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Vol.:(0123456789)
1 3
Journal of Neuro-Oncology
https://doi.org/10.1007/s11060-018-2789-5
TOPIC REVIEW
Renin angiotensin system andits role inbiomarkers andtreatment
ingliomas
AlexanderPerdomo‑Pantoja1,6· SoniaIlianaMejía‑Pérez1· LilianaGómez‑Flores‑Ramos2,4·
MontserratLara‑Velazquez3,7· CordeliaOrillac5· JuanLuisGómez‑Amador1· TaliaWegman‑Ostrosky2
Received: 15 June 2017 / Accepted: 1 February 2018
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018
Abstract
Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the
World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant
therapy have a mean overall survival of 15months and 100% recurrence. The renin-angiotensin system (RAS), the primary
regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local
regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, includinggliomas.
The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these
tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers
in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future.
The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving
immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effectsand are being considered for
use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis
and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.
Keywords Glioblastoma· Renin-angiotensin system· Brain tumor· Glioma· Angiotensinogen· Cancer· Gliomagenesis
Introduction
Gliomas are the most common intrinsic neoplasm of the
brain and are derived from glial cells. Gliomas are classified
into astrocytomas, oligodendrogliomas, and ependymomas
depending on the glial cell-type of origin [1]. Among these,
astrocytomas are the most prevalent [2].
Gliomas are graded according to the World Health Organ-
ization (WHO) classification mainly based on their neuro-
pathologic features, with presence of cytological atypia con-
ferring a grade II, anaplasia and mitosis activity conferring
a grade III, and microvascular proliferation and/or necrosis
seen in grade IV tumors [3–5]. Grade I is reserved to the
more circumscribed pilocytic astrocytomas [3], or to an
extremely rare diffuse astrocytoma without atypia [5]. Grade
I and II gliomas are consider low-grade and grade III and IV
high-grade as a reflection of their respective growth rate and
malignant potential. High-grade gliomas are more common
than low-grade gliomas and are considered deadly, with a
worse prognosis despite the standard of care, and significant
morbidity [6]. Gliomas can also be grouped, based on the
* Talia Wegman-Ostrosky
taliaw@gmail.com
1 Department ofNeurological Surgery, National Institute
ofNeurology andNeurosurgery “Manuel Velasco Suarez”
(INNN), 3877 Insurgentes Sur Av, La Fama, Tlalpan,
14269MexicoCity, Mexico
2 Division ofResearch, National Cancer Institute
(INCAN), 22 San Fernando Av, Sección XVI, Tlalpan.,
14080MexicoCity, Mexico
3 School ofMedicine, Plan ofCombined Studies inMedicine
(PECEM), National Autonomous University ofMexico
(UNAM), MexicoCity, Mexico
4 Institute ofBiomedical Research, National Autonomous
University ofMexico (UNAM), MexicoCity, Mexico
5 NYU School ofMedicine, NYU Langone Health, NewYork,
USA
6 Department ofNeurosurgery, Johns Hopkins University
School ofMedicine, Baltimore, USA
7 Department ofNeurosurgery, Mayo Clinic Campus Florida,
Jacksonville, USA
Journal of Neuro-Oncology
1 3
WHO classification and the growth pattern, behavior, and
recently the isocitrate dehydrogenase enzyme 1 and 2 (IDH
1/2) genetic status [4]. Circumscribed tumors that maintain
well-defined limits are grade I, while grade II–IV tumors are
diffuse with borders that are difficult to distinguish from the
surrounding nerve tissue [4, 7]. Diffuse gliomas are thought
to be more of a systemic illness of the brain than a focal one
due to their infiltrating nature. Gross total resection (GTR)
of diffuse gliomas does not prevent recurrence [8, 9].
Diffuse gliomas have a high recurrence rate and a ten-
dency to progress from low-grade (grade II) to high-grade
tumors, either anaplastic grade III or even secondary glio-
blastomas (GBM) grade IV. For these tumors, the most
important neurosurgical objective is to perform an extensive
cytoreduction and obtain tumor tissue for diagnosis [10].
Due to their aggressive nature, GBMs are considered incura-
ble and have an adverse prognosis with significant morbidity.
For patients treated with GTR, adjuvant radiation therapy,
and adjuvant chemotherapy with temozolomide (TMZ), the
mean survival is 14.6months [11]. Since our current treat-
ments have limited mortality benefit, it is necessary to inves-
tigate new ways to approach the diagnosis and treatment of
gliomas, including the incorporation of molecular targets
into the management of gliomas [10]. There exist several
genes that have been proposed as biomolecular markers of
aggressive illness that provide clues of the pathophysiol-
ogy of brain tumors and illuminate some potential targets
for treatment [12]. In GBM, the majority of these markers
are detected directly from tumor tissue. In comparison, cir-
culating proteins in the blood seen in other types of cancer
(such as prostate-specific antigen in prostate cancer) serve
as markers of disease giving valuable information about the
differential diagnosis, prognosis, and response to treatment
in a less invasive manner [13].
In the past few years, ten mechanisms known as the “hall-
marks” of cancer have been proposed to explain the path
taken by tumor cells to acquire features that give them the
capacity to become malignant [14]. These hallmarks are
connected to several biochemical pathways that have been
the focus of much research, including the renin-angiotensin
system (RAS) [15]. Classically, the RAS has been studied as
a fundamental systemic component of cardiovascular home-
ostasis. However, RAS also is expressed in several tissues
and organs (liver, kidneys, pancreas, reproductive organs,
and brain), where it has paracrine regulation. Interestingly,
some of these local effects are related to carcinogenesis
including gliomagenesis [16–18].
