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cross the brain barrier to begin the process that leads to the niche associated peptide (LAP) and latent TGF-β-binding protein
formation in the brain parenchyma. Thereafter cancer cells (LTBP). Its activation requires the dissociation from the
grow and invade the brain tissues by different mechanisms, complex, that may also be achieved by several integrins.
such as expansive growth, multicellular migration and The LAP peptides bound to TGF-β1 and TGF-β3 contain
individual cell migration. [5] an Arginine-Glycine-Aspartate (RGD) motif that can be
recognized by the RGD-binding integrins (αvβ3, αvβ5,
On the other side, the host tissue re-organizes its structure α5β1); this binding activates a driving force that leads to
and vasculature recruiting stromal cells, such as fibroblasts, breaking of LAPs and LTBP binding to TGF-β and releases
endothelial cells and tumor-associated macrophages, that the active form of TGF-β. [10,12] Integrin inhibitors with
sustain the tumor growth by producing and releasing extra- different molecular structures have been studied and are
cellular matrix (ECM) proteins, cytokines and growth factors. [6] in clinical trials as anti-angiogenic agents or in support of
other anti-cancer therapies, therefore integrin antagonists
METASTASIS FORMATION: EPITHELIAL- could represent a valuable and near-at-hand tool to inhibit
MESENCHYMAL TRANSITION the integrin dependent TGF-β activation and eventually
reduce metastatic spread. [13]
The epithelial to mesenchimal transition (EMT), identified
as one of the earliest steps of solid tumor progression, is Lung, breast cancer and melanoma are tumors that display
associated with tumor growth, invasion, metastasis and the EMT phenotype, [14,15] and in lung cancer, the expression
contributes to the conversion of tumors from low- to high- of markers of this transition has been associated with
grade malignancy. In epithelium-derived carcinoma, the prognosis. [16-18] This link between EMT and malignancy is
[7]
EMT program induces a series of functional and structural further supported by the finding that, in other cancer types,
changes aimed at the formation of tumor cells that will be EMT markers are overexpressed in 40% of tissue samples
able to invade surrounding tissues and lead to metastases and are associated with vascular invasion and advanced
formation. Invasion is a key step to progression toward clinical stage. [19]
a malignant phenotype and occurs when tumor cells
translocate from the relatively constrained initial neoplastic Once in the brain tissue, during reimplantation, the
mass into neighbouring host tissues. To accomplish this circulating tumor cells have been shown to undergo a
task, cancer cells must somehow detach from the primary mesenchimal to epithelial transition, thus reversing the
tumor and migrate through the ECM, opening up the EMT, to reacquire some of the original epithelial features
opportunity to penetrate the basal membrane surrounding necessary to survive in the new environment. [20]
a blood or lymphatic vessel, travel throughout the body via
the circulatory system, and colonize distant sites to form The knowledge of EMT mechanisms could clearly be an
metastatic foci. EMT is acknowledged to confer to cancer invaluable tool in defining molecular markers predicting
cells the molcular features required for these tasks. During tumors metastatic behaviour and prognosis and in
EMT, in fact, epithelial cells undergo a developmental identifying targets for new molecules that could inhibit the
switch that results in decreased adhesion and loss of cell EMT process.
polarity, increased proliferation, motility and invasiveness;
these changes are associated with the downregulation of THE ROLE OF MICRO-RNAS
epithelial cell surface markers and cytoskeleton components
(E-cadherin, zonula occludens-1, claudins, occludins, A number of recent studies has identified micro-RNAs
cytokeratins) and the upregulation of mesenchymal markers (miRNAs) as key regulators of cancer cells survival and
(vimentin and α-smooth muscle actin) together with ECM metastatic spread. Indeed, approximately 30% of human
components (collagens and fibronectin). Although the genes are likely to be regulated by miRNAs and miRNAs
[21]
[8]
molecular changes that occur in cancer cells during EMT have been shown to regulate a variety of biological
have been extensively documented, the molecular switches processes, including cell proliferation, cell differentiation
that turn on EMT still represent an open question and a and cell death. In this section miRNA involved in
[22]
crucial challenge because the possibility to inhibit this metastases, though with different molecular mechanisms
process could be of great impotance in reducing metastatic are described.
spread. In vitro and in vivo model systems have identified
several transduction pathways that lead to EMT and EMT- miRNAs are an endogenous, highly conserved class of
like phenotypes, many of which connect EMT to the ECM non-coding 20-24 nucleotides small RNAs that regulate
and the microenvironment surrounding tumors. [9] gene expression at post-transcriptional level by binding
to 3’-UTR of target mRNAs, thus leading to inhibition
[23]
Among these pathways, integrins and transforming growth of mRNA translation and degradation. Several reports
factor-beta (TGF-β) work synergistically to drive tumor have elucidated the role of certain miRNAs as a class of
cells towards EMT. [9-11] TGF-β, in fact, is secreted as oncogenes or tumor suppressors, depending upon their
inactive precursor in a complex with 2 peptides, latency targeted genes. In addition, several studies have reported
[24]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦ 91