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endothelium is therefore very important in counteracting to cancer cells features and therefore linked to the primary
cell extra-vasation but, nevertheless, cancer cells adopt tumour characteristics. [48]
different strategies to overcome this obstacle. Although
the exact molecular mechanisms that trigger BM are still Two very recent studies have demonstrated that meningeal
poorly understood, increasing evidence are shedding new lymphatic vessels are present in mouse central nervous
light on the processes underlying the ability of cancer cells system (CNS) and display all the classical features of
to cross the BBB. lymphatic vessels. [49,50] These findings have highlighted a
new path for cerebrospinal fluid flux and for immune cells
In a transendothelial migration model, highly metastatic leak, opening interesting avenues for future researches on
melanoma cells migration has ben found to be mediated by BM formation.
interaction of the α4β1 integrin with its ligand vascular cell
adhesion molecule-1 (VCAM-1) on the surface of activated LUNG CANCER
endothelial cells. VCAM-1 is expressed by endothelial cells
only upon activation by inflammatory stimuli like TNF-α Lung cancer is the leading cause of cancer-related deaths
or interferon-γ, suggesting that highly metastatic melanoma worldwide and is characterized by rapid progression
cells preferentially leave the blood vessels at sites of and metastases to brain that develop within months of
inflammation. [41] diagnosis and simultaneously affect different organs
besides the brain. Lung cancer is classfied into two
[51]
In a very similar experimental model, the matrix metallo- broad histological sub-types: Non-small-cell lung cancer
proteinase 1 (MMP1) was found to play a critical role in (NSCLC), representing about 85% of diagnoses, and
BBB penetration; in parallel experiments cyclooxygenase-2 SCLC, accounting for the remaining 15%; NSCLC is
(COX2)-mediated prostaglandin synthesis promotes further classified into adenocarcinoma, squamous-cell
proliferation of tumor initiating cells by activating carcinoma, and large-cell carcinoma. SCLC and NSLC
[52]
tumor-associated astrocytes followed by secretion of the are traditionally considered as different cancer types
chemokine CCL7. [42] but increasing evidence supports the notion that the two
histological sub-types can coexist. This mixed histology
The process of transendothelial migration of melanoma reinforces the hypothesis of common mutated precursors
cells has been further investigated by other in vitro studies for the two cancer types thus complicating prognosis and
showing that the ability of these cells to cross the BBB is therapy. [52]
related to melanotransferrin expression levels on the cell
surface, to the fibrinolytic system and to serine proteases Although several mechanisms concerning lung cancer cells
released by melanoma cells. [43-45]
survival strategies have been elucidated, the early molecular
This accumulating evidence indicates that inflammatory processes leading to BM are still poorly understood.
stimuli cotribute to the formation of breaches in BBB and of
a suitable surrounding in the brain parenchyma for cancer In SCLC patients BM are associated with poor prognosis.
cells. Previous evidence indicated that attachment to brain
microvasculature represented the first step for tumor
[53]
However, in contrast with these findings, other in vivo cell extra-vasation and growth. In particular, it was
studies suggest that trasendothelial cancer cells migration demonstrated that the interaction of SCLC cells with
does not necessarily imply a damage to vascular endothelial human BMVECs triggers the disassembly of tight junctions
cells: metastatic breast cancer cells, in mice, were found between brain endothelial cells and contributes to SCLC
to cross the endothelium in correspondence of sites where cells transendothelial migration, [54,55] thus suggesting that
the vessel wall shows discontinuity sites without causing brain microvasculature and mechanisms that regulate
apoptosis or hypoxia in endothelial cells. [46] cell-cell adhesion are likely to play an important role in
SCLC metastasis to brain. An intriguing mechanism was
Another interesting in vivo study demonstrated by highlighted in a study reporting that the interaction of
multiphoton laser scanning microscopy that in the mouse SCLC cells with BMVECs induces tumor cells to secrete
brain the essential steps in melanoma and lung cancer annexin A1 into tumor metastastic microenvironment. The
metastasis formation were first the arrest at vascular branch secreted annexin A1, previously reported to be upregulated
points and after extra-vasation, perivascular growth in close in human lung cancer and to be related to poor prognosis,
contacts to microvessels. [47] in turn promoted SCLC cells adhesion to brain endothelium
and transendothelial migration. [56,57]
In this scenario, the interactions of metastatic tumor
cells with BMVECs appear to be regulated by a number Other studies have shown that SCLC cells are abundantly
of effectors and mediators and represent a key step of surrounded by ECM components, including collagen
metastasis formation; however, the cellular mechanisms IV, tenascin, fibronectin and laminin; high expression of
that lead to BBB extra-vasation appear to be strictly related these components is associated with a poor prognosis.
[58]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦ 93