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induced cell death. in terms of motility and resistance to stress. [77]
EMT, CELL INVASION AND MOTILITY The class I PI3K isoform p110α is the most relevant
A
PI3K isoform affecting cell growth and survival. The gene
EMT is a biological process that allows immobile epithelial encoding this isoform, PIK3CA, is usually mutated in GBM
cells to acquire a mobile mesenchymal phenotype, becoming (27%). [78] In this malignancy, PIK3CA mutated form plays
detached and invasive. It was initially described in the a main role in cell growth under anchorage-independent
context of embryonic differentiation. [57] In tumor cells, this conditions. In MB, however, this PI3K isoform is typically
process, together with the induction of neo-angiogenesis, overexpressed, [79] promoting cell proliferation, for example,
initiates cancer metastasis, inducing enhanced migratory through the regulation of the leukemia inhibitory factor
properties, invasiveness and resistance to apoptosis. [58,59] receptor α (LIFR α). [80] The inhibition of p110α impairs
cancer cell growth, migration, and survival in these CNS
During EMT, a variety of transcription factors are malignancies. [16,79]
upregulated in metastatic cells, such as Snail, Slug,
Twist and Zeb ½. Snail can be activated by a number Other class I PI3K isoforms are also overexpressed in
[60]
A
of pathways, including hypoxia, HIF-1, HIF-2, Notch, brain tumors, such as p110δ, which has been reported to
nuclear factor kappa-light-chain-enhancer of activated be overexpressed at the mRNA level in primary GBM,
B cells (NF-kB), and transforming growth factor beta controlling migration in these cells. [81,82] The isoform
(TGF-β), a pro-apoptotic factor. Snail up-regulates AKT p110ϒ, which is overexpressed in primary MB, contributes
phosphorylation and Bcl-X countering the induction of to cisplatin resistance and has emerged as a novel target
l,
apoptosis, [61] and down-regulates cyclin D2, inhibiting cell for combinatorial treatments. [83] The class II PI3K isoform
cycle progression. [62] PI3KC2β, which is overexpressed in a variety of cancers,
acts as a modulator of cell migration, survival and
Twist, which promotes loss of E-cadherin mediated cell- proliferation in leukemia and brain tumors. The highly
[84]
cell adhesion and cell motility, [63] has been linked to the specific pan-PI3K inhibitor GDC-0941 has recently been
PI3K/AKT pathway in various malignancies. This link shown to have anti-migratory, anti-proliferative and pro-
is established by the AKT2 isoform, a Twist-mediated apoptotic effects in MB cell lines, showing synergy with
transcriptional regulator that activates Twist, constituting the standard chemotherapeutic drug etoposide and good
a positive feedback loop that promotes EMT. [64,65] Twist clinical tolerability. [85]
also maintains hyper-activation of the PI3K/AKT pathway
in breast cancer cells, through its transcriptional target Other elements of the PI3K/AKT pathway are also being
TGF-β2. [65] considered as potential targets to inhibit cell proliferation
and migration in GBM and MB. One example is AKT,
AKT hyper-activation and PIK3CA knock-in can promote which usually shows high levels of phosphorylation in these
EMT in various human cancers. [61-66] The association brain tumors. Its inhibition by KP-372-1, KP-372-2,
[86]
between EMT and PI3K activation has also been reported A-443654, or perifosine, was reported to inhibit cell growth
in ERα-negative endometrial carcinomas. [67] and induce radio-sensitizing effects in GBM and MB. [87-89]
Clinical trials of perifosine in GBM patients are ongoing. [90]
Twist overexpression has also been correlated with the
induction of tumor cell invasion in GBM. However, these PTEN is a tumor suppressor usually mutated and inactivated
[68]
malignancies usually do not metastasize out of the CNS, in GBM, with an inverse correlation between its expression
mainly due to their rapid relapse rate and poor prognosis. and glioma grade. In MB, PTEN is rarely mutated but
[69]
[91]
Even so, there are reports describing GBM metastasis [70] frequently downregulated, by promoter hypermethylation
involving the spread of GBM cells out the CNS through and/or allelic losses, inducing AKT activation. [86]
cerebrospinal fluid, blood or lymphatic vessels. [71,72]
PTEN, together with the MAPK signaling pathway, has a
Medulloblastoma, on the other hand, has a high tendency primary role in the regulation of G1/S cell cycle checkpoint-
to disseminate to the spinal cord and leptomeninges of the defective astrocytoma invasion, and its deletion increases
cerebellum and forebrain. These tumors are classified into migration, invasion and resistance to apoptosis in GBM
4 molecular subgroups: wingless (WNT), sonic hedgehog cell lines. [92] PTEN controls integrin-dependent migration
(SHH), group 3 and group 4. Group 3, characterized through the regulation of Src family kinase activation, in
[73]
by cMYC amplification, is associated with metastatic a PI3K/AKT-independent manner. The re-expression of
[93]
disease. [74] PTEN in GBM cell lines increases the cellular content and
activity of the p53 tumor suppressor protein inducing cell
The PI3K/AKT pathway is activated in 50% of GBMs. In cycle arrest and increasing the sensitivity of the tumor cells
the case of MB, there are a number of studies concerning to various chemotherapeutic agents such as etoposide. [94]
alterations in this pathway. [6,75,76] This pathway appears to
facilitate an invasive phenotype of GBM and MB, especially Upstream regulators of EMT induction, such as insulin-like
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦ 83