Accepted Manuscript

Commentary

The role of angiotensin II in cancer metastasis: Potential of renin-angiotensin

system blockade as a treatment for cancer metastasis

Shin Ishikane, Fumi Takahashi-Yanaga

PII: S0006-2952(18)30105-9
DOI: https://doi.org/10.1016/j.bcp.2018.03.008
Reference: BCP 13085

To appear in: Biochemical Pharmacology

Received Date: 29 January 2018

Accepted Date: 8 March 2018

Please cite this article as: S. Ishikane, F. Takahashi-Yanaga, The role of angiotensin II in cancer metastasis: Potential
of renin-angiotensin system blockade as a treatment for cancer metastasis, Biochemical Pharmacology (2018), doi:
https://doi.org/10.1016/j.bcp.2018.03.008

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: The role of angiotensin II in cancer metastasis: Potential of renin-angiotensin

system blockade as a treatment for cancer metastasis

Shin Ishikane and Fumi Takahashi-Yanaga

Department of Pharmacology, School of Medicine, University of Occupational and

Environmental Health, Japan

Corresponding Author: Shin Ishikane

Department of Pharmacology, School of Medicine, University of Occupational

and Environmental Health, Japan

1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu, Fukuoka 807-8555, Japan

Tel: +81-93-691-7424

Fax: +81-93-601-6264

E-mail: ishikane@med.uoeh-u.ac.jp

1
Abstract

Hypertension, which often exists as a comorbid condition in cancer patients, is

considered as a factor affecting cancer progression. The renin-angiotensin system (RAS)

plays an important role in the regulation of blood pressure, and angiotensin II (Ang II)

is a well-known pressor peptide in RAS. There is also accumulated evidence indicating

that Ang II plays a critical role in the metastasis of various cancers by modulating

adhesion, migration invasion, proliferation, and angiogenesis. Consistent with this, large

epidemiological studies have reported the potential beneficial effects of

angiotensin-converting enzyme (ACE) inhibitors and Ang II type 1 receptor blockers

(ARBs) against cancer metastasis; however, some of the results remain controversial.

Although the precise Ang II-related mechanisms involved in cancer metastasis are not

completely clear yet, a number of basic and meta-analytic studies have shown that ACE

inhibitors and ARBs reduce the metastatic potential of tumors. In this review, we

summarize the relationships among hypertension, RAS, and metastasis as demonstrated

in basic and clinical studies. Finally, we discuss the possibility of using RAS inhibitors

as anti-metastatic drugs.

Key words

2
Renin-angiotensin system, Angiotensin II, Hypertension, Cancer, Metastasis and

Renin-angiotensin system inhibitors

3
1. Introduction

Cancer is a major cause of death in the present world. The forms of cancer

therapy that are commonly employed are surgery, chemotherapy, targeted therapy, and

immunotherapy. Through early recognition and extirpation, it is possible to reduce the

death rate among cancer patients. However, the difficulty of removal of all cancerous

tissues increases greatly once distal metastasis has occurred. As metastasis is the major

cause of cancer-related death, preventing its occurrence is expected to be a beneficial

therapy for cancer patients [1, 2]. However, clinically usable anti-metastatic drugs have

not been developed.

The renin-angiotensin system (RAS) plays a pivotal role in controlling blood

pressure [3]. Angiotensin II (Ang II), in particular, is the key player. A high level of Ang

II is observed in the blood of approximately 90 of patients with malignant

hypertension and renal hypertension [4]. Therefore, RAS inhibitors, such as

angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor blockers (ARBs),

are used as major anti-hypertensive agents [5]. Hypertension, a frequent comorbid

condition in cancer patients [6, 7], is recognized as a risk factor for cancer progression

[8, 9]. Thus, the use of anti-hypertensive agents may influence patient survival

outcomes. Indeed, several studies have suggested that treatment with ACE inhibitors or

4
ARBs is not only effective against cardiovascular diseases, but is also capable of

suppressing cancer progression and lengthening survival period [10-12]. Although many

epidemiological studies have revealed that RAS inhibitors suppress the growth and

metastasis of various cancers [13-17], the relationship between RAS activity and

metastasis remains unclear [18-22].

In this review, we summarize recent data concerning the relationships among

hypertension, RAS, particularly Ang II, and metastasis. Finally, we discuss the

possibility of employing RAS inhibitors, which are widely used as anti-hypertensive

agents, as anti-metastatic drugs.

2. Hypertension increases the risk of cancer

Hypertension is a major chronic disease that is estimated to affect about 20 to

40% of the global human population with increasing prevalence [23]. Therefore, it is

reasonable that hypertension is a frequent comorbid condition in cancer patients [6, 7].

Hypertension has been established as a risk factor for various cancers, including breast,

stomach, kidney, and colon cancers [7-9]. In the case of renal cell carcinoma (RCC),

high levels of blood pressure were associated with increased risk [24]. Furthermore, it

has been reported that a decrease in renal cancer risk is associated as well with blood

5
pressure level, suggesting that hypertension could promote renal cancer and that

effective control of blood pressure may reduce renal cancer risk [7].

A cohort study on patients with a history of long-term hypertension reported that

the risks of cancer progression (kidney, prostate, colon, bladder, pancreatic, endometrial,

brain cancers and melanoma) increases as the level of hypertension increases [8, 24]. It

has also been reported that chronic kidney disease induces hypertension and activates

cancer metastasis [25]. The large prospective cohort study showed that elevated blood

pressure is significantly associated with cancer incidence and mortality in patients with

malignant melanoma and lung, liver, colon, or bladder cancer [9]. In the case of ovarian

cancer patients, hypertension has been reported to be associated with lower survival

periods [26]. Since cancer-related deaths often result from uncontrolled metastasis,

decreased survival periods which result in increases in cancer mortality could be

associated with metastasis formation.

Thus, the results of these clinical studies indicate that high blood pressure

increases not only the risk of cardiovascular mortality but also cancer mortality.

3. Hypertension and RAS

The RAS plays an important role in regulating circulatory volume through water

6
and electrolyte balance, and upregulation of this system causes hypertension [3]. Renin

is synthesized in the kidneys in its inactive form, called pro-renin, and is released into

circulating blood in response to low levels of sodium and low circulatory volume. In the

circulating blood, pro-renin is activated by proteolytic and non-proteolytic mechanisms

to produce the active form of renin. Active renin catalyzes the cleavage of the

glycoprotein angiotensinogen, generating angiotensin I (Ang I). Ang I is cleaved by the

angiotensin-converting enzyme (ACE), a zinc metalloprotease found in circulation or

bound to the cell membrane, to produce Ang II. Ang II, a multifunctional bioactive

octa-peptide and key player in RAS, increases systemic and local blood pressure by

vasoconstriction, retention of sodium and water in renal tubules, and stimulation of

aldosterone release from the adrenal gland [27] (Figure 1).

