International Journal of Urology (2015) 22, 721--730

doi: 10.1111/iju.12827

Review Article

Renin–angiotensin system blockade: Its contribution and controversy Akira Miyajima, Takeo Kosaka, Eiji Kikuchi and Mototsugu Oya Department of Urology, Keio University School of Medicine, Tokyo, Japan

Abbreviations & Acronyms AII = angiotensin II ACEI = angiotensinconverting enzyme inhibitor ARB = angiotensin II receptor blocker AT1R = angiotensin II type 1 receptor AT2R = angiotensin II type 2 receptor CDDP = cis-dichlorodiammineplatinum CRPC = castration-resistant prostate cancer FDA = US Food and Drug Administration HIF-1a = hypoxia inducible factor 1a IPSS = International Prostate Symptom Score LUTS = lower urinary tract symptoms MCP-1 = monocyte chemoattractant protein 1 NF-jB = nuclear factor-jB PI3K = phosphatidylinositol-3 kinase PKC = protein kinase C PS = performance status RAS = renin–angiotensin system RCC = renal cell carcinoma ROS = reactive oxygen species TGF-b = transforming growth factor-b UUO = unilateral ureteral obstruction VEGF = vascular endothelial growth factor Correspondence: Akira Miyajima M.D., Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected] Received 10 March 2015; accepted 27 April 2015. Online publication 29 May 2015 © 2015 The Japanese Urological Association

Abstract: Angiotensin II is a key biological peptide in the renin–angiotensin system that regulates blood pressure and renal hemodynamics, and extensive experimental studies have shown that angiotensin II promotes diverse fibrotic changes and induces neovascularization in several inflammatory diseases. It is known that angiotensin II can be controlled using renin–angiotensin system blockade when angiotensin II is the main factor inducing a particular disease, and renin–angiotensin system blockade has assumed a central role in the treatment of inflammatory nephritis, cardiovascular disorders and retinopathy. In contrast, renin–angiotensin system blockade was found to have not only these effects but also other functions, such as inhibition of cancer growth, angiogenesis and metastasis. Numerous studies have sought to elucidate the mechanisms and support these antitumor effects. However, a recent meta-analysis showed that renin–angiotensin system blockade use might in fact increase the incidence of cancer, so renin–angiotensin system blockade use has become somewhat controversial. Although the renin–angiotensin system has most certainly made great contributions to experimental models and clinical practice, some issues still need to be resolved. The present review discusses the contribution and controversy surrounding the renin–angiotensin system up to the present time.

Key words: angiogenesis, angiotensin II, carcinogenesis, fibrosis, inflammation.

Introduction AII is a key biological peptide in the RAS that regulates blood pressure and renal hemodynamics. AII is known to induce TGF-b, a potent fibrotic and apoptotic cytokine, in various diseases. Cardiovascular diseases1,2 and kidney diseases3,4 based on fibrotic changes in particular are caused by the AII-induced TGF-b pathway, and many studies have described the mechanisms and have attempted to inhibit the consequences. RAS inhibitors, ACEI and ARB, which inhibit the angiotensin pathway, are widely used to treat hypertension and protect the kidneys or heart from glomerular fibrosis5 and cardiocerebral attack,6,7 respectively. RAS blockade also inhibits the development of diabetic retinopathy development by preventing neovascularization.8 Therefore, RAS blockade plays a substantial role in controlling fibrotic and angiogenic changes in these disorders. There are two major subtypes of AII receptor, the AT1R and AT2R. AT1R belongs to the seven transmembrane domain superfamily, and its stimulation activates classical second messenger systems that lead to the rapid production of diacylglycerol and inositol 1,4,5-triphosphate, as well as the activation of PKC.9 Only AT1R undergoes rapid internalization on agonist binding, but the non-peptide AT1R blocker does not internalize.10 Therefore, in clinical practice, patients must be administered with AT1R blocker on a daily basis. Increasing evidence suggests that AT1R is expressed in various malignancies,11–14 and AT1R expression was found to be significantly involved in tumor growth,15–18 metastasis19–21 and angiogenesis.22,23 The first significant retrospective short study was based on the records of 5207 patients. Lever et al. in 1998 reported clinical evidence that long-term RAS blockade might have a protective effect against carcinogenesis.24 This is the evidence that generated the most attention regarding RAS blockade and malignancy at that time, and this unpredictable but beneficial side-effect to tumor growth and metastasis has been recognized. Since then, many studies carried out over the past 15 years have suggested that this unique peptide,

