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We
researched and reviewed peer-reviewed articles to provide an overview of the
primary and metastatic brain tumor growth, dissemination mechanisms in their
microenvironment. We studied the role of alternative pre-mRNA splicing events
of KCNMA1, which encodes the pore forming α- subunit of calcium-activated
voltage-sensitive potassium (BKCa) channels, in migration,
invasion, proliferation, dispersal of brain tumor. It is conceivable that by
targeting epigenetic events and gene variants that contribute to brain tumor
growth, we might attenuate tumor diffusion, distant metastasis and
angiogenesis. We reviewed literature on the alternative splicing events of
KCNMA1, specific to brain tumor, its microenvironment and the biological
activity of known alternatively spliced isoforms. The blood-brain tumor barrier
(BTB) prevents delivery of anticancer drugs to micro-macro metastases requiring
novel strategies to enhance drug delivery across the BTB. We also revealed the
interaction between the BKCa channel isoform expression and
VEGF secretion in brain tumors that can be exacerbated under hypoxia with
significant implications on neoangiogenesis, vascular permeability and
anticancer drug delivery.
Keywords: KCNMA1, BKCa channels, Splice
variants, Gliomas, Metasttic brain tumors, Drug delivery, Blood brain-tumor barrier
INTRODUCTION
Primary and metastatic cancers
Primary brain tumors
start in the brain or brain’s contiguous structures. Most common types of
primary brain tumors are gliomas, which begin in the glial tissue. Major types
of brain tumors are gliomas that also include, astrocytoma arising from
astrocytes and oligodendrogliomas arising from oligodendrocytes or from a glial
precursor cell. In children, medulloblastoma is common arising from cerebellar
primitive neuroectodermal tumor (PNET), originating from the posterior fossa
and can spread to other parts of the brain and to the spinal cord. In fact,
there are 16 types of brain tumors according to WHO report. The 2016 CNS WHO presents
major restructuring of the diffuse gliomas, medulloblastomas and other
embryonal tumors and incorporates new entities that are defined by both
histology and molecular features, including glioblastoma [1]. This report
addresses the challenges of primary brain tumor diagnosis, prognosis and
targeted treatment based on the molecular basis of the tumor. Secondary brain
tumors or metastatic brain tumors are those that spread to the brain from
somewhere else in the body. For example, cancers of the lung, breast, kidney,
stomach, colon and melanoma skin cancer have the potential to travel through
the bloodstream and lodge themselves in the brain. Then they will begin to grow
into new tumors in the new microenvironment supported by increased
vascularization by avoiding host immune response (Figure 1). With
more-sensitive and accurate detection of distant metastases by improved imaging
modalities should increase incidence of brain metastases and prolong survival
of patients. Innovative preclinical models that more accurately represent
clinical brain metastases and imaging
techniques will pave way to developing anticancer drugs to manage brain
metastases.
Brain tumor dissipation
New generation sequencing (NGS) technologies
have contributed to the giant leap in understanding the genomic and epigenomic
analyses of both primary and metastatic brain tumor tissues and tumor cells.
Mutations identified at the genome or transcriptome levels helped us understand
the differences in gene regulation of cellular functions in identical brain
tumors as related but functionally different tumor entities [2-6]. Novel
mutations detected in brain metastases suggested potential drivers tumor
progression [7], strengthening the argument that brain tumors are highly
heterogeneous with complex microenvironments. Epigenetics play an important
role in cancer initiation, growth and progression.