Ang II binds to the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor

(AT2R), both of which belong to the G-protein-coupled receptor superfamily but have

different tissue distribution and are involved in different intracellular signaling

pathways [28]. Most physiological effects of Ang II are mediated by AT1R, whereas

AT2R triggers effects that are the opposite of those mediated by AT1R. For example, in

vascular physiology, AT1R stimulation causes vasoconstriction by the activation of

phospholipase C through the heterotrimeric Gq protein in vascular smooth muscle cells

7
[29]. On the other hand, AT2R stimulation thought to be lead vasodilation through

increasing of vascular nitric oxide (NO) production, whereas the exact signaling

pathways and the functional roles of AT2R are not clarified yet [29]. AT1R is expressed

in many adult tissues, including blood vessels, the adrenal cortex, liver, kidney, and

brain. On the other hand, AT2R is predominantly expressed during fetal life, but is

present at a low level in a few adult tissues such as the adrenal medulla, uterus, and

ovarian follicles [28, 30].

In addition to its effects on blood vessels, Ang II has been shown to play a role in

various pathological situations related to tissue remodeling, such as alterations of

fibrosis, vascular permeability and inflammatory cascade [31, 32]. The role of Ang II in

cell proliferation, migration, tissue invasion and angiogenesis suggests that this peptide

might also be involved in tumor metastasis. Further, it has been also suggested that the

signal evoked through ATR1promotes cancer metastasis, whether the signal evoked

through AT2R shows opposite effects as described in section 4.

4. Ang II in distal hematogenous metastasis

As tumor metastasis is the major cause of cancer-related death, the initiation of

metastasis threatens cancer patients’ lives. Distal hematogenous metastasis consist of

8
multistep processes: (1) intravasation from the primary site into the blood stream, (2)

dissemination through blood circulation, (3) adhesion to vascular endothelial cells, (4)

migration into and invasion of the targeted organs, and finally (5) proliferation and

angiogenesis (Figure 2). As Ang II upregulates angiogenesis and could increase

vascular permeability [33, 34], intravasation might be accelerated by Ang II. However,

since majority of the studies about the relationship between Ang II and distal

hematogenous metastasis were focused on the steps 3-5 (mentioned above), we would

like to shed the light to these steps in this section.

4.1. Effects of Ang II on tumor adhesion to vascular endothelial cells

The adhesion of circulating cancer cells to the endothelium and the subsequent

trans-endothelial migration of these cells are critical steps in the metastatic process [35].

Cell adhesion occurs under forces exerted by the flow of blood (hemodynamic shear

stress) and is promoted by adhesion molecules specialized for interaction under shear

conditions. It is revealed that the hemodynamic shear stress up-regulates expression of

adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1),

and vascular endothelial cell adhesion molecule-1 (VCAM-1) on microvascular

endothelial cells [36]. Therefore, identifying the molecules that mediate interactions

9
between cancer cells and endothelial cells is necessary in designing specific methods for

the prevention of metastasis. The pathophysiological roles of cell adhesion molecules in

the process of inflammation have been extensively studied [37, 38]. The cells interact

with adhesion molecules on the vascular endothelium in a sequential fashion, rolling

along the endothelial surface until they are firmly attached, at which point they

extravasate to the target tissues. Selectins play a major role in the rolling of circulating

tumor cells. Multiple selectins have been identified. L-selectin is expressed mainly on

leukocytes, E-selectin on endothelial cells, and P-selectin on endothelial cells and

platelets. After rolling, tumor cells firmly adhere to the activated endothelium, which is

mediated by cell adhesion molecules such as ICAM-1, VCAM-1, and integrins. This

then leads to the subsequent trans-endothelial migration of the cells. These adhesion

molecules are induced upon inflammation, and Ang II is well-known inflammatory

agent [32, 37]. In fact, Ang II treatments can enhance the expression of these adhesion

molecules on several tissues, such as vascular endothelial cells, smooth muscle cells,

and platelets. Although reports on this pathway are still few, Amano et al. have shown

that endogenous AT1R signaling promotes tumor metastasis by upregulating

P-selectin–mediated platelet adhesion to metastatic tumor cells and endothelial cells in

lung tissue [39]. P-selectin is an adhesion molecule expressed on the surface of platelets,

10
and its expression increases upon the activation of platelets [40]. Because P-selectin

knockout mice have shown a significant reduction in tumor volume and metastasis [41],

this molecule seems to be involved in cancer. Furthermore, we have found that Ang II

upregulates E-selectin expression in lung vascular endothelial cells, thereby increasing

the number of adherent melanoma cells that form metastatic colonies in the lung

(manuscript in preparation). These results suggest that the Ang II-AT1R signaling

pathway plays a role in the adhesion of tumor cells to vascular endothelial cells through

the upregulation of the expression of adhesion molecules. The upregulation of EC

adhesion molecule may have a potential role in Ang II-induced tumor metastasis.

4.2. Effects of Ang II on tumor migration and invasion

Cancer cells employ a broad spectrum of migration and invasion mechanisms.

Inhibiting the migration and invasion of cancer cells is a primary strategy in cancer

treatment, and the activity of RAS is involved in these processes. The Ang II-AT1R

pathway plays a significant role in tumor cell invasion via the upregulation of the

vascular endothelial growth factor (VEGF) in invasive ovarian carcinomas. Tumor cell

invasion has been shown to be completely inhibited by candesartan (ARB) [42].

Furthermore, Ang II upregulates the proliferation, migration, and invasion of

11
hepatocellular carcinoma cells, and the overexpression of AT1R could enhance these

effects. In contrast, high AT2R expression had the opposite effect [43].

Rodrigues-Ferreira et al. have recently shown that Ang II may act directly on breast

cancer cells to accelerate the development of metastasis in vivo [44]. Microarray studies

revealed an increase in the expression levels of matrix metalloproteinase (MMP)-2,

MMP-9, and ICAM-1 in response to Ang II [44, 45]. MMPs belong to a zinc-dependent

endopeptidase family, and MMP-2 and -9 in particular play a key role in tumor

metastasis by degrading the extracellular matrix (ECM) and basement membranes [46].

As the enzymatic degradation of ECM is a crucial step in cancer invasion and migration,

these MMPs are upregulated in various malignancies.

The overexpression of AT1R has been reported to enhance tumor invasiveness,

as indicated by an increase in the expression of epithelial to mesenchymal transition

(EMT) markers [47]. Okamoto et al. reported that Ang II activates intrahepatic

cholangiocarcinoma (ICC) cell migration by mediating the occurrence of EMT [48].

They found that Ang II enhances the vimentin expression and the capability of cells to

migrate, and that it reduces E-cadherin expression in ICC cells. On the other hand,

AT2R stimulation has been reported to inhibit metastasis [49]. In this study,

AT2R-interacting protein 3a showed a potential to inhibit the migration and invasion of

12
ovarian carcinoma cells through the extracellular signal-regulated kinase (ERK)/EMT

pathway.

Taken together, Ang II facilitates migration and invasion in tumor cells at least

by upregulating the expression of MMP-2 and -9 and mediating EMT via AT1R

stimulation, whereas AT2R stimulation might inhibit migration and invasion through

ERK/EMT signal pathway.

4.3. Effects of Ang II on tumor growth and angiogenesis

Tumor growth requires the maintenance and expansion of a vascular network [50,

51], and the RAS plays important roles in the regulation of vascular homeostasis [52].

Therefore, one may speculate that Ang II induces tumor angiogenesis and growth. In a

number of experiments using tumor-bearing models, RAS inhibitors caused a reduction

in tumor growth and angiogenesis in different cell lines: prostate cancer cells [53],

melanoma cells [33], lung carcinoma cells [54], pancreatic cancer cells [55], and renal

carcinoma cells [56]. Because Ang II receptors are expressed in tumor cells and in the

tumor microenvironment [1], it is necessary to consider direct action on tumor cells and

indirect action on the tumor microenvironment in order to understand the effect of RAS

on cancer growth.