Epidemiologic studies have debated concerning the use of
antihypertensive drugs as protective agents against cancer,
and their role as neoadjuvant chemotherapy [15]. One of the
first studies to investigate the protective effect of RAS block-
ers on cancer in a clinical setting was a retrospective cohort
study based on 5207 patients, which found that the incidence
of fatal cancers was reduced in patients with long-term use
ofangiotensin-2 converting enzyme inhibitors (ACEIs) [19].
Going further, other epidemiological studies have combined
the genotype with the RAS blockers therapy, such as the
Rotterdam Study, a prospective cohort study with 7983 par-
ticipants with 1 of 4 cancers (colorectal, lung, breast, or
prostate cancer). The results showed that RAS inhibitors
seemed to protect against cancer in patients harboring the
ACE DD genotype [20]. Recently, Sun etal. published a
meta-analysis including 55 studies to evaluate the associa-
tion between RAS blockers and recurrence, metastasis and
survival in cancer patients. They found that those who used
RAS blockers had a longer progression-free survival (PFS)
and disease-free survival. In addition, it appears that the
positive influence of the RAS blockers in overall survival
(OS) depends on the cancer type and type of RAS inhibitor
used [21].
The role of RAS in CNS tumors has aroused increasing
interest among researchers in the field of neuro-oncology
over the past 20years. The purpose of this review is to
highlight the current knowledge concerning the relation-
ship between RAS and gliomagenesis, bearing in mind the
potential application of the RAS components as biomarkers
or treatment targets in cancer of the CNS.
The circulating RAS andthelocal RAS
The RAS plays an important action regulating the systemic
circulation in the human body in response to low blood pres-
sure or decrease in serum sodium levels. A component of
this model is angiotensinogen (AGT), a protein synthesized
and secreted by the liver into the general circulation. This
protein is converted through another step into angiotensin I
(AngI) by the protein renin from the renal juxtaglomerular
apparatus. Subsequently, AngI is converted to angiotensin
II (AngII) by the pulmonary angiotensin-converting enzyme
(ACE). AngII is an active octapeptide that acts primarily on
AngII receptor type 1 (AT1R). This promotes cardiovascular
homeostasis by upregulating the serum levels of aldosterone,
constricting blood vessels, and increasing salt reabsorption
and water retention at the level of the kidneys.
The new understanding of RAS is far more complex
than its classic view, and two important concepts have
been added. First, the system is not only expressed at a
systemic level but also works locally in a paracrine func-
tion in the vasculature, kidney, heart, lungs, liver and
central nervous system (CNS). Second, other peptides,
enzymes, and receptors have been added to the previous
framework of the RAS network, and include other bioac-
tive peptides in addition to AngII. Novel bioactive RAS
peptides discovered are angiotensin III (AngIII), angio-
tensin IV (AngIV), angiotensin (3–7), and angiotensin
Journal of Neuro-Oncology
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(1–7), derived to a greater or lesser degree from AngII
[15, 22, 23]. Moreover, when renin releases Ang1 from
AGT, an additional large protein (des(Ang I)AGT) is
formed. Both AGT and des(Ang I)AGT are non-inhibitory
serpins and can inhibit angiogenesis [24]. (Fig.1).
The effects of the bioactive angiotensin peptides are
expressed mainly through AT1R and AT2R, but also
through the Mas receptor, the AngII receptor type 4
(AT4R), the insulin-regulated aminopeptidase (IRAP),
and ACE2 [22, 23, 25] (Fig.2). Furthermore, Ang-(1–7)
functions principally through the G protein-coupled
receptor Mas [26]. Currently, it is considered that ACE2/
Ang-(1–7)/Mas axis and AngII/ATR2 are antagonists of
the ACE/Ang II/AT1R axis, particularly under pathologi-
cal conditions [26, 27].
RAS inthebrain
In the early 1960s, AngII was found to be a neuroactive
peptide based on injections into dog heads that had a
central hypertensive response [28]. In the 1980s, it was
demonstrated that AngII does not penetrate the blood–brain
barrier (BBB) and consequently inferred that the brain AngII
does not come from systemic RAS [29]. Later, it was shown
that all essential substrates and enzymes needed for the syn-
thesis, metabolism, and action of the bioactive angiotensin
peptides can be produced locally in the brain, apart from
the peripheral system [30]. Nevertheless, all RAS compo-
nents have not been found in a single brain cell [31]. Fur-
thermore, the different brain RAS elements are distributed
in a heterogeneous and mismatched pattern, with some of
the components with a broad distribution and others with
restrained locations [32, 33]. This fact implies that the brain
RAS requires a complex network of intercellular interactions
to produce its bioactive neuropeptides, with the possibility
that biochemical or enzymatic pathways being used [31].
Peripheral angiotensins are capable of interacting with the
brain RAS at the circumventricular organs (CVO), structures
in the brain that represent a connection between the CNS and
the peripheral blood flow and are characterized by their large
vasculature and lack of a BBB [34]. It is considered that the
peripherally produced angiotensins play a significant role in
the control of certain behavioral, endocrine, and autonomic
Fig. 1 Scheme from left to right of AGT gene, mRNA, and Protein.
AGT gene is located on the long arm of chromosome 1 (1q42.3), with
five exons and four introns and 13 kilobases total (kb). AGT is a pro-
tein that contains 452 amino acids, classified as a member of the Ser-
pins family. AGT Angiotensinogen
Journal of Neuro-Oncology
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functions through interactions at the CVOs. On the other
hand, the brain angiotensins perform central actions that are
not directly related to the systemic ones [34–36].
In the brain, this central system has been linked to neu-
roinflammation, sensory information, learning and mem-
ory, neurodegeneration, neuroprotection, emotional stress
responses, and gliomagenesis [22].