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receptor.31,34,35 In contrast, although many previous studies reported an association between AII stimulation and described positive findings in terms of cell proliferation, some cancer cells expressing AT1R show decreased or no significant regulation of cell proliferation in response to AII stimulation.15,36–41 The accurate direct effects of AII in cell proliferation are still controversial, and apparently contradictory evidence now exists. Our previous reports also examined the direct effect of AII on prostate cancer cell and bladder cancer cell proliferation; however, AII at a clinically achievable concentration had no direct effects on cancer cell proliferation.19,42,43 Similarly, the role of AT1R activation in cell survival is paradoxical, and both survival and apoptotic effects have been reported. In colon cancer cells, activation of AT1R suppresses CDDP-induced apoptosis through the activation of NF-jB, and results in production of the anti-apoptotic molecules BCL-XL and survivin.37 AII stimulation in MCF-7 breast cancer cells suppresses adriamycin-induced apoptosis through the PI3K-Akt pathway and subsequent suppression of caspase 9.44 In contrast, studies with lung adenocarcinoma cells have shown that AII could induce apoptosis through AT1R activation,45,46 whereas other studies also showed that AII at clinically achievable concentrations had no effect on cell survival.19,42,43,47 These results suggest that the direct effects of AII on cancer cell proliferation or apoptosis might differ in different cell types, possibly as a result of alternative physiological pathways that can be initiated by RAS.

AII, is implicated in tumor growth and metastasis. In contrast, a recent meta-analysis of selected studies suggested that ARB might increase cancer risk.25 Nevertheless, several multi-institutional studies have shown that ARB did not increase the cancer incidence.26,27 Although whether RAS blockade increases or decreases the incidence of cancer remains a topic of debate, most experimental models suggest RAS blockade could slow down or inhibit tumor progression, as RAS blockade has favorable effects on tumor cell proliferation, angiogenesis and cell replication. The purpose of the present review was, therefore, to discuss the controversial effects of RAS blockade in experimental models and clinical practice.

Basic mechanisms implicated in RAS Role of AII in cell proliferation, apoptosis and survival Accumulating evidence in experimental studies suggest that the potent cascades of AII to enhance cell proliferation in malignancies are similar to cellular events occurring in nonmalignant diseases (Fig. 1). AII could stimulate cell proliferation directly through AT1R, and result in the activation of various intracellular cascades of protein kinases, which are usually associated with growth factor stimulation.9,28–31 In breast cancer cells, AII stimulation could induce increased cell proliferation through MAP/ERK kinase and PI3K signaling.17,32 AII-mediated AT1R activation could also stimulate cellular proliferation of androgen-sensitive and androgeninsensitive prostate cancer cell lines through the MAP/ERK kinase and signal transducers and activator of transcription 3 pathways.18,33,34 Furthermore, activation of AII-AT1R signaling induces increased cellular proliferation by interaction with signal transduction through epidermal growth factor

Proposed effects of RAS in tumor angiogenesis The molecular basis for RAS and its effect on tumor angiogenesis are currently under investigation. A proposed mechanism of AII on the promotion of tumorigenesis might be Cancer

Benign Disease

Normal cells Tumor cells

AT1R Cell Signaling

Cell Signaling Signaling pathways: Jak/Stat, MAPK,P13K

Immune cells Classical macrophage Local RAS

transcription factors: HIF-1α Signaling

Local RAS

Signaling

Tumor-associated macrophage AT1R Cytokine,Chemokine Growth factor Receptor

Antocrine/Paracrine

Fibroblast cells Extracellular matrix Inflammation. Immune response etc

Inflammation. Immune response etc

Clinical consequences

Angiogenesis, Immuno suppression, Migration etc

Neovascular

Tumor growth, Metastasis etc

Remodeling, Fibrosis, Tumor killing etc

Blood vessel Fig. 1 AT1R signaling-related events in benign disease and cancer. Pathophysiological and biological events are similar in both diseases.