13
4.3.1. Role of AT1R and AT2R on tumor cells: Direct action

Several tumor cells, such as melanoma, pancreatic, renal, breast, bladder, and

prostate cancer cells, have been reported to express the angiotensin II receptors (Table

1) [55, 57-62]. It has also been shown that the expression levels of ACE, AT1R, and

AT2R are upregulated in tumor tissues [63]. AT1R is a major component in the

regulation of cell proliferation, angiogenesis, and inflammation. The activation of AT1R

by Ang II has been shown to stimulate the expression of VEGF, angiopoietin 2,

fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), all of which

are involved in cell proliferation and/or angiogenesis [64-66]. Since the stimulation of

VEGF expression by Ang II is mediated by AT1R, this effect was completely abolished

by candesartan [59]. In addition, since cell proliferation induced by Ang II or epidermal

growth factor (EGF) was inhibited by candesartan, ARB could inhibit the proliferation

of prostate cancer cells by inhibiting not only Ang II signaling but also EGF signaling.

Uemura et al. have shown that Ang II enhances the proliferation of prostate

cancer cells through AT1R-mediated activation of the mitogen-activated protein kinase

(MAPK) and phosphorylation of the signal transducer and activator of transcription 3

(STAT3) [53, 67]. A recent study also confirms the pro-tumorigenic role of AT1R. In

14
this study, the overexpression of AT1R in a breast cancer cell line increased the

proliferation of cells, the expression of poly (ADP-ribose) polymerase (PARP) and

X-linked inhibitor of apoptosis protein (XIAP), and the activation of MAPK and

Smad3/4 [47]. Treatment with losartan (ARB) attenuated these effects.

Thus, Ang II facilitates cellular proliferation and angiogenesis via AT1R,

whereas the role of the AT2R in tumorigenesis remains unclear. Several studies have

reported that AT2R contributes to tumor malignant transformation, and strategies to

block AT2R should be considered in inhibiting cancer growth [58, 68]. However, other

researchers suggest that Ang II signaling via AT2R has anti-proliferative effects through

apoptosis induction in cancer cells such as lung adenocarcinoma, colorectal cancer,

hepatocellular carcinoma, insulinoma, and prostate cancer cells [69-71]. In vivo studies

have revealed that chemical carcinogen-induced tumorigenesis is significantly enhanced

in the colon and lungs of AT2R-deficient mice [72]. The growth of pancreatic

carcinoma grafts was also accelerated in these mice [73]. Consistent with these findings,

AT2R has been shown to be a suppressor of tumor growth in vitro and in vivo [74, 75].

These findings suggest that the induction of AT2R expression in tumor tissues

suppresses tumor growth by inducing apoptosis. Thus, AT2R is a potential target for

cancer treatment.

15
4.3.2. Ang II signaling in cells in the tumor microenvironment: Indirect action

Since it is well-documented that neoplastic cells are influenced by their

environment, the tumor microenvironment niche is important for tumor growth and

metastasis [76, 77]. A complex host-tumor interplay is required to facilitate tumor

proliferation, escape from appropriate host-mediated immune clearance and matrix

remodeling, and metastasis to distal sites. A number of macrophages and fibroblasts

infiltrated within the tumor bed are positive predictors of metastatic potential, poor

prognosis, and shortened survival. These cells called tumor-associated macrophages

(TAMs) and cancer-associated fibroblasts (CAFs), and are expressed Ang II receptors

[1, 33, 78]. In addition, a large body of evidence suggests that Ang II signaling via

AT1R could regulate the secretion of growth factors and cytokines from tumor cells into

the tumor microenvironment. This enhances the proliferation of macrophages,

fibroblasts, and vascular-forming endothelial cells, resulting in the activation of tumor

cell proliferation [79]. While the implication of AT1R in the inflammatory and immune

processes is well defined, little is known about the contribution of AT2R. Although

AT2R functions are still somewhat controversial, the majority of studies support the

idea that AT2R is involving in an anti-inflammatory action [79, 80]. Therefore, it could

16
be suggested that the actions of the AT2R can be suppressed tumor microenvironmental

cell.

Because macrophages can release various angiogenic growth factors, including

VEGF, PDGF, EGF, basic FGF, interleukin (IL)-6, IL-8, and transforming growth

factor- (TGF-), it has been suggested that the infiltration of TAMs plays a pivotal role

in tumor angiogenesis [76, 81]. Egami et al. suggested that the host AT1R is

preferentially expressed on TAMs, which release VEGF, and therefore the Ang II-AT1R

pathway promotes tumor angiogenesis and growth in a TAM- and VEGF-dependent

manner [33]. In fact, macrophages express AT1R intensively, and Ang II enhances

macrophage inflammatory functions through AT1R [82]. The Ang II-AT1R signaling

has also been reported to affect the tumor microenvironment by promoting

macrophage mobilization and infiltration into the tumor bed via signaling pathways

involving the monocyte chemoattractant protein-1 (MCP-1) [83]. Fujita et al. have also

shown that the host stromal AT1R pathway is important in tumor growth and

tumor-associated angiogenesis using AT1R-deficient mice treated with or without AT1R

antagonists [54]. These observations suggest that Ang II-AT1R signaling accelerates

angiogenesis, thereby activating tumor growth. Consistent with these results,

candesartan has been shown to prevent RCC progression and lung metastasis by

17
inhibiting angiogenesis through the reduction of VEGF and TGF- expression in mouse

models as well as in clinical trials [16, 56].

CAFs, another class of important cells in the tumor microenvironment, are

associated with the initiation, growth, angiogenesis, invasion, and metastasis of cancer

[84]. Although there are few studies on the relevance between CAFs and Ang II

signaling, Ang II has been suggested to induce cancer progression through CAF

activation. CAFs are known to accelerate tumor cell proliferation by secreting many

kinds of growth factors, including VEGF. Furthermore, the immunosuppressive effect

of CAF, which is induced by Ang II enhancing the expression of nitric oxide synthase

(NOS) and (C-X-C motif) ligand (CXCL)-12, has been observed and has been shown to

be modifiable by ARB treatment [78]. Thus, the activity of CAFs may be regulated by

Ang II and may affect the tumor microenvironment.

In addition to TAMs and CAFs, Kupffer cells (KCs) have been shown to express

AT1R and ACE [85]. In mice implanted with colorectal cancer cells, there was an

increase in metastasis when KCs were depleted. Captopril (ACE inhibitor) and

irbesartan (ARB) were also shown to increase the anti-tumor effect of KCs and decrease

the extent of liver metastasis in individuals with colorectal cancer [85, 86].

18
 Considering the direct and indirect actions of Ang II, Ang II-AT1R signaling

could promote tumor growth and tumor-associated angiogenesis via direct effects on

tumor cells and indirect effects on the tumor microenvironment.