Neuroinflammation is mainly regulated by the effects
of AngII; the activation of AT1R leads to inflammation,
increased oxidative stress, disruption of the BBB and finally
neurotoxicity. In addition, the activation of AT2R induces
DNA repair pathways and cellular differentiation [37]. It is
important to mention that the components of RAS are not
expressed homogeneously in the CNS. The AT1R and AT2R
share a comparable pattern of distribution, but not equal,
which has been seen in humans and other mammalians [31,
38]. Opposite to AT1R that prevail in adult species, AT2R is
highly expressed in the developing brain [31, 39, 40]. AT1R
is localized in high densities in areas related to neuroendo-
crine functions and cardiovascular autonomic regulation and
the limbic system [31]. These areas include the anterior pitu-
itary, area postrema, subfornical organ, median eminence,
lateral geniculate body, the solitary nucleus, inferior olivary
nucleus, the anterior ventral third ventricle region, and para-
ventricular, preoptic and supraoptic nuclei of the hypothala-
mus [22, 33]. Moreover, AT2R is found with higher densities
in the amygdala, caudate-putamen, hippocampus, thalamus,
globus pallidus, medial geniculate body, among others [22,
33].
On the other hand, AT4R has been found in basal ganglia,
cerebellum, anterior pituitary, neocortex, lateral geniculate
body, ventral lateral thalamic nucleus, motor cortex, and in
motor neurons of the brain stem and ventral horn of the
spinal cord [22, 37]. This pattern of distribution of AT4R
coincides with recent findings that suggest an essential role
of AngIV in memory enhancing and cognitive facilitation,
Fig. 2 Renin-angiotensin system in the brain. Peptides and enzymes
that participate in the conversion of angiotensinogen to angiotensin
I, as well as active forms and receptors. ACE angiotensin-converting
enzyme, ACE 2 angiotensin-converting enzyme 2, Ang III angiotensin
3, AT1R angiotensin II receptor type 1, AT2R angiotensin II receptor
type 2, MASR maspin receptor
Journal of Neuro-Oncology
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effects that have been seen in response to ARBs [41]. Just
as the AT4R, the Mas receptor which is found in hippocam-
pus and amygdala, has been related to memory and learning
[37, 42]. Furthermore, the ACE2/Ang-(1–7)/Mas axis could
have an active and promising neuroprotective effect facing
ischemic stroke, as Ang-(1–7) increases the production of
both neuronal nitric oxide synthase (NOS) and endothelial
NOS [37].
Role ofRAS incancer
Analyzing the RAS under the Hanahan and Weinberg para-
digm of the tumorigenesis hallmarks gives an understanding
of how this system provides cancer cells with functional
capabilities that allow them to survive, proliferate and dis-
seminate [14]. Multiple experiments have demonstrated the
effect of RAS on sustaining proliferative signaling, evading
growth suppressors, resisting apoptosis, inducing angiogene-
sis, deregulating cellular energetics, as well as playing a role
in inflammation, cellular migration, invasion and metastasis
[14, 15, 18, 43–50].
Distinct profiles of the gene expression of components of
RAS have been described in several types of cancers. For
example, the AGT gene has been associated with gastric can-
cer and H. Pylori, breast cancer in the post-menopause stage,
colorectal cancer, or renal cell carcinoma [51–54]. Pringle
etal. showed that the G allele of AGT rs699 (g.9543T > C;
c.803T > C), which is associated with a 10–20% increase in
plasma AGT levels, was decreased in prevalence in women
with endometrial cancer. They also found that the AT1R sin-
gle nucleotide polymorphism (SNP) rs5186 (g.49331A > C;
c.*86A > C), which is known to be associated with over-
expression of the AT1R, is more prevalent in women with
endometrial cancer [55]. This same AT1R SNP and the SNP
rs1492078 (g.4520T > C; c.-869T > C) were studied in a
prospective cohort study in Netherlands. Having the AT1R
rs1492078 (g.4520T > C; c.-869T > C) polymorphism cor-
related with a decreased risk of developing renal cancer,
whereas AT1R rs5186 (g.49331A > C; c.*86A > C) showed
an increased risk. These associations were more significant
in patients with a prior history of hypertension [56].
Accumulating evidence has suggested that AT1R is
expressed in various tumors and that its expression is sig-
nificantly associated with tumor growth. The expression of
the AT1R receptor has been correlated with more aggressive
disease [18, 57–59]. Arrieta etal. analyzed 77 breast tumors
and found that the expression of the AT1R receptor was
associated with a higher mitotic index, cellular proliferation
and angiogenesis [60].
AT1R and AT2R are G protein couple receptors with plei-
otropic activities with antagonistic effects. When activated,
AT1R promotes cellular proliferation and angiogenesis,
whereas AT2R has antiproliferative properties [15]. AT1R
activates several intracellular signaling pathways, includ-
ing second messengers PLCβ and Rho GEFs, and inositol
triphosphate, diacylglycerol and reactive oxygen species,
epidermal growth factor receptor (EGFR), platelet-derived
growth factor receptor (PDGFR), insulin-like growth fac-
tor-1 receptor (IGF-1R), G proteins including Ras, Rho
and Rac, and receptor activator of nuclear factor-κB ligand
(RANKL) [61]. Further, AngII leads to the upregulation of
transforming growth factor beta (TGF-β) in neuroinflamma-
tory processes, through the activation of AT1R and throm-
bospondin-1 (TSP-1) [62]. Importantly, AT1R signaling
leads to potent induction of vascular endothelial growth
factor (VEGF) [61]; the knowledge of this mechanism led
to the development of the interesting work of Levin etal.
where they describe a better survival in glioma patients
using angiotensin system inhibitors that were receiving
bevacizumab (BVZ) with/without cytotoxic chemotherapy
compared to those who were not using them [63]. While the
role of AT2R in cancer is less understood, it had been pos-
sible to see its effects. For instance, in an AT2R knockout
mice model, it was demonstrated that inhibition of AT2R
delays tumor growth by impairing VEGF expression [64].