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through the modulation of tumor angiogenesis, which is crucial for tumor growth. AII stimulates the expression of several pro-angiogenic factors including VEGF, angiopoietin 2, basic fibroblastic growth factor and platelet-derived growth factor.20,48–51 RAS blockade is frequently associated with reduced VEGF expression, and the most direct evidence for RAS in tumor angiogenesis comes from xenograft studies of tumors that were implanted into AT1R-knockout mice, which have reduced angiogenesis and tumor growth compared with wild-type, and reductions in tumor size after treatment with AT1R antagonists.21,23 In the model of renal cell carcinoma lung metastases, the ARB candesartan reduced tumor volume and microvascular density in metastatic sites.19 Similar results were reported in a model of colorectal cancer liver metastases, using captopril (an ACEI) or irbesartan (an ARB).52 Although AII promotes the expression and/or secretion of various molecules in malignancy, such as interleukin-8, granulocyte-colony stimulating factor and MCP-1,39,53–55 accumulating evidence suggests that VEGF is one of the crucial factors in RAS-mediated tumor angiogenesis.42,43,56 However, the detailed molecular mechanisms of introducing angiogenic factors have not been fully elucidated, compared with those of vascular cells. AII through AT1R signaling leads to downstream activation of transcription factors, such as NF-jB, STAT family members and HIF-1a in endothelial cells.57–60 Recent studies in vascular cells have shown that enhanced VEGF production by AII could be largely due to a potent stabilization of AII-dependent HIF-1a through ROS production.61 In addition, the AT1R pathway is also activated by AII-induced HIF-1a through a PKC-dependent mechanism.59 A few studies on malignancy attempted to elucidate the mechanism of the increase in AII-dependent VEGF.23,62 The authors reported that AII stimulation of various types of cancer cells increases the expression of VEGF through ERK1 and ERK2 signaling, PKC, activator protein 1, and NF-jB. Although our recent findings show that AII significantly induced VEGF production through HIF-1a and Ets-1 upregulation under normal oxygen conditions in the human CRPC cell line, further work is required to elucidate the detailed molecular mechanism regarding angiogenesis through the AT1R pathway.57 In addition, several questions regarding angiotensin receptors function and expression have still not been answered. Although AT2R is believed to mediate physiological actions opposing those mediated by AT1R, how AT2R functions or expresses in each situation is unknown. Further study is required to elucidate how these two receptors mediate each other, and how expression of the receptors is regulated in each pathophysiological situation.

From basic discovery to clinical trials Compared with the accumulated evidence obtained in experimental results, there have been fewer studies that examined the clinical outcomes of RAS inhibitors, such as ACEI or ARB, in cancer treatment. Wilop et al. retrospectively analyzed 287 patients with advanced non-small cell lung cancer undergoing first-line platinum-based chemotherapy.63 They reported that patients receiving either ACEI or ARB had © 2015 The Japanese Urological Association

3.1 months longer median survival than non-recipients (11.7 vs 8.6 months). They concluded that the addition of ACEI or ARB to platinum-based first-line chemotherapy might contribute to the prolonged survival in patients with advanced lung cancer. Similarly, Nakai et al. also retrospectively evaluated combination therapy with gemcitabine and ACEI or ARB using data from 155 patients with advanced pancreatic cancer, and reported the use of ACEI or ARB with gemcitabine was an independent prognostic factor for both progression-free survival and overall survival in patients with advanced pancreatic cancer.64 Both studies proposed that RAS inhibition combined with chemotherapeutic agents lead to better clinical outcomes, although these analyses were based on retrospective cohorts and did not evaluate the therapeutic efficacy of newly introduced RAS inhibitors. Furthermore, they did not fully evaluate the detailed mechanisms to determine whether any synergistic action exist or not in these clinically applicable regimens. We have reported the possible synergistic mechanism of combination therapy with CDDP and ARB in a bladder cancer model.47 Our findings suggest that the increased ROS generation by using CDDP could upregulate AT1R expression, and enhanced VEGF production. Meanwhile, the inhibition of RAS might be important when anticancer agents are administered. These results are extremely relevant to the clinical outcome reported by Wilop et al. The therapeutic efficacy of introducing RAS inhibitors in malignancy was evaluated in several prospective studies (Table 1). Uemura et al. carried out a pilot trial of the ARB, candesartan, in 23 advanced CRPC patients, and reported six patients (26.1%) showed a prostate-specific antigen response, and half of the patients showed an improved or stable performance status.33 Yoshiji et al. presented clinical evidence showing that RAS blockade contributed to the suppression of tumor recurrence.65 They demonstrated that ACEI in combination with vitamin K suppressed the recurrence of hepatocellular carcinoma after curative therapy, although the exact impact of a single ACEI agent by itself might not have been fully evaluated because of the limited number of patients in the study. In addition to cancer therapeutics, previous reports have examined the potent efficacy of RAS inhibitors in preventing carcinogenesis. The first impressive retrospective short study was based on the records of 5207 patients. Lever et al. reported the first clinical evidence that long-term RAS blockade might have a protective effect against carcinogenesis.24 Following this high-impact report, Ronquist et al. designed a retrospective nested case–control study to assess the association between the risk of prostate cancer and use of the ACEI, captopril, and other antihypertensive drugs.66 No clear association was apparent between the use of antihypertensive drugs and prostate cancer. However, a specific focus on users of captopril showed a lower risk of prostate cancer development. Subsequently, they prospectively proved ACEI might reduce biochemical failure after radical prostatectomy, although the study size was small.67 A prospective cohort study was also carried out using 1051 patients with a high risk of keratinocyte cancer.68 They reported that users of ACEI or ARB had statistically signifi723