5. Effect of RAS inhibitors on cancer metastasis in clinical studies

ACE inhibitors effectively act as drugs for the treatment of hypertension and heart

failure by reducing the production of Ang II, which indirectly blocks the signal

transduction through AT1R and AT2R. In contrast, ARBs selectively block the action of

AT1R [87]. The first clinical evidence for the anti-tumorigenic capabilities of RAS

inhibitors was reported by Lever et al. In a large retrospective cohort study, they showed

that the long-term use of ACE inhibitors had potent protective effects against

carcinogenesis, whereas no significant effect was observed with other type

anti-hypertensive drugs (e.g. calcium-channel blockers, diuretics, β-blockers) [13].

The relationship between RAS inhibitors and cancer metastasis has been

demonstrated in several clinical studies. Miyajima et al. investigated the impact of RAS

blockade on the prognosis of patients with RCC after surgery [16]. In this cohort study,

the inhibition of RAS suppressed subsequent tumor metastasis and/or progression and

improved disease-specific survival. In another retrospective investigation, which was

19
performed by Tanaka et al., RAS inhibitors were analyzed as a prognostic factor

alongside other standard prognostic factors in patients who had undergone

nephroureterectomy for localized upper-tract urothelial carcinoma (UTUC) [17]. The

study revealed that subsequent tumor metastasis was significantly suppressed in patients

who were administered ACE inhibitors or ARBs. Multivariate analysis showed that in

addition to other standard prognostic factors, the administration of ACE inhibitors or

ARBs was an independent predictor of an increase in metastasis-free survival [17].

From these results, the use of RAS inhibitors was shown to have the potential to

increase metastasis-free survival and disease-specific survival.

On the other hand, several studies have reported that RAS inhibitors do not have

beneficial effects on cancer incidence and metastasis. An increase in the incidence of

some cancers among recipients of ARBs was first recognized in the Candesartan in

Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) study, in

which the effects of candesartan were compared to those of a placebo in patients with

chronic heart failure [18]. In this randomized controlled trials (RCT), although

candesartan significantly reduced cardiovascular deaths and hospitalization among heart

failure patients, a significant increase in the risk of cancer deaths was observed. Wang et

al. investigated possible associations between the incidental intake of ACE inhibitors,

20
ARBs, β-blockers, and aspirin with cancer survival in a large number of patients treated

for non–small-cell lung cancer [20]. They reported that the incidental receipt of ACE

inhibitors/ARB was not associated with distal metastasis-free survival, progression-free

survival, or overall survival, implying that the putative effect of ACE inhibitors and

ARBs is limited to progression at the primary site and does not affect metastasis.

Sun et al. reported that the type of cancer can influence the effect of RAS

inhibitors on mortality [14]. Improvement in mortality rates upon the administration of

RAS inhibitors was found in patients with RCC, gastric cancer, pancreatic cancer,

hepatocellular carcinoma, upper-tract urothelial carcinoma, and bladder cancers. In

addition, outcomes tended to be better in patients with rectal/colorectal cancer, lung

cancer, prostate cancer, glioblastoma, head and neck squamous cell carcinoma,

oropharynx cancer, and melanoma, although there was no statistical significance.

Conversely, the administration of RAS inhibitors had no beneficial effects on patients

with acute myelocytic leukemia and multiple myeloma.

Thus, there is a discrepancy in the reported effects of RAS inhibitors on the risk

of cancer occurrence, progression, and metastasis. We also note that RAS inhibitors

were shown to have a beneficial effect in some cohort and nested case-control studies

and studies with long-term follow up. On the other hand, it appears that the significant

21
benefits of RAS inhibitors are not observable in RCT [19, 88]. These results suggest

that clinical trial designs, cancer types, and duration of follow up could affect the result

of determining whether RAS inhibitors have beneficial effects against cancer. In order

to obtain a clear conclusion, large scale RCT with long-term follow up for each type of

cancer may be required. In addition, elucidating the role of RAS in cancer occurrence

and development may help in selecting cancer types for RCT.

6. The difference between ARBs and ACE inhibitors

Whereas only a few studies have focused on the differences between the effects of

ARBs and ACE inhibitors, several have shown that the type of RAS inhibitors may

influence the effect of blocking RAS on tumor formation in primary and metastatic sites.

Compared with ACE inhibitors, ARBs may produce better clinical results [14] since

some peptides that are involved in to the RAS pathway, such as angiotensin-(1-7) [Ang

(1-7)] and bradykinin [65], could influence the anti-tumor effects of ARBs or ACE

inhibitors (Figure 1).

Ang (1-7) is a heptapeptide produced by an ACE-dependent pathway. It

suppresses many Ang II-induced events [89], an effect which is mediated by the Mas

receptor (MasR). The ACE2/ Ang (1-7)/MasR axis, which is an alternative arm of RAS,

22
has been reported to inhibit tumor progression via multiple mechanisms such as

arresting tumor proliferation, promoting tumor apoptosis, and inhibiting tumor

angiogenesis [75]. Moreover, Ang (1-7) abolished Ang II-induced migration, invasion,

VEGF expression, and MMP-9 activity [90]. Thus, although Ang (1-7) could compete

with the action of Ang II in cancer progression, ACE inhibitors could suppress the

production of this peptide. Further, although it is not established theory, angiotensin

(3-8) fragment, which is denoted as angiotensin IV (Ang IV), has been reported to be

involved in the promotion and progression of cancer by inhibiting insulin-regulated

aminopeptidase IRAP and/or hepatocyte growth factor (HGF) /c-MET signaling

[91-93].

ACE inhibitors stabilize a peptide, bradykinin, which has been reported to cause

cancer progression. Bradykinin is implicated in the increased secretion of endothelin-1

in melanoma cells, which stimulates their growth and survival [94] and enhanced

migration of human cholangiosarcoma cells [95]. Therefore, although ACE inhibitors

prevent Ang II-induced tumor progression, this benefit may be blunted and even

possibly reversed by the reduction of Ang (1-7) production and bradykinin

accumulation. As a result, ARBs might show better clinical outcomes than ACE

inhibitors.

23
 Although further investigation is needed to confirm these speculations, such

RAS-associated peptides may be important factors in understanding the mechanism by

which RAS regulates cancer metastasis.

7. Future directions

Hypertension is often found as a comorbid condition in cancer patients, and has

been considered as a cancer progressive factor. Moreover, many chemotherapies are

potentially responsible for the onset of hypertension [96]. Usually, this iatrogenic

hypertension resolves when chemotherapy is stopped [97]. However, since the use of

chemotherapeutic drugs is associated with a significant increase in patient survival,

hypertension management becomes pivotal to avoid the interruption of effective

chemotherapy. Despite this, optimal anti-hypertensive medication has not yet been

defined.

Based on our understanding of the relationship between RAS and cancer metastasis

as deduced from in vitro experiments and animal models, Ang II induces cancer

metastasis by upregulating the hallmarks of metastasis, including adhesion, invasion,

migration, proliferation, and angiogenesis. Thus, the use of RAS inhibitors appears to be

a promising strategy in preventing cancer metastasis. However, a definite conclusion

24
has not been drawn from clinical trials. Although there are several reasons for this

contradiction, the difference in the expression levels of Ang II receptors among the

different types of cancer and patient could be one reason [98, 99].