Recently, antihypertensive drugs have been studied as
potential adjuvants in the treatment of cancer [18]. For
instance, a retrospective analysis of 269 bladder cancer
patients treated with ACEIs and angiotensin II receptor
blockers (ARBs) resulted with better overall survival (OS)
and cancer-specific survival (CSS) [65]. The effect of better
OS using ARBs has also been seen in patients with meta-
static breast and colorectal cancer by enhancing the effects
of BVZ [66]. Furthermore, the use of Ang-(1–7) inhibitors
is currently being studied in-vivo and in-vitro preclinical
models. Ang-(1–7) inhibitors work by obstructing cancer
cell growth, tumorigenesis, metastasis, and proliferation,
decreasing the expression of oncogenes, protein kinases and
cell cycle regulators, diminishing the expression of apopto-
sis inhibitors and promoting apoptosis, and also inhibiting
blood vessel formation in tumor cell lines. This has led to the
study of the use of Ang-(1–7) inhibitors as potential adju-
vants in chemotherapy and chemoprevention agents [67].
RAS ingliomagenesis andpotential
biomarkers
Several known clinical criteria serve as good prognostic
markers for gliomas such as younger age, maximal safe
resection, better Karnofsky Performance Score (KPS) and
lower WHO grade [3]. In the case of GBM, some biomark-
ers have shown to offer prognostic value. Of these mark-
ers, the IDH 1/2 mutation, the methylation of the promoter
Journal of Neuro-Oncology
1 3
O6-methylguanine-DNA methyltransferase (MGMT), and
the loss of heterozygosity (LOH) of 1p19q are used rou-
tinely for diagnostic and prognostic purposes, and they are
all considered good prognostic factors [68, 69]. Just as these
biomarkers are associated with carcinogenesis, the expres-
sion and regulation of RAS genes play a significant role in
the development and behavior of tumors, including gliomas.
This has been demonstrated both in-vivo and in-vitro, and
as a result, it has been hypothesized that the detection of
particular RAS components can lead to their application as
molecular biomarkers and that RAS antagonists could be
protective against cancer [15, 43].
The discovery of the RAS peptides and receptors in
GBM has encouraged their study from a different perspec-
tive. Indeed, in 2004, Juillerat-Jeanneret etal. reported that
AGT, prorenin, ACE, AT1R, and AT2R are produced and
expressed by human GBM and GBM cell in cultures. Also,
the presence of AGT in the pseudocyst of GBM, and ACE
expression in tumor-related vasculature were seen [17]. In
another study, Bradshaw etal. demonstrated that the com-
ponents of the RAS are also expressed in cancer stem cells
of GBMs [70]. Some specific RAS components have been
investigated in relation with gliomagenesis and have given
signs about how they could be applied as biomarkers, such
as the following.
AGT
In a retrospective study, predictor factors of BVZ response
were analyzed in recurrent GBM patients. An association
between the low and high expression of AGT and HLA class
II gene (human leukocyte antigen complex class II DQ alpha
1, HLA-DQA1) respectively, and a prolonged PFS and OS
in recurrent GBM patients treated with BVZ [71]. Further,
preliminary data from a prospective analysis performed by
our research team revealed a relation of the rs5050 AGT
polymorphism with prognosis in astrocytoma patients. In 48
patients harboring primary astrocytoma, a significant corre-
lation was found between the blood-detected GG-genotype
of rs5050 AGT and a lower survival rate (2 months in the
recessive group vs. 11 months in other groups, p 0.018) [72].
An extensive paper of the relation of several variants of the
AGT and gliomas is in progress [73].
ACE gene
Several studies have demonstrated a correlation between the
ACE I/D polymorphism and certain types of cancer [74–80].
Recently, a Chinese population study identified the ACE DD
genotype as a risk factor for glioma. The DD genotype is
correlated with a higher plasma ACE activity in compari-
son to the other genotypes [81, 82]. This case-controlled
trial compared the ACE I/D genotypes between 800 glioma
patients and 800 controls, and it showed a higher presence
of ACE DD genotype in the glioma cases [83].
AT1R andAT2R
AT1R exhibits a range of effects in angiogenesis, cellular
proliferation, inflammation and cellular apoptosis as a posi-
tive regulator. In contrast, AT2R downregulates angiogen-
esis and inflammation [18]. This variability in biological
responses highlights the complexity of the role of RAS in
angiogenesis and cellular proliferation, either in a direct or
indirect way. These biological effects could suggest a link
between AT1R and AT2R and cancer in tumoral prolifera-
tion and angiogenesis. For instance, according to a transcrip-
tional network analysis, the positive expression of AT1R
and AT2R correlates with the regulation of different sets
of hub genes related to glioma progression. This hub-based
study reported that AT1R and AT2R inhibitions downregu-
late genes involved in protumoral functions in cells from
the C6 glioma cell line, suggesting both Ang-II receptors as
potential therapeutic targets [84].
A particular aspect to consider is the reliability of the
anti-AT1R antibodies for Western blot analysis and immu-
nohistochemistry. It has been reported the difficulty of pro-
ducing highly specific antibodies for G protein-coupled
receptors (such as AT1R), and a study performed in a mice
model demonstrated the lack of specificity of a commercial
panel of anti-AT1R antibodies [85]. Therefore, even though
AT1R isoforms have not been described in humans, it has to
be considered other quantitative or qualitative methods for
its detection (for instance, Northern blot or RT-PCR), either
for research or clinical purposes.