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Table 1 Representative clinical evidence of RAS blockade in non-urological diseases Reference

Design

Study population

Fryzek et al.69

Prospective

Christian et al.68 Yoshiji et al.65 Lever et al.24

Prospective Prospective Retrospective

Hypertension, breast cancer incidence Keratinocyte cancer incidence Hepatocellular cancer Hypertension, cancer incidence

Pheffer et al.71 Dahlof et al.72

Prospective Prospective

Yusuf et al.73 Sipahi et al.25 Bangalore et al.74 ARBT26

Prospective Meta-analysis Meta-analysis Meta-analysis

All-cause mortality Cardiovascular event, cancer incidence Recurrent stroke, cancer incidence Hypertension, cancer incidence Hypertension, cancer incidence Hypertension, cancer incidence

Study size (n) 49 950 1051 87 5207 7599 9133 20 93 324 138

Type of RAS blockade

Outcome

ACEI, ARB, ca channel blocker, diuretics, b-blocker ACEI or ARB ACEI and VitK ACEI (vs calcium channel blocker or b-blocker) CHARM trial (candesartan vs placebo) LIFE study (losartan vs atenolol)

Not significant

PEoFESS study (telmisartan vs placebo) ACEI or ARB ACEI or ARB ACEI or ARB

332 515 168 769

Reduced cancer risk Reduced recurrence Reduced cancer risk Modest increase cancer death Modest increase cancer risk Modest increase cancer risk Modest increase cancer risk No cancer risk in ARB No cancer risk in ARB

ACEI, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers.

cantly reduced risks of basal cell carcinoma and squamous cell carcinoma. The greatest reduction in keratinocyte cancer was seen among people who initiated use of ACEI or ARB during the study period. In contrast with positive remarks regarding cancer prevention in patients taking ACEI or ARB, several studies have failed to find a decrease in the risk of developing cancer for breast cancer and prostate cancer.69,70 The first indication of a possible increase in cancer risk with ARB was noted in the CHARM (Candesartan in Heart failure - Assessment of moRtality and Morbidity) trial of candesartan.71 Since then, several clinical studies suggested that RAS blockade might increase prostate cancer incidence, although the increase is not significant.72,73 In addition, Sipahi et al. recently found in their large-scale meta-analysis that patients using ARB had a slight, but significant, increased risk of developing lung cancer (0.9% vs 0.7% in control, P = 0.01). There was an excess of prostate cancer in the ARB group compared with the control group, although it was not significant in meta-analysis (1.7% vs 1.3% in the control group, P = 0.076).25 They did not also find a significant increase in the risk of cancer development in other solid cancers, and the type of drug was biased in their study. There was also no increase in cancer incidence with RAS blockade therapy compared with controls in 15 large, parallel, long-term, multicenter, double-blind clinical trials of these agents involving 138 769 participants.26 In addition, the network meta-analysis from 70 randomized controlled trials (324 168 participants) suggested ARB and ACEI had no cancer risk and cancer-related deaths.74 Furthermore, the patients with glomerulonephritis are reported to show a higher incidence of cancer and cancer mortality compared with the general population. A multiinstitutional study including 3288 adult patients showed that administration of ACEI and ARB to glomerulonephritis patients did not increase the cancer incidence, and recipients of RAS blockade had markedly lower rates of all-cause mortality and cancer mortality.27 Furthermore, no in vivo or in vitro experimental model has shown any pathophysiological evidence to support “RAS blockade-induced carcinogenesis.” Although several meta-analyses have suggested “RAS 724