There is a possibility that the anti-cancer effects of ARBs may differ depending on

the activation of peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ

belongs to the nuclear hormone receptor superfamily of ligand-dependent transcription

factors. Activation of PPARγ has been shown to modulate various hallmarks of cancer

through its pleiotropic effects on cells in the tumor microenvironment [100]. Recently, it

was demonstrated that PPARγ controls tumor progression by affecting various cellular

processes, including cell proliferation, apoptosis, angiogenesis, inflammation, and

metastasis. Indeed, the telmisartan (ARB), which is a partial PPARγ activator, has been

shown to inhibit cell proliferation by inducing apoptosis in various cancer cell lines

[101]. Telmisartan induced cell cycle arrest in hematologic and non-hematologic

malignancies, depending on PPARγ activity [102, 103]. Thus, PPARγ activation could

be involved in the anti-cancer effects of ARBs. More comparative studies are needed to

investigate the effect of the type of ARBs on their anti-cancer effects.

As anti-hypertensive agents based on ACE inhibition and AT1R antagonism are

already used clinically without causing serious side effects, they may provide a useful

25
adjunctive therapeutic strategy in the treatment of cancer metastasis. This would be

effective if these drugs could be demonstrated to inhibit metastasis at doses comparable

with those of hypertension treatment drugs. While the type of cancers and RAS inhibitor

may influence the anti-cancer effects, accumulated findings support the possibility that

RAS inhibitors could suppress cancer metastasis and improve survival. To confirm the

beneficial effects of RAS inhibitors in cancer treatments, further verification of the

anti-cancer effects of RAS inhibitors in large-scale and well-designed basic and clinical

studies are warranted.

Acknowledgments

This work was supported by a GrantinAid for Young Scientists B (Grant

Number 26861319, S. Ishikane); Grant-in-Aid for Scientific Research (C) (Grant

Number 17K08598, F. Takahashi-Yanaga); the Fukuoka Foundation for Sound Health

Cancer Research Fund (Grant Number A4, S. Ishikane); and the Suzuken Memorial

Foundation (Grant Number 14-044, S. Ishikane).

Financial interests

No financial interest is declared by the authors.

26
References

[1] Hanahan D, Weinberg R A. Hallmarks of cancer: the next generation. Cell 2011;

144(5): 646-74.

[2] Sethi N, Kang Y. Unravelling the complexity of metastasis - molecular

understanding and targeted therapies. Nature reviews. Cancer 2011; 11(10): 735-48.

[3] Dzau V J. Circulating versus local renin-angiotensin system in cardiovascular

homeostasis. Circulation 1988; 77(6 Pt 2): I4-13.

[4] Catt K J, Cran E, Zimmet P Z, Best J B, Cain M D, Coghlan J P. Angiotensin II

blood-levels in human hypertension. Lancet 1971; 1(7697): 459-64.

[5] Yacoub R, Campbell K N. Inhibition of RAS in diabetic nephropathy. International

journal of nephrology and renovascular disease 2015; 8 29-40.

[6] Chow W H, Dong L M, Devesa S S. Epidemiology and risk factors for kidney

cancer. Nature reviews. Urology 2010; 7(5): 245-57.

[7] Chow W H, Gridley G, Fraumeni J F, Jr., Jarvholm B. Obesity, hypertension, and the

risk of kidney cancer in men. The New England journal of medicine 2000; 343(18):

1305-11.

[8] Radisauskas R, Kuzmickiene I, Milinaviciene E, Everatt R. Hypertension, serum

lipids and cancer risk: A review of epidemiological evidence. Medicina (Kaunas,

27
Lithuania) 2016; 52(2): 89-98.

[9] Stocks T, Van Hemelrijck M, Manjer J, Bjorge T, Ulmer H, Hallmans G, et al. Blood

pressure and risk of cancer incidence and mortality in the Metabolic Syndrome and

Cancer Project. Hypertension 2012; 59(4): 802-10.

[10] Meier C R, Derby L E, Jick S S, Jick H. Angiotensin-converting enzyme inhibitors,

calcium channel blockers, and breast cancer. Archives of internal medicine 2000;

160(3): 349-53.

[11] Nakai Y, Isayama H, Ijichi H, Sasaki T, Sasahira N, Hirano K, et al. Inhibition of

renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving

gemcitabine. British journal of cancer 2010; 103(11): 1644-8.

[12] Rosenthal T, Gavras I. Angiotensin inhibition and malignancies: a review. Journal

of human hypertension 2009; 23(10): 623-35.

[13] Lever A F, Hole D J, Gillis C R, McCallum I R, McInnes G T, MacKinnon P L, et

al. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?

Lancet 1998; 352(9123): 179-84.

[14] Sun H, Li T, Zhuang R, Cai W, Zheng Y. Do renin-angiotensin system inhibitors

influence the recurrence, metastasis, and survival in cancer patients?: Evidence from a

meta-analysis including 55 studies. Medicine 2017; 96(13): e6394.

28
[15] Shen J, Huang Y M, Wang M, Hong X Z, Song X N, Zou X, et al.

Renin-angiotensin system blockade for the risk of cancer and death. Journal of the

renin-angiotensin-aldosterone system : JRAAS 2016; 17(3).

[16] Miyajima A, Yazawa S, Kosaka T, Tanaka N, Shirotake S, Mizuno R, et al.

Prognostic Impact of Renin-Angiotensin System Blockade on Renal Cell Carcinoma

After Surgery. Annals of surgical oncology 2015; 22(11): 3751-9.

[17] Tanaka N, Miyajima A, Kikuchi E, Matsumoto K, Hagiwara M, Ide H, et al.

Prognonstic impact of renin-angiotensin system blockade in localised upper-tract

urothelial carcinoma. British journal of cancer 2012; 106(2): 290-6.

[18] Pfeffer M A, Swedberg K, Granger C B, Held P, McMurray J J, Michelson E L, et

al. Effects of candesartan on mortality and morbidity in patients with chronic heart

failure: the CHARM-Overall programme. Lancet 2003; 362(9386): 759-66.

[19] Sipahi I, Debanne S M, Rowland D Y, Simon D I, Fang J C. Angiotensin-receptor

blockade and risk of cancer: meta-analysis of randomised controlled trials. The Lancet.

Oncology 2010; 11(7): 627-36.

[20] Wang H, Liao Z, Zhuang Y, Liu Y, Levy L B, Xu T, et al. Incidental receipt of

cardiac medications and survival outcomes among patients with stage III non-small-cell

lung cancer after definitive radiotherapy. Clinical lung cancer 2015; 16(2): 128-36.

29
[21] Morris Z S, Saha S, Magnuson W J, Morris B A, Borkenhagen J F, Ching A, et al.

Increased tumor response to neoadjuvant therapy among rectal cancer patients taking

angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Cancer

2016; 122(16): 2487-95.

[22] Yoon C, Yang H S, Jeon I, Chang Y, Park S M. Use of

angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers and cancer

risk: a meta-analysis of observational studies. CMAJ : Canadian Medical Association

journal = journal de l'Association medicale canadienne 2011; 183(14): E1073-84.

[23] Kearney P M, Whelton M, Reynolds K, Muntner P, Whelton P K, He J. Global

burden of hypertension: analysis of worldwide data. Lancet 2005; 365(9455): 217-23.

[24] Haggstrom C, Rapp K, Stocks T, Manjer J, Bjorge T, Ulmer H, et al. Metabolic

factors associated with risk of renal cell carcinoma. PloS one 2013; 8(2): e57475.