Ang‑(1–7)/Mas receptor
It has been demonstrated that some RAS components are
part of a counter balance axis that opposes AngII. Among
these counteractive RAS components are Ang-(1–7) and
the MAS receptor. This Ang-(1–7)/Mas axis plays an anti-
tumorigenesis role, decreasing growth and invasiveness in
some kinds of cancer [15, 86]. In-vitro, Ang-(1–7)/Mas sign-
aling inhibition by podocalyxin increased cell invasion and
proliferation in GBMs [87].
RAS blockers ingliomas
Antihypertensive drugs, in particular those that target
RAS components, like ACE inhibitors (ACEI) and AT1R
antagonists, have been studied as an emerging therapy to
affect tumor progression. So far, there are four known clus-
ters of RAS blockers: direct renin inhibitors (DRI) (i.e.
aliskiren), ACEIs (i.e. captopril, enalapril), AT1R blockers
Journal of Neuro-Oncology
1 3
(i.e. losartan) and aldosterone antagonists (i.e. spironolac-
tone) [88]. The use of approved antihypertensive drug to
treat cancer could be advantageous due to their availabil-
ity, good side effect profile, and low cost since they do not
need to go through preclinical studies and some early clini-
cal trials. However, outcomes are difficult to predict due to
the complexity of the RAS role in carcinogenesis [15, 67].
According to retrospectives analyses, antihypertensive drug
therapy has prophylactic and protective potential in suscep-
tible individuals against several types of cancer, including
prostate and breast [19, 89–91].
In the context of gliomas there has been some works
that use RAS blockers (Table1). Rivera etal. published
the first study that demonstrated the presence of AT1R
on glioma cells, as well as the impact of the blockage of
AT1R with a losartan (a selective AT1R antagonist which
is able to cross the BBB) on the tumor development. In this
study, the authors inoculated glioma cells subcutaneously
in rats, which posteriorly were treated with different losar-
tan doses for 30days. Interestingly, the results showed a
dose-dependent change in the behavior of subcutaneous C6
rat gliomas using losartan. The higher dosage of losartan,
the greater decrease in tumoral volume, mitotic index, cell
proliferation, and the number of capillary vessels [16]. The
presence of angiogenic cytokines related to tumor angio-
genesis (VEGF, PDGF, bFGF, EGF, TNFα, and TGF α and
β) is insignificant in the brain under normal conditions [92].
However, the stimulation of AT1R in glioma can lead to
the overexpression of some of these growth-related factors,
and therefore, promote cell proliferation and angiogenesis.
It has been observed during glial tumorigenesis that AT1R
can induce the expression of PDGF, which in turn causes
liberation of VEGF [93]. This anti-angiogenic mechanism,
along with the increase of bioavailability of AngII for AT2R,
Table 1 Summary of reports RAS blockers in gliomas
AT1R angiotensin II type-1 receptor, ACE aldosteron converting enzyme, OS overall survival, PFS progression-free survival, KPS Karnofsky
performance status, RT radiotherapy, TMZ temozolamide, FLAIR fluid attenuated inversion recovery, MRI magnetic resonance imaging, BVZ
Bevacizumab
Author & year Antihypertensive group Antihypertensive drug Effect or outcomes on
gliomas
Type of assay
Rivera etal. 2001 [16] AT1R antagonist Losartan ↓ Tumor volume
↓ Mitotic index
↓ Cell proliferation
↓ Vascular density
In vivo; subcutaneously
inoculated C6 rat glioma
cells implantation
Jiullerat-Jeanneret etal.
2000 [94]
ACE inhibitor Lisinopril No significance difference
in glioma features
In vivo; stereotactic trans-
plantation of the rat glioma
G2 cells in syngeneic rat
brains
Jiullerat-Jeanneret 2004
[17]
Renin-selective inhibitor RO0663525 ↓ DNA synthesis
↑ Apoptosis
In vitro; human glioblastoma
cells in culture
Arrieta etal. (2005) [97] AT1R antagonist Losartan In vivo:
↓ Tumor volume
↑ Apoptotic rate
↓ Growth factors
In vitro:
↓ Cell viability
↑ Apoptosis rate
In vivo; subcutaneously
inoculated C6 rat glioma
cells implantation. Invitro;
C6 glioma cells cultures
Carpentier etal. (2012)
[101]
ACE inhibitor & AT1R
antagonist
Not specified ↓ Steroid dosage required Clinical retrospective study;
GBM patients treated with
standard of care
Carpentier etal. (2015)
[100]
ACE inhibitor & AT1R
antagonist
Not specified ↑ OS
↑ PFS
↑ KPS Post-RT
↑ Steroid doses
Clinical retrospective study;
GBM patients treated with
RT and TMZ
Carpentier etal. (2016)
[102]
AT1R Antagonist Not specified ↓ Volume of peri-tumoral
hyper T2-FLAIR signal
(decreased edema)
Cross sectional study; GBM
patients treated with ARBs
for high blood pressure,
with pre-operative MRI
without steroids
Levin etal. (2017) [63] ACE inhibitor & AT1R
antagonist
Not specified ↑ OS Clinical retrospective study;
Grade II–IV gliomas
patients treated with
chemotherapy and/or BEV
Journal of Neuro-Oncology
1 3
could explain the response of the inoculated gliomas to the
AT1R antagonist seen in this experiment.