blockade-induced carcinogenesis,” no in vitro or in vivo experimental studies have supported such an effect so far. How has this discrepancy arisen? RAS blockade is basically used for chronic hypertensive patients. RAS blockade has been utilized in cancer models that have not suffered from hypertension, as most experimental cancer designs cannot reproduce a state of chronic hypertension. In contrast, clinical hypertension might be a risk factor for carcinogenesis, and each RAS blocker has its selectivity. Therefore, these reasons make it harder to determine whether RAS blockade induces or inhibits cancer in a clinical study. Although there still might be some difficulties, prospective randomized clinical studies are required to solve the discrepancy. The FDA sought to respond to this discrepancy with a larger meta-analysis of 31 clinical trials (n = 155 816) of ARB that found no evidence of any excess of site-specific cancer, including lung, solid/skin cancer or cancer death (FDA safety communication, 3 June 2011). The FDA then revisited the 19 rodent carcinogenicity assays of nine ARB, starting with those for losartan in 1994, for any evidence of dosage-related lung tumorigenicity in this class. Assays were carried out in five strains of rats, and five strains of wild-type and transgenic mice per protocols and dosages sanctioned by the FDA executive carcinogenicity assessment committee. Accordingly, there was neither promotion of background lung tumors in the mouse, nor initiation of de novo lung tumors in the rat. In the end, they proposed that further randomized studies were definitely required in each malignancy to understand the role of RAS blockade in clinical cancer growth.75

RAS in urological diseases (Table 2) Inflammatory kidney diseases Urologists often encounter patients with UUO, which is caused by congenital disorder, ureteral calculi or urothelial cancer. Once UUO happens, intrarenal pelvic pressure increases and renal tubular cells undergo stretching, resulting in cytokine or mediator secretion.76 In the obstructed kidney of UUO in particular, AII is elevated, which is a strong inducer of TGF-b. UUO causes an increase in TGF-b, profibrotic © 2015 The Japanese Urological Association

RAS blockade: Contribution and controversy

Table 2 Representative clinical evidence of RAS blockade in urological diseases Reference

Design

Study population

Ronquist et al.67 Uemura et al.33

Prospective Prospective

Tatokoro et al.96

Prospective

Prostate cancer Castration-resistant prostate cancer Advanced RCC

Ito et al.92 Ibrahim et al.85

Retrospective Prospective

LUTS Kidney transplantaion

Study size (n)

Type of RAS blockade

Outcome

62 23

ACEI ARB

Reduced PSA failure Improved PS

51

ACEI or ARB with IFN-a, cimetidine, cox-2 inhibitor ARB ARB

Favorable response

4298 153

Lower IPSS Reduced all-cause graft loss

ACEI, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; PS, performance status; RCC, renal cell carcinoma; LUTS, lower urinary tract symptoms; IPSS, International Prostate Symptom Score.

and pro-apoptotic cytokine, leading to tubulointerstitial fibrosis, tubular apoptosis and inflammatory infiltration of lymphocytes in the obstructed kidney. At the end of this cascade, the obstructed kidney of UUO loses tubular volume and becomes atrophic.76 Ishidoya et al. clearly showed that ARB ameliorated TGF-b expression accompanied by a decrease in interstitial fibrosis and tubular proliferation in the obstructed kidney of the experimental UUO model.77 RAS blockade was also reported to show inhibitory effects on glomerular fibrosis in an experimental nephritis model, which is immune-mediated.78,79 Taken together, ARB could have therapeutic potential in both non-immune and immune mediated renal inflammation models. In addition, several clinical trials and meta-analyses have shown that ARB had the therapeutic effects of inhibiting proteinuria and pathological changes caused by immunoglobulin A nephropathy, glomerular nephritis or diabetic nephropathy.80–82