[25] Seeger-Nukpezah T, Geynisman D M, Nikonova A S, Benzing T, Golemis E A. The

hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease. Nature

reviews. Nephrology 2015; 11(9): 515-34.

[26] Watkins J L, Thaker P H, Nick A M, Ramondetta L M, Kumar S, Urbauer D L, et al.

Clinical impact of selective and nonselective beta-blockers on survival in patients with

ovarian cancer. Cancer 2015; 121(19): 3444-51.

30
[27] Timmermans P B, Wong P C, Chiu A T, Herblin W F, Benfield P, Carini D J, et al.

Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacological

reviews 1993; 45(2): 205-51.

[28] Timmermans P B, Chiu A T, Herblin W F, Wong P C, Smith R D. Angiotensin II

receptor subtypes. American journal of hypertension 1992; 5(6 Pt 1): 406-10.

[29] Berry C, Touyz R, Dominiczak A F, Webb R C, Johns D G. Angiotensin receptors:

signaling, vascular pathophysiology, and interactions with ceramide. American journal

of physiology. Heart and circulatory physiology 2001; 281(6): H2337-65.

[30] Nouet S, Nahmias C. Signal transduction from the angiotensin II AT2 receptor.

Trends in endocrinology and metabolism: TEM 2000; 11(1): 1-6.

[31] Hsueh W A, Do Y S, Anderson P W, Law R E. Angiotensin II in cell growth and

matrix production. Advances in experimental medicine and biology 1995; 377 217-23.

[32] Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J.

Inflammation and angiotensin II. The international journal of biochemistry & cell

biology 2003; 35(6): 881-900.

[33] Egami K, Murohara T, Shimada T, Sasaki K, Shintani S, Sugaya T, et al. Role of

host angiotensin II type 1 receptor in tumor angiogenesis and growth. The Journal of

clinical investigation 2003; 112(1): 67-75.

31
[34] Bodor C, Nagy J P, Vegh B, Nemeth A, Jenei A, MirzaHosseini S, et al.

Angiotensin II increases the permeability and PV-1 expression of endothelial cells.

American journal of physiology. Cell physiology 2012; 302(1): C267-76.

[35] Dimitroff C J, Descheny L, Trujillo N, Kim R, Nguyen V, Huang W, et al.

Identification of leukocyte E-selectin ligands, P-selectin glycoprotein ligand-1 and

E-selectin ligand-1, on human metastatic prostate tumor cells. Cancer research 2005;

65(13): 5750-60.

[36] Ishibazawa A, Nagaoka T, Yokota H, Ono S, Yoshida A. Low shear stress

up-regulation of proinflammatory gene expression in human retinal microvascular

endothelial cells. Experimental eye research 2013; 116 308-11.

[37] Hagi-Pavli E, Farthing P M, Kapas S. Stimulation of adhesion molecule expression

in human endothelial cells (HUVEC) by adrenomedullin and corticotrophin. American

journal of physiology. Cell physiology 2004; 286(2): C239-46.

[38] Kobayashi H, Boelte K C, Lin P C. Endothelial cell adhesion molecules and cancer

progression. Current medicinal chemistry 2007; 14(4): 377-86.

[39] Amano H, Ito Y, Ogawa F, Eshima K, Suzuki T, Oba K, et al. Angiotensin II type

1A receptor signaling facilitates tumor metastasis formation through

P-selectin-mediated interaction of tumor cells with platelets and endothelial cells. The

32
American journal of pathology 2013; 182(2): 553-64.

[40] Nurden A T. Platelets, inflammation and tissue regeneration. Thrombosis and

haemostasis 2011; 105 Suppl 1 S13-33.

[41] Ludwig R J, Boehme B, Podda M, Henschler R, Jager E, Tandi C, et al. Endothelial

P-selectin as a target of heparin action in experimental melanoma lung metastasis.

Cancer research 2004; 64(8): 2743-50.

[42] Suganuma T, Ino K, Shibata K, Kajiyama H, Nagasaka T, Mizutani S, et al.

Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma

cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis,

and peritoneal dissemination. Clinical cancer research : an official journal of the

American Association for Cancer Research 2005; 11(7): 2686-94.

[43] Xu Z W, Yan S X, Wu H X, Chen J Y, Zhang Y, Li Y, et al. The influence of

TNF-alpha and Ang II on the proliferation, migration and invasion of HepG2 cells by

regulating the expression of GRK2. Cancer chemotherapy and pharmacology 2017;

79(4): 747-58.

[44] Rodrigues-Ferreira S, Abdelkarim M, Dillenburg-Pilla P, Luissint A C, di-Tommaso

A, Deshayes F, et al. Angiotensin II facilitates breast cancer cell migration and

metastasis. PloS one 2012; 7(4): e35667.

33
[45] Zhao Y, Wang H, Li X, Cao M, Lu H, Meng Q, et al. Ang II-AT1R increases cell

migration through PI3K/AKT and NF-kappaB pathways in breast cancer. Journal of

cellular physiology 2014; 229(11): 1855-62.

[46] Zitka O, Kukacka J, Krizkova S, Huska D, Adam V, Masarik M, et al. Matrix

metalloproteinases. Current medicinal chemistry 2010; 17(31): 3751-68.

[47] Oh E, Kim J Y, Cho Y, An H, Lee N, Jo H, et al. Overexpression of angiotensin II

type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and

promotes tumor growth and angiogenesis. Biochimica et biophysica acta 2016; 1863(6

Pt A): 1071-81.

[48] Okamoto K, Tajima H, Nakanuma S, Sakai S, Makino I, Kinoshita J, et al.

Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction

between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4

axis in intrahepatic cholangiocarcinoma. International journal of oncology 2012; 41(2):

573-82.

[49] Ping H, Guo L, Xi J, Wang D. Angiotensin II type 2 receptor-interacting protein 3a

inhibits ovarian carcinoma metastasis via the extracellular HMGA2-mediated

ERK/EMT pathway. Tumour biology : the journal of the International Society for

Oncodevelopmental Biology and Medicine 2017; 39(6): 1010428317713389.

34
[50] Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature

medicine 1995; 1(1): 27-31.

[51] Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic

switch during tumorigenesis. Cell 1996; 86(3): 353-64.

[52] Brunner H R, Laragh J H, Baer L, Newton M A, Goodwin F T, Krakoff L R, et al.

Essential hypertension: renin and aldosterone, heart attack and stroke. The New

England journal of medicine 1972; 286(9): 441-9.

[53] Uemura H, Ishiguro H, Nagashima Y, Sasaki T, Nakaigawa N, Hasumi H, et al.

Antiproliferative activity of angiotensin II receptor blocker through cross-talk between

stromal and epithelial prostate cancer cells. Molecular cancer therapeutics 2005; 4(11):

1699-709.

[54] Fujita M, Hayashi I, Yamashina S, Fukamizu A, Itoman M, Majima M. Angiotensin

type 1a receptor signaling-dependent induction of vascular endothelial growth factor in

stroma is relevant to tumor-associated angiogenesis and tumor growth. Carcinogenesis

2005; 26(2): 271-9.

[55] Fujimoto Y, Sasaki T, Tsuchida A, Chayama K. Angiotensin II type 1 receptor

expression in human pancreatic cancer and growth inhibition by angiotensin II type 1

receptor antagonist. FEBS letters 2001; 495(3): 197-200.

