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growth Factor-1 receptor (IGF-1R), c-MET and the CXCR4 One of the upstream pathways controlling MMP production
receptor, have been proposed as potential targets to inhibit is the PI3K/AKT pathway. [116] As a consequence, drugs like
GBM or MB invasion. wortmannin, a drug that inhibits the secretion of MMP-
2, blocks GBM invasion through the down-regulation of
IGF-1R is typically overexpressed in malignant GBM, the PI3K/AKT/NF-kB signaling pathway. [117] Since Snail
[95]
and its activation by IGF-1 contributes to Snail and induces MMP-9 expression, EMT seems to be necessary
Twist expression though PI3K/AKT signaling pathway for intravasation of lymph vessels in GBM and other
activation. [96,97] Therefore, IGF-1R tyrosine kinase cancers. [119]
inhibitors or IGF-1 inhibitors, such as osthole, have been
used to inhibit GBM proliferation, migration and EMT. [97,98] PI3KS IN INFLAMMATION/
In a recent study of 218 cases of human GBM, IGF-1R MICROENVIRONMENT
overexpression was reported as an independent prognostic
factor associated with shorter survival time and a less The process of inflammation has been extensively
favorable response to temozolomide. [99] linked to tumor progression, as it can stimulate immune
suppression, angiogenesis and tumor metastasis. [119,120] In
C-MET expression levels correlate with tumor grade in CNS response to tumor-derived growth factors and chemokines,
malignancies, [100] and its activation also mediates EMT- inflammatory cells of the immune system are recruited to the
promoting signals in cancer cells via class I PI3K. [101,102] In tumor microenvironment. There, cells normally involved
A
MB, c-MET signaling is deregulated, thus inducing tumor in chronic inflammation, such as mast cells, granulocytes
growth and an anaplastic histology. [103] The use of c-MET and monocytes, provide the tumor with angiogenic factors,
kinase inhibitors, such as SGX523, suppressed tumor enzymes for extracellular matrix (EM) remodeling and
growth in GBM cell lines. [104] This inhibition blocked the growth factors to create a favorable milieu for expansion
EMT induced by VEGF ablation in a GBM mouse model [105] and dissemination. [121,122]
and induced an effective decrease in MB cell migration and
invasion. [106,107] Members of the class I PI3K family have also been
implicated in tumor-associated inflammatory responses.
Stromal cell derived factor (SDF-1) or CXCL2 and its In myeloid cells, p110γ can be activated via tumor-derived
chemokine receptor CXCR4 can induce EMT in GBM via chemoattractants, such as IL-6, Il-8, TNF-α and CSF-1.
activation of PI3K/AKT and extracellular-signal-regulated Upon activation, p110γ promotes extravasation into the
kinases (ERK) pathways, and its inhibition suppressed tumor microenvironment (TME) via integrin α4β1 and
EMT in glioma cell lines by upregulating E-cadherin. [108] promotes inflammation-associated tumor progression. [26,123]
This is in line with other reports indicating a crucial role of
However, single agents targeting the PAM pathway have p110y for immune cell chemotaxis, as well as for chronic
been reported to be an inefficient approach in MB and to inflammation. [124]
increase invasion in the surviving fraction of GBM. [109]
Therefore, new therapeutic approaches should be based Microglial cells are resident macrophages of the CNS.
on increasing the therapeutic window by targeting two Depending on the signaling context, these cells possess a
different routes, namely the PAM and ERK pathways, dual role in tumor biology. By secreting cytokines like IL-
or on combining PAM inhibitors with chemotherapeutic 6, IL-10 and immune suppressive molecules, gliomas can
agents. [110] polarize microglia into tumor supporting M2 phenotypes that
participate in matrix remodeling and cell invasion. [125-127] In
MicroRNAs have also been shown to play an important a recent study, PAM signaling was upregulated in microglial
role in various CNS malignancies, and miR-142-5p and cells that were exposed to glioma derived factors, indicating
miR-25 are upregulated in all of them. [111] In MB, miR-21 that PAM signaling is needed to force microglial cells into
suppression inhibited tumor migration. [112] MiR-183 has a a tumor supportive M2 state. [128] This result was supported
pro-tumorigenic effect in the MYC-driven MB subgroup by a report showing that mTOR inhibition with rapamycin
through the inhibition of apoptosis, deregulation of the polarizes microglia cells to express a tumor suppressive
mTOR pathway and modulation of cell motility and M1 phenotype. [129] To date, the exact molecular mechanism
migration. [113] by which PI3K signaling contributes to M2-polarization
of microglia is still unknown and should be the subject of
During the EMT process, malignant cells start to intravasate further investigation.
into the surrounding blood vessels in order to migrate to
other parts of the body. To accomplish this, the extracellular The tumor microenvironment of MB is also being
matrix and basement membrane of blood vessels have to investigated. A recent study associated the SHH-MB subtype
be degraded by matrix metalloproteases (MMP). [114] The with high infiltration of tumor associated macrophages
most relevant metalloproteases in this invasive process are (TAM) and strong expression of the inflammatory genes
MMP-2 and MMP-9. [115] CSF1R and CD163. [130] It has been shown that PI3K binding

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