Renal transplantation In renal transplantation, obvious evidence exists showing that RAS blockade is useful in the treatment of hypertension, post-transplantation erythrocytosis and the reduction of proteinuria. Although the prolongation of graft survival remains the primary goal in any transplantation protocol, the influence of RAS blockade through ARB on post-transplantation outcomes, such as patient/graft survival and rate of losing renal function, remains unclear. Up until now, many experimental animal models have shown that RAS inhibitors decreased proteinuria, glomerular capillary pressure, tubular atrophy and glomeruosclerosis, and most of them concluded that RAS blockade was beneficial in post-renal transplantation.83 However, analyses of large databases and meta-analyses of small prospective clinical studies have reported differences in improved outcomes, detrimental effects or no effect of posttransplantation RAS blockade therapy compared with other antihypertensive agents.84 This might be because the prevalence of interstitial fibrosis and tubular atrophy in kidney transplants varies depending on the time from transplantation and the immunological circumstances. A recent prospective randomized trial studied the impact of the ARB, losartan, on the development of interstitial fibrosis and tubular atrophy in kidney transplant recipients by surveillance biopsies during the first 5 years after transplantation.85 In the present study, © 2015 The Japanese Urological Association

the incidences of interstitial fibrosis and tubular atrophy were lower in the losartan group (13%) than the placebo group (27%). Although the difference did not reach statistical significance (P = 0.08), all-cause graft loss was lower in the losartan group (155 vs 32%, P = 0.05). The potential benefit of RAS blockade in renal transplantation still needs to be fully elucidated and validated in future larger clinical trials.

LUTS In the experimental setting of rats, AII induced urethral tone whereas both losartan and PD123319 (AT2R inhibitor) significantly lowered urethral resistance.86 This phenomenon initially did not attract much attention; however, recently several publications have shown the beneficial effects of RAS inhibitors in LUTS. An ovariectomized rat study showed that prolonged estrogen deprivation leads to voiding dysfunction and urethral hypercontractility, which is manifest in increases in basal pressure, capacity, micturition frequency and decreased voiding pressure. These symptoms were associated with increased ACE activity, and upregulation of AT1R and AT2R in the urethral tissue.87 In addition, estrogen replacement and prolonged ARB administration with losartan prevent the functional and molecular alterations seen in ovariectomized rats, suggesting that these pharmacological strategies might be useful for the treatment of urological complications associated with prolonged estrogen deficiency. The RAS inhibitor, telmisartan, was found to decrease AT1R expression in both the urothelium and detrusor muscle in rats with bladder outlet obstruction,88 and treatment with losartan prevented urodynamic and structural changes in mice with bladder outlet obstruction.89 Celso et al. also showed that RAS blockade with losartan or captopril prevented neurogenic contraction and voiding frequency in renovascular hypertensive rats.90 Olmesartan was observed to ameliorate bladder dysfunction by recovering bladder blood flow and decreasing oxidative stress in spontaneous hypertension rats.91 A large clinical study including 3790 men showed that IPSS was lower in patients with hypertension receiving RAS inhibitors than in hypertensive patients who were not receiving any medication.92 That study also observed that the voiding symptoms score was significantly lower in patients with ARB, and that there was also a tendency for the storage symptoms score to be lower in ARB-treated patients. 725