35
[56] Miyajima A, Kosaka T, Asano T, Asano T, Seta K, Kawai T, et al. Angiotensin II

type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting

tumor angiogenesis. Cancer research 2002; 62(15): 4176-9.

[57] Arrieta O, Villarreal-Garza C, Vizcaino G, Pineda B, Hernandez-Pedro N,

Guevara-Salazar P, et al. Association between AT1 and AT2 angiotensin II receptor

expression with cell proliferation and angiogenesis in operable breast cancer. Tumour

biology : the journal of the International Society for Oncodevelopmental Biology and

Medicine 2015; 36(7): 5627-34.

[58] Dolley-Hitze T, Jouan F, Martin B, Mottier S, Edeline J, Moranne O, et al.

Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell

carcinoma? British journal of cancer 2010; 103(11): 1698-705.

[59] Herr D, Rodewald M, Fraser H M, Hack G, Konrad R, Kreienberg R, et al.

Potential role of Renin-Angiotensin-system for tumor angiogenesis in receptor negative

breast cancer. Gynecologic oncology 2008; 109(3): 418-25.

[60] Shirotake S, Miyajima A, Kosaka T, Tanaka N, Maeda T, Kikuchi E, et al.

Angiotensin II type 1 receptor expression and microvessel density in human bladder

cancer. Urology 2011; 77(4): 1009.e19-25.

[61] Otake A H, Mattar A L, Freitas H C, Machado C M, Nonogaki S, Fujihara C K, et

36
al. Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and

attenuates growth of murine melanoma. Cancer chemotherapy and pharmacology 2010;

66(1): 79-87.

[62] Dominska K, Piastowska-Ciesielska A W, Pluciennik E, Lachowicz-Ochedalska A,

Ochedalski T. A comparison of the effects of Angiotensin IV on androgen-dependent

and androgen-independent prostate cancer cell lines. Journal of the

renin-angiotensin-aldosterone system : JRAAS 2013; 14(1): 74-81.

[63] Carl-McGrath S, Ebert M P, Lendeckel U, Rocken C. Expression of the local

angiotensin II system in gastric cancer may facilitate lymphatic invasion and nodal

spread. Cancer biology & therapy 2007; 6(8): 1218-26.

[64] Escobar E, Rodriguez-Reyna T S, Arrieta O, Sotelo J. Angiotensin II, cell

proliferation and angiogenesis regulator: biologic and therapeutic implications in cancer.

Current vascular pharmacology 2004; 2(4): 385-99.

[65] Ager E I, Neo J, Christophi C. The renin-angiotensin system and malignancy.

Carcinogenesis 2008; 29(9): 1675-84.

[66] Zhao Q, Ishibashi M, Hiasa K, Tan C, Takeshita A, Egashira K. Essential role of

vascular endothelial growth factor in angiotensin II-induced vascular inflammation and

remodeling. Hypertension 2004; 44(3): 264-70.

37
[67] Uemura H, Ishiguro H, Nakaigawa N, Nagashima Y, Miyoshi Y, Fujinami K, et al.

Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells:

a possibility of tyrosine kinase inhibitor of growth factor. Molecular cancer therapeutics

2003; 2(11): 1139-47.

[68] Huang M M, Guo A B, Sun J F, Chen X L, Yin Z Y. Angiotensin II promotes the

progression of human gastric cancer. Molecular medicine reports 2014; 9(3): 1056-60.

[69] Zhou L, Luo Y, Sato S, Tanabe E, Kitayoshi M, Fujiwara R, et al. Role of two types

of angiotensin II receptors in colorectal carcinoma progression. Pathobiology : journal

of immunopathology, molecular and cellular biology 2014; 81(4): 169-75.

[70] Ager E I, Chong W W, Wen S W, Christophi C. Targeting the angiotensin II type 2

receptor (AT2R) in colorectal liver metastases. Cancer cell international 2010; 10 19.

[71] Du H, Liang Z, Zhang Y, Jie F, Li J, Fei Y, et al. Effects of angiotensin II type 2

receptor overexpression on the growth of hepatocellular carcinoma cells in vitro and in

vivo. PloS one 2013; 8(12): e83754.

[72] Takagi T, Nakano Y, Takekoshi S, Inagami T, Tamura M. Hemizygous mice for the

angiotensin II type 2 receptor gene have attenuated susceptibility to

azoxymethane-induced colon tumorigenesis. Carcinogenesis 2002; 23(7): 1235-41.

[73] Doi C, Egashira N, Kawabata A, Maurya D K, Ohta N, Uppalapati D, et al.

38
Angiotensin II type 2 receptor signaling significantly attenuates growth of murine

pancreatic carcinoma grafts in syngeneic mice. BMC cancer 2010; 10 67.

[74] Chow L, Rezmann L, Imamura K, Wang L, Catt K, Tikellis C, et al. Functional

angiotensin II type 2 receptors inhibit growth factor signaling in LNCaP and PC3

prostate cancer cell lines. The Prostate 2008; 68(6): 651-60.

[75] Liu Y, Li B, Wang X, Li G, Shang R, Yang J, et al. Angiotensin-(1-7) Suppresses

Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of

Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor.

Molecular medicine (Cambridge, Mass.) 2015; 21 626-36.

[76] Noy R, Pollard J W. Tumor-associated macrophages: from mechanisms to therapy.

Immunity 2014; 41(1): 49-61.

[77] Maru Y. The lung metastatic niche. Journal of molecular medicine (Berlin,

Germany) 2015; 93(11): 1185-92.

[78] Nakamura K, Yaguchi T, Ohmura G, Kobayashi A, Kawamura N, Iwata T, et al.

Involvement of local renin-angiotensin system in immunosuppression of tumor

microenvironment. Cancer science 2017.

[79] George A J, Thomas W G, Hannan R D. The renin-angiotensin system and cancer:

old dog, new tricks. Nature reviews. Cancer 2010; 10(11): 745-59.

39
[80] Pandey A, Goru S K, Kadakol A, Malek V, Sharma N, Gaikwad A B. H2AK119

monoubiquitination regulates Angiotensin II receptor mediated macrophage infiltration

and renal fibrosis in type 2 diabetic rats. Biochimie 2016; 131 68-76.

[81] Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and

angiogenesis. Journal of leukocyte biology 1994; 55(3): 410-22.

[82] Okamura A, Rakugi H, Ohishi M, Yanagitani Y, Takiuchi S, Moriguchi K, et al.

Upregulation of renin-angiotensin system during differentiation of monocytes to

macrophages. Journal of hypertension 1999; 17(4): 537-45.

[83] Shirotake S, Miyajima A, Kosaka T, Tanaka N, Kikuchi E, Mikami S, et al.

Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1

receptor in prostate cancer. The American journal of pathology 2012; 180(3): 1008-16.

[84] Tchou J, Conejo-Garcia J. Targeting the tumor stroma as a novel treatment strategy

for breast cancer: shifting from the neoplastic cell-centric to a stroma-centric paradigm.

Advances in pharmacology (San Diego, Calif.) 2012; 65 45-61.

[85] Wen S W, Ager E I, Neo J, Christophi C. The renin angiotensin system regulates

Kupffer cells in colorectal liver metastases. Cancer biology & therapy 2013; 14(8):

720-7.