Understanding the precise mechanism helps us
in developing diagnosis, prognosis and treatment strategies for affected cancer
patients. For example, overexpression of Ezh2 plays a role in many cancers,
including breast cancer and brain tumors. H3K27M serves as an oncohistone and,
if mutated it contributes to tumor development as Ezh2 is no longer able to
methylate the histone and gene expression is aberrantly upregulated. We studied
the methylation status of the promoter region using low grade and high-grade
glioma cell lines and showed that there is a significant difference in the
expression of genes between low and high-grade glioma cells, when treated with
5-aza plus TSA. Our study suggested that studying the methylation status of
ADFP, CDCP1 and ZFP42 in brain tumor biopsies may indicate the potential
aggressive nature of gliomas [8]. More functional genomics and cell-based
molecular analyses are required to qualify mutated or amplified genes as
clinical and therapeutic markers. A case in point is the data available from
The Cancer Genome Atlas (TCGA) and The Human Protein Atlas that refers to
testing of KCNMA1 and BKCa channels as a pathological marker
in cancer [9].
The complication in understanding metastatic
process and metastatic spread in the brain calls for rationalized tumor model
systems. Researchers are using both in vitro and ex vivo primary
brain tumor model systems to better understand the molecular mechanisms
of brain tumors and neovascularization for designing targeted novel
anti-metastatic therapies [10]. Metastatic brain tumors dissipate and colonize
in distant parts of brain metastases grow by drafting existing blood vessels
and/or by forming new blood vessels. The unique brain microenvironment such as
hypoxia promotes tumor cell survival, tumor growth and resistance to therapy.
The ion channels are shown to be involved in hypoxia-induced aggressiveness of
glioblastomas [11]. We also found that KCNMA1 and the alternate splicing of
KCNMA1, which encode for BKCa channels, under hypoxia impact vascular
endothelial growth factor (VEGF) secretion in glioma cells (Figure 2).
Hence, there is an opportunity to control cancer growth by developing safe and
effective VEGF and BKCa channel inhibitors.
Biomarkers of brain tumors: Due to the multi-factorial and
heterogeneous nature of brain tumors (primary and metastatic), it is extremely
difficult to identify the most optimal and novel biomarker for effective
management of brain tumor patients. The risk loci for glioma susceptibility,
5p15.33 (TERT), 8q24.21 (CCDC26), 9p21.3 (CDKN2A-CDKN2B), 20q13.33 (RTEL1) and
11q23.3 (PHLDB1) are identified by a large genome-wide association study.
Biomarker research had relied heavily on quantifying increase or decrease in
gene expression in tumors, but these changes may not always result in altered
protein expression. The epigenetic silencing of the MGMT (O6-methylguanine-DNA
methyltransferase) DNA-repair gene by promoter methylation is an independent
prognostic factor in GBM [12] and in metastatic brain tumor patients [13]. A
targeted drug, temozolomide has been effective in prolonging the survival in
patients with silenced MGMT but ineffective in patients with active MGMT.
Epidermal growth factor receptor (EGFR) amplification and presence of EGFR
variant (EGFRvIII) overexpression are observed in GBM [14] and metastatic brain
tumors [15].
Mutations of the isocitrate dehydrogenase
genes (IDH1 and IDH2) predict prolonged progression-free and overall survival
of glioma patients [16]. Therefore, molecular markers of brain tumors can
predict survival and will become increasingly important in the diagnosis,
prognosis and treatment of brain tumors. We showed that KCNMA1 and BKCa channel are overexpressed in high-grade gliomas [17]. Perhaps the
brain tumors are likely to exploit tumor micro environmental factors in brain
by overexpressing potassium ion channels such as BKCa and KATP channels to gain functional advantages over normal cells (Figure
3).
KCNMA1/BKCa channels in brain tumor biology
Ion channels are implicated in the
development of several cancers. We and others have demonstrated that BKCa channel is overexpressed in gliomas and plays a regulatory role in
glioma invasion and migration [18-28]. There is now evidence that KCa–Ca2+ channel complexes found in cancer cells and
contribute to cancer-associated functions such as cell proliferation, cell
migration and the capacity to develop metastases [29]. Studies including our
work indicate that BKCa channels contributed to the high
proliferative or invasive potential in a number of malignant cell lines, such
as non-metastatic (MCF-7) breast cancer cells [18], brain-specific metastatic
(MDA-MB-361) breast cancer cells [29-32], human prostate cancer [33],
colorectal carcinogenesis [34] and glioma [16].
