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Adhesion of SCLC cells to the ECM components requires The miR-145 expression levels were not significantly
β1-integrins, whose activation results in suppression of different between primary lung adenocarcinoma samples
chemotherapy-induced apoptosis by stimulation of the with and without lymph node involvement and recent
[67]
PI3K-dependent pathway. Thus, ECM via β1 integrin- studies have found a downregulation of miR-145 expression
[59]
mediated PI3K activation confers to SCLC resistance to in lung cancer primary tumors and BM. Silencing of miR-
apoptosis, allowing SCLC cells to survive even in presence 145 was found to contribute to BM via downregulation of
of DNA damage. the fascin homolog 1 (FSCN1) protein, an actin-binding
protein involved in cell migration, and upregulation of
Taken together, this evidence indicates that adhesion miR-145 target protein, such as EGFR, OCT-4, MUC-1,
processes play important roles in SCLC cells survival c-MY, [68,69] that are involved in cell proliferation and survival.
strategies linked to metastasis and furthermore suggest that
interference with adhesion molecules or receptors could be miR-328 has been associated with NSCLC BM and
an interesting topic for future researches. mediates NSCLC migration. In patients with BM, the
elevated expression of miR-328 in both primary and brain
Approximately 40% of all NSCLC patients suffer from BM. metastatic NSCLC samples suggests that this miRNA may
The prognosis of patients with BM of NSCLC is remarkably be involved in driving the access of metastatic cells to the
poor, with a median survival time of 1-2 months for brain. In agreement with this finding, in vitro miR-328 over-
untreated patients and 6 months for those receiving surgery, expression in A549 and H1703 cells was shown to increase
radiotherapy and chemotherapy. While SCLC metastatic cell migration. [70]
[60]
brain tumors do not respond to systemic chemotherapy
and poorly respond to molecularly targeted therapies, Another class of RNAs termed long non-coding RNAs
[58]
NSCLC patients frequently display activating epidermal (lncRNAs) appear to play a role in lung cancer metastasis
growth factor receptor (EGFR) mutations. Complete and spread. lncRNAs are a class of non-protein coding
[61]
partial response rates to tyrosine kinase inhibitors have been transcripts, longer than 200 nucleotides, associated with
recorded in clinical studies with gefitinib and erlotinib [62,63] the progression of cancer. Some members of the lncRNAs
and these treatments improved overall survival (OS) rates. family are involved in metastases formation such as the
However, other genes or genetic alterations have been metastasis-associated lung adenocarcinoma transcript 1
reported to be involved in BM of lung cancer. (MALAT1), HOX anti-sense intergenic RNA, and anti-

sense non-coding RNA in the INK4 locus. In lung cancer
[71]
An interesting study performed by microarray in lung
adenocarcinoma and squamous cell carcinoma samples has cells MALAT-1 was found to enhance cell motility by
[72]
shown different expression profiles of EMT-related genes modulating the expression of motility-related genes and
in primary tumors compared to tumor-derived BM. to promote lung cancer BM by inducing EMT in both in
[64]
[72]
In particular, BM had signifi cantly lower integrin αvβ6 vitro and in vivo NSCLC models.
and N-cadherin expression than the primary tumors, thus
supporting the hypothesis that the disseminated tumor cells, Another documented mechanism involved in BM
deriving from primary tumors with marked mesenchymal formation is represented by integrin receptors activation.
features, once inside the brain, undergo the reverse process Several studies that have investigated αvβ3, αvβ5 and αvβ6
of EMT called mesenchymal-to-epithelial transation. expression in BM and corresponding primary tumors [73,74]
found that αvβ3 activation strongly promotes metastatic
Gene expression profiles of miRNAs in lung cancer, growth in the brain by inducing endothelial cell proliferation
aimed at identifying molecular markers as predictor of and network formation. [75]
patient survival, identified several miRNAs targeting genes
involved in crucial pathways such as the EGFR- and KRas- Interestingly, a recent study performed on formalin fixed
dependent pathways. [65,66] paraffin-embedded human primary NSCLC and BM
specimen showed that expression of αvβ3, αvβ5 and αvβ6
miR-145, a miRNA involved in metastatic spread in integrins is associated with pathological parameters such
several cancer types and discussed above, has been found as enhanced tumor cell proliferation index and increased
to be downregulated in the BM compared to primary lung hypoxia-inducing factor (HIF-1a) expression. Moreover,
adenocarcinoma samples and its upregulation in lung αvβ3 and αvβ5 were mainly expressed on proliferating
adenocarcinoma cells suppresses proliferation of tumor endothelium of sprouting vessels, in agreement with
cells. previous observations that have hypothesized their
involvement in neoangiogenesis. [76]
The mechanism by which miR-145 causes these latter
effects was hypothesized to be the targeting c-Myc, EGFR Among factors that stimulate vascular proliferation and
and NUDT1; however, in vitro invasion assays did not vessel formation, MMP have been shown to promote
[67]
confirm that upregulation of miR-145 was implied in lung endothelial cell migration and induce vascular endothelial
adenocarcinoma cancer cell migration and invasion. growth factor (VEGF) release, leading to development of

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