One year before, Jiullerat-Jeanneret etal. conducted an
invitro and invivo study, where they demonstrated renin
immunoreactivity in both human brain parenchyma and
GBM cells, and high expression of ACE in tumor vascu-
lature. Their most significant finding was the higher ami-
nopeptidase A (APA) activity in tumor vessels, which was
demonstrated not to be related to neovascularization. This
APA overexpression was downregulated by TGFβ, infer-
ring a role of this peptide in the APA activity regulation in
endothelial cells. In the animal model used for evaluating the
invivo expression of APA and the effects of the angiotensins
blockage, they found that chronic intake of lisinopril did
not affect the glioma growth or size in their rat model. The
difference between the treated and non-treated groups was
not significant for glioma features, including tumor size and
APA activity in tumor vessels [94]. This study was interest-
ing in an additional sense because it proposed the APA as
a potential marker of chronic dysfunction of the metabolic
BBB, including loss of TGFβ capacity. It infers the accumu-
lation of AngIII in the tumor surroundings, instead of AngII
or AngIV which both own a significant role in the preserva-
tion of the normal BBB [95]. The anti-edema effect of the
glucocorticoids in brain tumor coincides with this finding,
as the steroids promote the ACE activity and diminish APA
expression, and therefore increasing AngII [95].
A subsequent invitro study by Jiullerat-Jeanneret etal.
evaluated the expression and function of the RAS peptides
and enzymes in GBM cell cultures. They found that AGT,
prorenin, ACE, AT1R, and AT2R are formed, and hetero-
geneously expressed, in human GBM and GBM cells in
culture. Furthermore, they detected AGT in the fluid from
human GBM pseudocyst, as well as ACE in tumor vessels
(as it was showed in their previous studies [94]). This sup-
ported the statement that all RAS components are potentially
found, but non-homogeneously, in the tumor environment.
The cell proliferation and survival were not affected by add-
ing AGT, des(Ang I)AGT, tetradecapeptide renin substrate
(AGT1-14), AngI, AngII or AngIII, directly to the GBM
cell cultures. Then, they evaluated the inhibition of the renin
and ACE enzymes. Cell proliferation was not altered with
the ACEI administration (captopril -thiol ACEI-, or lisino-
pril -non-thiol ACEI-). On the other hand, one of the renin
inhibitors tested, the RO0663525 (a synthetic renin-selective
inhibitor) decreased the DNA synthesis, the number of via-
ble tumor cells, and induced apoptosis (in cells previously
deprived of fetal calf serum), suggesting its potential use
with other drugs to delay tumoral progression [17]. This
difference in the effect of the renin inhibitors can be due
to the lipophilicity and structure of the inhibitor and to an
intracellular function of renin. The blockage of this intracel-
lular action of the renin could prevent the activation of ERK
pathways, which are involved in tumor survival signaling
[96].
In 2005, Arrieta etal. assessed the impact of selective
AT1R blockage with losartan on the synthesis of neoangio-
genesis-related growth factors and the induction of apoptosis
in C6 glioma rat subcutaneous tumor models and cultured
C6 glioma cells [97]. In the animal model, rats were given
an injection of C6 glioma cells, and subsequently developed
tumor subcutaneously at the inoculation site. Next, losartan
(40- or 80mg/kg−1) was administered orally, once a day, per
30days. The tumoral volume had a dose-dependent reduc-
tion with the use of losartan, greater in 80mg/kg−1 losar-
tan group, without a natural decrease in the control group.
Apoptotic rate was measured in these tumors, and only the
80mg/kg−1 losartan dose had a significant effect. Platelet-
derived growth factor (PDGF), basic fibroblast growth factor
(bFGF) and VEGF concentrations were significantly dimin-
ished as a result of treatment with Losartan. No difference
was seen on hepatocyte growth factor (HGF) between groups
[97]. It is remarkable that the effect of the AT1R blockage
on the reduced tumor growth coincides with the diminish-
ing of these angiogenic growth factors, mainly with PDGF.
The reduction of VEGF and bFGF was not related to losar-
tan dosage as it was to the reduction of PDGF; hence we
can infer that their reduction was due to the blockage of the
PDGF stimuli, instead of AT1R. Additionally, within the
first hours of administration of concomitant losartan and
AngII, glioma cell cultures showed a decline in cell viabil-
ity and increase in the rate of apoptosis, while when AngII
was given alone, a rise in cell proliferation was observed
[97]. This phenomenon might be caused by the existence of
ATR1 and ATR2 in the glioma cells and their dual effects
[16, 18, 98, 99].
In 2015, Carpentier etal. reported the first retrospec-
tive analysis that evaluated the effect of AngII inhibitors
on the clinical outcome in newly diagnosed GBM patients
treated with RT and TMZ with/without AngII inhibitors.
Prior to the commencement of the study, 73% of the AngII
inhibitors-treatment group had already been taking ARBs
and 27% had already been using ACEIs. They found that
the cohort treated with AngII inhibitors (ARBs or ACEIs)
had better outcomes in comparison to the control group.
These results were reflected in a significantly higher perfor-
mance status (better KPS) at one and six months post-RT,
as well as longer PFS and OS [100]. An intriguing point of
this study might be the gathering of both AngII inhibitors
(ARBs and ACEIs) in only one group. On the one hand,
the improvement of the functional and survival outcomes
observed in these GBM patients warrants further investiga-
tion with prospective trials; but on the other hand, it remains
unclear if a difference exists between the ARBs and ACEIs
effects in a clinical setting. As the pre-clinical studies that
we commented earlier can hint it, ARBs and ACEIs have
Journal of Neuro-Oncology
1 3
a discrepancy between their effects in glioma. ARBs have
shown to reduce the tumor growth, and the neoangiogenesis-
related growth factors (PDGF, VEGF, bFGF) expressed in
C6 glioma rat models [16, 97]; whilst the ACEIs, except
for renin-selective RO0663525, did not show an impact on
GBM cell proliferation [17, 94].