The metastatic brain tumor cells colonize and
develop distant metastases and subvert the microenvironment to avoid host
immune response (Figure 4). The BKCa channel regulates proliferation of the human neuroblastoma cells
through PKC and PKA protein kinases [35]. However, a few studies concluded that
BKCa channels are not required for the
proliferation in glioma [36] or breast cancer cells [37].
KCNM1-endoded BKCa channels in brain tumors as therapeutic
targets: Several
potassium channels, including BKCa channels with defined molecular identities have been proposed as
candidates for therapeutic intervention in cancer [38]. Treatment strategies
include classical small molecules as inhibitors as well as gene therapy
approaches targeting potassium channels as direct targets for adjuvant cancer
therapy are proposed [39]. A recent review discussed the important role of BKCa channels in glioma cell biology, including
cell division, invasion and migration [40]. Proteomic and array studies have
shown BK channel’s role in cancer and its interaction with various other
proteins [18]. Therefore, some of these protein-protein interactions in
cancers, especially in brain tumors can be exploited for developing new class
of targeted therapies.
Alternative splicing in brain tumors
In humans, most pre-mRNAs undergo alternative
splicing and disruption of normal splicing patterns can cause diseases [41]. A
vast majority of human genes contains introns. Most pre-mRNAs undergo
alternative splicing. Several excellent reviews provide detailed information on
splicing and the regulation of splicing [42]. The discovery of alternative RNA
splicing can greatly influence protein levels and functions. In cancer,
abnormal splicing often leads to tumor-promoting splice variants that are
translated into activated oncogenes or inactivated tumor suppressors [42,43].
Of all tissues, the brain shows maximum alternative splicing of exons [16].
Growing evidence indicates that alternative or aberrant pre-mRNA splicing
resulting in protein isoforms with diverse functions occurs during the
development, progression and dispersal of glioma cells [44].
Genome-wide studies have identified genes
expressing splice isoforms more frequently in glioma than in normal brain [45].
For example, KCNMA1 was shown to undergo alternative pre-mRNA splicing at
several sites in humans and mice [46,47] to generate physiological diversity in
BKCa channels. We have identified two new KCNMA1
variants (KCNMA1E22 and KCNMA1ΔE2) as shown in Figure 5. These isoforms
showed differences in calcium/voltage sensitivity and regulation of cellular
signalling pathways [48,49]. However, the cause-effect of KCNMA1 splicing in
functional modification of BKCa channels in gliomas is still
unclear. We recently reported that the high-grade gliomas express KCNMA1v and
BKCa channel isoform accelerate growth and
transformation of low grade-glioma to GBM [17].
BBB/BTB: Challenges of imaging and delivery
of anticancer drugs to brain tumors
A significant number of primary and
metastatic brain tumor cases are reported each year in the US and around the
world. Estimates show that about fifty percent of patients receiving brain
radiation and/or surgical resection have recurrences in the brain within a
year, severely shortening life expectancy [19]. Targeting brain tumors is
extremely difficult because brain provides a “safe haven” for tumor cells (Figure
3).
The cerebral microvessels/capillaries that
form the blood-brain barrier (BBB) not only protect the brain from toxic agents
in the blood but also pose a significant hindrance to the delivery of 98% of
CNS small and large therapeutic molecules. Different strategies are being
employed to circumvent the physiological barrier posed by blood-brain tumor
barrier (BTB). Research now is focusing on targeted cancer therapy by
supplementing conventional chemotherapy and radiotherapy with monoclonal
antibodies (MAbs). The purpose of antibody treatment of cancer is to induce the
direct or indirect destruction of cancer cells, either by specifically
targeting either the tumor or the tumor vasculature [50]. The EGFR is often
amplified and mutated in human gliomas, but its expression is low or
undetectable in normal brain and hence targeted by cetuximab (Erbitux®).