[86] Neo J H, Malcontenti-Wilson C, Muralidharan V, Christophi C. Effect of ACE

40
inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer

liver metastases. Journal of gastroenterology and hepatology 2007; 22(4): 577-84.

[87] Stergiou G S, Skeva, II. Renin-angiotensin system blockade at the level of the

angiotensin converting enzyme or the angiotensin type-1 receptor: similarities and

differences. Current topics in medicinal chemistry 2004; 4(4): 473-81.

[88] Sipahi I, Chou J, Mishra P, Debanne S M, Simon D I, Fang J C. Meta-analysis of

randomized controlled trials on effect of angiotensin-converting enzyme inhibitors on

cancer risk. The American journal of cardiology 2011; 108(2): 294-301.

[89] Fraga-Silva R A, Ferreira A J, Dos Santos R A. Opportunities for targeting the

angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor pathway in

hypertension. Current hypertension reports 2013; 15(1): 31-8.

[90] Cambados N, Walther T, Nahmod K, Tocci J M, Rubinstein N, Bohme I, et al.

Angiotensin-(1-7) counteracts the transforming effects triggered by angiotensin II in

breast cancer cells. Oncotarget 2017; 8(51): 88475-87.

[91] Pilar Carrera M, Ramirez-Exposito M J, Duenas B, Dolores Mayas M, Jesus Garcia

M, De la Chica S, et al. Insulin-regulated aminopeptidase/placental leucil

Aminopeptidase (IRAP/P-lAP) and angiotensin IV-forming activities are modified in

serum of rats with breast cancer induced by N-methyl-nitrosourea. Anticancer research

41
2006; 26(2a): 1011-4.

[92] Vauquelin G, Michotte Y, Smolders I, Sarre S, Ebinger G, Dupont A, et al. Cellular

targets for angiotensin II fragments: pharmacological and molecular evidence. Journal

of the renin-angiotensin-aldosterone system : JRAAS 2002; 3(4): 195-204.

[93] Yamamoto B J, Elias P D, Masino J A, Hudson B D, McCoy A T, Anderson Z J, et

al. The angiotensin IV analog Nle-Tyr-Leu-psi-(CH2-NH2)3-4-His-Pro-Phe (norleual)

can act as a hepatocyte growth factor/c-Met inhibitor. The Journal of pharmacology and

experimental therapeutics 2010; 333(1): 161-73.

[94] Andoh T, Akira A, Saiki I, Kuraishi Y. Bradykinin increases the secretion and

expression of endothelin-1 through kinin B2 receptors in melanoma cells. Peptides

2010; 31(2): 238-41.

[95] Montana V, Sontheimer H. Bradykinin promotes the chemotactic invasion of

primary brain tumors. The Journal of neuroscience : the official journal of the Society

for Neuroscience 2011; 31(13): 4858-67.

[96] Milan A, Puglisi E, Ferrari L, Bruno G, Losano I, Veglio F. Arterial hypertension

and cancer. International journal of cancer 2014; 134(10): 2269-77.

[97] Azizi M, Chedid A, Oudard S. Home blood-pressure monitoring in patients

receiving sunitinib. The New England journal of medicine 2008; 358(1): 95-7.

42
[98] Deshayes F, Nahmias C. Angiotensin receptors: a new role in cancer? Trends in

endocrinology and metabolism: TEM 2005; 16(7): 293-9.

[99] Rocken C, Rohl F W, Diebler E, Lendeckel U, Pross M, Carl-McGrath S, et al. The

angiotensin II/angiotensin II receptor system correlates with nodal spread in intestinal

type gastric cancer. Cancer epidemiology, biomarkers & prevention : a publication of

the American Association for Cancer Research, cosponsored by the American Society of

Preventive Oncology 2007; 16(6): 1206-12.

[100] Reka A K, Goswami M T, Krishnapuram R, Standiford T J, Keshamouni V G.

Molecular cross-regulation between PPAR-gamma and other signaling pathways:

implications for lung cancer therapy. Lung cancer (Amsterdam, Netherlands) 2011;

72(2): 154-9.

[101] Samukawa E, Fujihara S, Oura K, Iwama H, Yamana Y, Tadokoro T, et al.

Angiotensin receptor blocker telmisartan inhibits cell proliferation and tumor growth of

cholangiocarcinoma through cell cycle arrest. International journal of oncology 2017;

51(6): 1674-84.

[102] Kozako T, Soeda S, Yoshimitsu M, Arima N, Kuroki A, Hirata S, et al.

Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in

adult T-cell leukemia cells. FEBS open bio 2016; 6(5): 442-60.

43
[103] Fujihara S, Morishita A, Ogawa K, Tadokoro T, Chiyo T, Kato K, et al. The

angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor

growth of esophageal adenocarcinoma via the AMPKalpha/mTOR pathway in vitro and

in vivo. Oncotarget 2017; 8(5): 8536-49.

[104] Shimomoto T, Ohmori H, Luo Y, Chihara Y, Denda A, Sasahira T, et al.

Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer.

Clinical & experimental metastasis 2012; 29(8): 915-25.

44
Figure legends

Figure 1. Angiotensin related peptides and their biological effects. Angiotensinogen is

cleaved by renin to produce Ang I. Ang I is subsequently cleaved by the ACE to

generate the hypertensive active peptide Ang II. ACE also actively degrades the

vasoactive peptide bradykinin. Therefore, ACE inhibitors reduce Ang II production and

increased bradykinin levels. Ang I and Ang II can further be cleaved into Ang III, Ang

IV and Ang (1-7) by ACE, ACE2, and several peptidases such as AP-A and AP-N. The

biological effects of Ang II are mediated by two types of receptors (AT1R and AT2R)

and ARBs selectively block only ATR1. Ang (1-7) and Ang IV bind to MasR and AT4R,

respectively. Abbreviations: Ang, angiotensin; ACE, Ang-converting enzyme; AP,

aminopeptidase; ARB, Ang II receptor blocker; AT1R, Ang II type 1 receptor; AT2R,

Ang II type 2 receptor; MasR, Mas receptor; AT4R , Ang IV receptor.

Figure 2. Schematic representation of various steps of distal hematogenous metastasis

formation in which angiotensin related peptides are potentially involved. Distal

hematogenous metastasis consist of multistep processes; (1) intravasation, (2)

dissemination, (3) adhesion, (4) migration and invasion and (5) proliferation and

angiogenesis. Angiotensin related peptides reported to affect each steps. Abbreviations:

45
Ang, angiotensin; CAF, cancer-associated fibroblast; TAM, tumor-associated

macrophage.

46
47
48
Table 1
Protein expression of AT1R and AT2R on cancer and tumor-associated tissue cells
Cell type AT1R AT2R References
bladder cancer  NA [60] a,
breast cancer   [57] a, [59] a
colon cancer  NA [104] b
gastric carcinoma   [99] a
melanoma  NA [61] a
ovarian cancer  NA [42] a
pancreatic cancer  NA [55] a
prostate cancer   [62] a
renal cell carcinoma   [58] a
cancer-associated fibroblast  NA [78] b
tumor-associated macrophage  NA [33] a
Kupffer cell  NA [85] a
Symbol: , protein expression has been reported; NA, date not available.
a
Detected by immunohistochemistry.
b
Detected by Western blotting.

49
Graphical abstract

50