulating triggered by miR-181c can easily open the way to brain
E-cadherin expression through direct targeting of ZEB1 parenchyma to circulating cancer cells.
and ZEB2, transcriptional repressors of E-cadherin.
Furthermore, expression of the miR-200 family in A very recent study has demonstrated that miRNAs
mammary carcinoma cells induced mesenchymal-epithelial contained in exosomes released by human and mouse tumors
transition by up-regulating E-cadherin expression and that metastasize to lung, liver or brain, like breast cancer,
inhibited migration of these tumor cells, thus suggesting trigger cellular changes in target organs by promoting the
[28]
that downregulation of these miRNAs may be an important formation of tumoral niche and organ-specific invasion.
step in tumour progression. The organ sites where tumor derived exosomes take contact
and release their content is related to integrins expressed
miR-145 was found downregulated in several tumor types on the exosomes surface: α6β4 preferentially interacts with
including breast, gastric, lung, ovary, prostate cancer lung cells, αvβ5 mediates exosomes delivery to liver. [39]
and esophageal squamous cell carcinoma and notably,
accumulating evidence indicates that the processing of These new findings suggest that the exosome miRNAs
miR-145 is also involved in cancer metastasis. [22,29] In breast content and integrin expression can be useful to predict the
cancer, miR-145 suppress breast cancer cell line invasion tendency of primary tumors to metastasize and to determine
and metastasis by targeting mucin-1, a glycoprotein that the preferential organ sites of future metastases; in addition,
can help tumor cells to escape immunosurveillance; in this evidence highlights the role of integrins as potential
[30]
addition, miR-145-dependent regulation of 3’UTR of the valuable targets to inhibit exosomes interactions with
JAM-A and fascin decreased motility and invasiveness of metastatic sites.
MDA-MB-231, MCF-7 and other breast cancer cells. [31]
CROSSING THE BBB
miRNA analysis could also be intrumental for prognostic
purposes: in a retrospective study on 256 melanoma patients, The key step during BM formation is the migration of cancer
divided into three cohorts, four miRNAs (miR-150-5p, miR- cells through BBB. Anatomically, the BBB is formed by
15b-5p, miR-16-5p and miR-374b-3p) were identified as a brain microvascular endothelial cells (BMVECs), that form
prognostic signature that, in combination with stage, was tight junctions without pores, and perivascular elements
able to distinguish primary melanomas that metastasized including pericytes, astrocytes, oligogendrocytes and the
to the brain from non-brain metastatic primary tumors. basement membrane. This complex structure represents
[32]
Although at the present time the biological significance of a physical barrier for cells and molecules, selected on the
these miRNAs disregulation may be difficult to understand, basis of their molecular weight and charge. In addition,
nevertheless the notion, togheter with classical staging this barrier regulates the diffusion processes and the brain
parameters, could be of great importance to clinicians to set parenchyma homoeostasis by highly selective transport
specific therapeutic strategies. mechanisms mediating flux of solutes and molecules and by
a metabolic barrier consisting of highly specific enzymes. [40]
Interestingly, miRNA can also modulate gene expression
in adjacent cells within the microenvironment and even in Tumor cells recognize and bind to components of the
distant cells, since miRNAs have been detected in the blood vascular membrane, thereby initiating extra-vasation and
and in other body fluids; indeed, circulating miRNAs, promoting the formation of the tumoral niche that will
[33]
extra-cellular vesicles-and exosomes-associated miRNA host the new neoplastic formation. The brain vascular

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