New therapeutic MAbs such as Herceptin, ABX-EGF, EMD 720000 and h-R3 are
routinely used in the clinic. These promising MAbs, however, have poor
penetration across BTB, rendering them ineffective against brain tumors.
Targeting tumor and tumor blood vessel
specific marker(s) is a good strategy to control tumor growth [26]. It is
however, critical to study whether tumor-specific drug delivery has the
potential to minimize toxicity to normal tissues, and improve bioavailability
of cytotoxic agents to neoplasms. The established blood vessels feeding the
proliferating brain tumor edges as well as the brain tissue surrounding the
tumor are similar to intact BBB [51]. Therefore, understanding the biochemical
regulation of the BBB permeability in its normal and abnormal states (BTB) is
crucial as new anticancer drugs targeting brain tumors are being developed.
The dynamic contrast enhanced magnetic
resonance imaging (DCE-MRI) is primarily used for human brain tumor detection.
However, detection of tumor microsatellites (smaller than 1 mm) remains
challenging. In addition, BTB collapse is visualized as gadopentate
(Gd-DTPA)-contrast enhancing lesions on brain MRI. There is an opportunity to
increase Gd-DTPA delivery to diffused brain tumors for better detection. Research,
presently should be focused towards delivering contrast enhancing agents and
therapeutic drugs selectively to diffused brain tumors and distant metastases
for accurate detection and proper management of disease in patients.
We recently reviewed and reported on the
advance made in drug delivery research focused on several innovative methods,
including nanoparticles, microparticles as carriers of anticancer agents, PEG
technology, encapsulating anticancer drugs in liposomes and MAbs for the
delivery of anticancer payloads [38,52]. We also reported on the significant
differences between normal human brain and brain tumor capillaries, including
differential expression of ion channels including BKCa [51] and KATP channels [53]. Based on these studies, there are number
of researchers who are studying the molecular targeting by tumor-specific
antigens and specific agents to circumvent delivery challenges posed by
BBB/BTB.
CONCLUSION
We know that primary and metastatic brain
tumors are distinct in their etiology, biology, response and resistance to
anticancer drugs. Hence innovative preclinical and clinical study designs are
required to develop effective diagnosis, prognosis and treatment. We should embrace
the new DNA, RNA, protein sequencing and imaging technologies to understand
each tumor type and customize treatment strategies. Furthermore, studies are
essential to understand the host microenvironment including molecular
aberrations such as gene mutations and alternative splicing. Specifically, in
hypoxic microenvironment metastatic brain tumor cells adapt very well and
thrive by forming new blood vessels. Targeting VEGF and VEGFR that are involved
in angiogenesis with Bevacizumab like molecules should take a priority. In
addition, BBB/ BTB pose hurdles to anti-cancer drug and imaging agents’
delivery. These challenges are different in primary and metastatic brain
tumors. Molecules involved in extravasation, metabolism, cell adhesion and
cellular signalling in brain-specific metastatic clones should be identified
for targeted therapies.
More effective anticancer drugs and specific
biologics similar to clinically used inhibitors of EGFR, HER2, PI3K and BRAF,
should be developed to get an upper hand on unique challenges posed by both
primary and metastatic brain tumors. Finally, our work suggests that validating
KCNMA1/BKCa channel variants in clinically
relevant tumor samples will be useful in identifying biological process that
promote malignancy and affect prognosis and survival of brain tumor patients.
ACKNOWLEDGEMENT
The authors thank the Scintilla Group,
Bangalore, India; Anderson Cancer Institute and Mercer University Medical
Center, Savannah, GA, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA;
Cedars-Sinai Medical Center, Los Angeles, CA, USA; American Cancer Society,
USA; Georgia Cancer Coalition, Atlanta, GA, USA; and NIH for providing the
opportunity and research grant support.
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