Concerning the glucocorticoid use, the AngII inhibitors-
treated group required a lower steroid dosage, consistent
with two previous studies of the same group, which reported
that RAS blockade is related to vasogenic edema reduc-
tion and steroid-sparing effect in GBM [101, 102]. In the
prospective and retrospective studies by Carpentier etal.,
from 2012 to 2016 respectively, which were focused on the
anti-edema effect of the AngII inhibitors, the ARBs were
examined independently of the ACEIs. The results revealed
a lower steroid-dosage needed [101], and peri-tumoral
edema reduction on MRI (on the T2-Fluid Attenuated Inver-
sion Recovery (FLAIR) and Apparent Diffusion Coefficient
(ADC) sequences) on the part of ARBs [102].
Particularly remarkable is the fact that the potential
anti-edema effect has been recently proposed for a broad
spectrum of inflammatory brain disorders (such as neuro-
degenerative disorders, stroke, affective disorders, radia-
tion-induced damage, and traumatic brain injury), because
of the excessive brain AT1R activity found in early stages
for these disorders [103, 104]. Indeed, an invivo study by
Zhang etal. describes that the AngII induces neuroinflam-
mation and provoke BBB breakdown via oxidative stress
[105]. Additionally, the benefit of the ARBs on the modula-
tion of the BBB has already been reported. Fleegal-DeMotta
etal. studied invitro the effect of AngII and Telmisartan
(an AT1R inhibitor) in brain microvessel endothelial cells
(MECs). They found that AngII was related to an increase
in 125I-albumin permeability in MECs. This effect did not
change with the addition of PD123, 319 (an AT2R blocker),
but it was hindered by the use of telmisartan, which reduced
the transcytotic and paracellular BBB MEC permeability
[106]. Moreover, the ARB-induced vascular normalization
also may be related to the inhibitory action of the AT1R
blockage against the VEGF-induced vascular leakage, as it
was seen in an ischemic animal model [107].
Recently, Levin etal. published a relevant retrospective
clinical analysis, which evaluated the impact on survival of
the ARBs in GBM patients (newly diagnosed and recur-
rent GBM) treated with chemotherapy and/or BVZ. Also in
this study, the patients treated either with ACEIs or AngII
inhibitors, were analyzed as the same ARBs group. The
authors concluded that the use of ARBs offers a meaningful
OS advantage in glioma patients, particularly in recurrent
GBM patients treated with low-dose BVZ (7.5mg/kg every
3–4 weeks) with ARBs exposure [63]. Some aspects of this
work are worth mentioning. GBMs overexpress VEGF and
other neovascularization factors, and hence, anti-angiogenic
therapies have been proposed as part of the treatment for
these tumors. In regards to this, BVZ (a humanized mono-
clonal anti-VEGF antibody), is the most studied anti-VEGF
drug on GBM. However, the results of BVZ are far from
being entirely satisfactory. According to an extensive review
by Lu-Emerson etal. clinical evidence has shown that,
despite promising results in phase II trials for the use of this
anti-VEGF drug in GBM [108], the results of the addition
of BVZ to RT and TMZ-based chemotherapy in randomized
phase III trials exhibited an increase in PFS only but did not
show a significant gain in OS [108–110]. This information
supports the relevance of the results found by Levin etal. as
their combined treatment of BVZ and ARBs prolonged OS
in their patients. They also reported a more significant ben-
efit in recurrent GBM when it was given low-dose BVZ with
ARBs [63], which coincides with their previous work that
mentions a better outcome using BVZ at half the standard
dose for progressive or recurrent GBM [111].
A 2013 study by Lombardi etal. proposed antiangiogenic-
induced hypertension as a clinical biomarker of prognosis
in patients with recurrent GBM treated with antiangiogenic
drugs, either BVZ or sorafenib (a small inhibitor of sev-
eral tyrosine protein kinases, such as VEGFR and PDGFR).
In this retrospective analysis, they found that patients who
developed antiangiogenic-induced hypertension had a bet-
ter disease control rate, 6month PFS, and longer overall
survival [112]. It is noteworthy that the authors did not men-
tion the characteristics of the antihypertensive treatment (for
instance, type of drug: ARB, ACEI, or other), even though it
can be assumed, according to the methodology and results,
that all patients who exhibited hypertension started pre-
scription. Based on the new-found evidence, it may raise
the question of whether the antiangiogenic-induced hyper-
tension was the positive prognosis factor, or was the use
of antihypertensive drugs. Although theories had been pro-
posed about the mechanism by which antiangiogenic therapy
induces hypertension, it remains not entirely clear [113].
Nevertheless, it has been a matter of debate the use of ACEIs
to treat this condition. The report of some cases supports
the notion that ACEIs play a role as a counterbalance of the
antiangiogenic effect of BVZ and lessen its clinical activity
in solid tumors [114]. The reason for this response is related
to changes in the tumor microenvironment given by ACEIs;
it has been demonstrated that the chronic ACEI treatment
leads to the accumulation of bradykinin, substance P, and
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which
may undermine the profits of the antiangiogenic drugs [115,
116].
Low blood perfusion in tumors is another aspect to take
account when clinicians treat them through systemic drugs.
Tumor hypoperfusion is caused mostly by the increase in
vascular permeability and vascular compression. The reduc-
tion in blood perfusion leads to a drop of oxygen diffusion,
Journal of Neuro-Oncology
1 3
creating a hypoxic tumor microenvironment, and hinder
drugs penetration. Stylianopoulos and Jain proposed a math-
ematical model to predict the optimal therapeutic strategy to
reach the vascular normalization and relief of solid stress,
according to the tumor microenvironment features, in order
to improve the oxygen and drug delivery [117]. In accord-
ance with this work, Jain etal. performed a study by which
they demonstrated that the use of Losartan inactivates can-
cer-associated fibroblasts (CAFs) and diminishes the produc-
tion of matrix components (such as hyaluronan and collagen)
that are responsible for the solid stress and blood vessels
compression in collagen-rich tumors, and therefore amelio-
rating the vascular perfusion [118]. This identified effect of
ARBs increases drug and oxygen delivery into the tumor
environment, by reducing intratumor hydrostatic pressure
and vascular compression, improving tumor perfusion, and
therefore, enhancing chemo- and oxygen-dependent radio-
therapy [118–120]. It is noteworthy that at the beginning of
the experiments, the authors tested the effect of lisinopril
(ACEI) versus losartan (selective AT1R inhibitor) on the
matrix, to determine the function of angiotensin receptor
signaling in tumor fibrosis. Interestingly they found a lower
impact on desmoplasia with lisinopril, suggesting an anti-
desmoplasia effect of AT2R (as ACEIs block both AT1 and
AT2 receptors) [118].
The ACE/Ang II/AT1R axis contributes to an immuno-
suppressive tumor milieu by promoting desmoplasia, stim-
ulating abnormal vasculature formation, and modulating
proinflammatory factors and immune cells [121]. Evidence
shows that this immunosuppressive milieu limits the effects
of novel immune checkpoint blockers. Therefore, it has been
suggested that ARBs have the potential to enhance immu-
notherapy of GBM and other tumors [63, 121–123]. ARBs
have shown to reduce infiltration of immunosuppressive cell
types, and augment delivery of intratumoral effector T cells
and immunotherapeutic drugs. This ARBs effect can poten-
tially allow lower dosage of immunotherapy and, in turn,
reduce the undesired side effects [121].
Besides the potential effect of increasing the tumor oxy-
gen delivery and radiosensitivity [120], the ARBs have also
been suggested as therapy for preventing radiation-induced
brain damage [104]. This topic has attracted attention in
multiple settings, ranging from nuclear power plant acci-
dents to space missions [124–126]. So far, the mechanism
of reduction of radiation injury is not completely under-
stood, but it might be related to the indirect inhibition of
TGF-β (contributor to radiation-induced fibrosis) via AngII
blockage [125]. Evidence suggests that the use of ARBs can
prevent or mitigate the irradiation-induced cognitive impair-
ment. In two studies, Robbins etal. demonstrated in an irra-
diation rat model that the L-158,809 (AT1R inhibitor) [127]
and ramipril (ACEI) [128] given before, during, and after
fractioned whole-brain irradiation prevent the perirhinal
cortex-dependent cognitive impairment after irradiation.
The effect of Ramipril on the irradiation-induced reduction
in neurogenesis remains unclear [128, 129].
Due to the evidence given by all pre-clinical and clinical
studies on the positive effects of AngII inhibitors in gliomas,
new clinical trials are running nowadays with the purpose of
testing the potential beneficial role of these drugs in GBM.
For instance, the Captopril was proposed in 2013 as part of
the treatment protocol named Coordinated Undermining of
Survival Paths, CUSP9* in recurrent GBM patients. This
protocol consists of nine drugs (including captopril) added
concomitant to low continuous doses of TMZ in relapsed
GBM, to block 17 different GBM growth-enhancing path-
ways. Clinical outcomes regarding this protocol have not
yet been reported [130, 131]. For the same year, the Angio-
tensin II Receptor Blockers, Steroids, and Radiotherapy in
Glioblastoma (ASTER) trial was registered in France, which
is a multicenter, double-blinded, and randomized study.
Carpentier etal. will assess the clinical outcomes in GBM
patients undergone to the standard management (RT with
TMZ-based chemotherapy), treated with losartan versus Pla-
cebo. In the 2018 update, the study is ongoing, whilst the
recruitment has already been completed [132].
Conclusion
Our understanding of the RAS, a model that was considered
canonical for a long time, has evolved enormously in recent
years. In the same way, our learning about the mechanisms
and biochemical pathways related to gliomas has advanced
at a fast pace reaching new limits. Despite these facts, the
part of this iceberg of knowledge that remains under the
surface is still immense. The pursuit of a better understand-
ing of pathways and their complex networks has led us to
the discovery of a connection between this new concept of
RAS and gliomagenesis. The detection of RAS peptides and
receptors in gliomas has attracted the interest particularly
of neuroncologists, neurologists, and neurosurgeons due to
their potential application as molecular biomarkers or targets
for treatment. Advantages are clear, for instance, as biomark-
ers, some of the RAS components can be detected by blood
sample, and as targets for treatments, ARBs are widely avail-
able for a lower cost in comparison to other anti-neoplastic
agents. So far, the evidence is scarce to determine the com-
prehensive role of the RAS in the glioma pathophysiology
and immunology, but it is enough to encourage the design
of randomized clinical trials (such as CUSP9* and ASTER)
aimed to elucidate the impact of specific RAS components
and ARBs therapy in glioma patients.
Acknowledgements Special thanks to Alejandro Lafuente for his
invaluable help with the figures of this review.
Journal of Neuro-Oncology
1 3
Funding This project was funded by CONACYT
(Salud-2013-01-202720).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Research involving human participants and/or animals This article
does not contain any studies with human participants or animals per-
formed by any of the authors
Informed consent This article does not require informed consent.
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