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RCC Goldfarb et al. first reported AT1R expression in normal tubulointerstitium and RCC, suggesting a pharmacological framework for the differential effects of angiotensin-mediated function.11 Dolley-Hitze et al. showed that AT1R and AT2R proteins were overexpressed in the most aggressive forms of RCC, and that AT2R expression correlates with progressionfree survival.93 In an experimental setting, Miyajima et al. proved that candesartan dramatically decreased metastatic lung tumors by inhibiting tumor angiogenesis.19 Similarly, a recent report showed that RAS blockade decreased tumor proliferation and the metastatic potential of RCC in a murine metastatic model.94 Although RAS inhibitors, such as candesartan and the other ARB except telmisartan, showed no induction of cell cytotoxicity and apoptosis, only telmisartan showed cytotoxicity in urogenital cancer in vitro, as telmisartan has not only AT1R blockade, but also peroxisome proliferatoractivated receptor c activation.95 Tatokoro et al. carried out a phase II trial of combination treatment consisting of interferon-a, cimetidine, cyclooxygenase-2 inhibitor and RAS drugs in 51 patients with advanced RCC.96 Complete response was observed in four patients (8%), and a partial response in seven patients (14%). The other 24 patients (45%) had stable disease for at least 6 months. In addition, Keizman et al. retrospectively showed that RAS inhibitors might improve the clinical outcome of sunitinib treatment in metastatic RCC.97 Another recent report including 557 RCC patients showed that no administration of RAS inhibitors, longer tumor length, high-grade tumor and positive microvascular invasion were independent risk factors for a decrease in subsequent disease-specific survival after surgery for RCC.98 For patients with RCC, the risk of distant metastasis is directly related to subsequent prognosis. However, there is no standard perioperative chemotherapy for localized RCC in both neoadjuvant and adjuvant settings. Molecular-targeting agents also have toxicity profiles that differ from those accompanying current chemotherapeutic agents, whose symptoms might overlap with those of the chronic illnesses of patients with metastatic RCC, such as hypertension, hyperglycemia and pneumonitis. Thus, a new strategy that is both effective and possesses adequate tolerability would be a very important breakthrough in the adjuvant setting after nephrectomy. As RAS inhibitors are already used as antihypertensive drugs with a safe profile, RAS inhibitors might be an effective strategy from a clinical viewpoint in the adjuvant treatment of patients with localized RCC after surgical treatment.

Prostate cancer The roles of the AII and AT1R pathways in prostate cancer cell proliferation are controversial.18,42,57,99 We and other researchers previously reported that AII or ARB at clinically 726

achievable concentrations had no direct effect on prostate cancer cell proliferation in vitro.57,99 In order to study and clarify the role of AT1R and cell proliferation in prostate cancer, we generated the androgen-independent subline C4-2. C4-2 cells were grown in RPMI-1640 containing 10% charcoal-stripped fetal bovine serum, and passaged on reaching subconfluence. These cells were cultured successfully for 6 months and named C4-2AT6. We investigated and compared AT1R expression in androgen-dependent LNCaP cells, and in androgen independent C4-2 and C4-2AT6 cells. Although the three cell lines expressed AT1R, C4-2AT6 cells showed a significantly higher AT1R expression than other cells. To examine the effects on cell proliferation, C4-2AT6 cells were incubated with various concentrations of AII or ARB. Neither AII nor ARB affected their proliferation in all the cell lines we examined.57 Although there might exist heterogeneities in the response of AII with a given cancer type, the accurate impact of AII on the cellular proliferative effect is still controversial, as there is no significant evidence of a promising benefit in AII-AT1R signaling for cancer cell proliferation. Taking these findings into consideration, we believe the direct effect of RAS signaling pathways in prostate cancer cell proliferation is extremely limited. Therefore, we have focused on the indirect effects of RAS in prostate cancer or CRPC (Fig. 2). The development and establishment of a blood supply has an important role in the development and growth of cancer cells by providing oxygen, nutrients and various growth factors.100 In prostate cancer, several studies have shown that microvessel density served as a predictor of high-grade

Castration Resistance Castration Sensitive Renin-Angiotension system

Although the mechanisms have not yet been fully elucidated, and whether RAS inhibitors are also effective in non-hypertensive patients is unknown, RAS inhibitors could be an effective treatment of choice for LUTS patients.

Angiotensinogen Angiotensin I Angiotensin II ARB AT1R AT1R expression

P13K/AKT signalling pathway

HIF1α ETS1 VEGF MCP1

Aggressive angiogenesis in CRPC microenvironment Fig. 2 AT1R expression and angiogenesis increase as prostate cancer acquires castration resistance. © 2015 The Japanese Urological Association

RAS blockade: Contribution and controversy

prostate cancer and biochemical failure after treatment.101–104 We previously demonstrated that the degree of tumor angiogenesis, including VEGF, microvessel density based on CD34 expression, was correlated to the progression of prostate cancer. Furthermore, we have reported that vasohibin-1, a novel angiogenic molecule that was specifically expressed in activated vascular endothelial cells, represented a clinically relevant predictor of patient prognosis.105 The infiltration of macrophages presents in different types of human malignancies, and there have been numerous reports regarding the role of macrophages in tumor progression or tumor angiogenesis. MCP-1 is thought to be associated with tumor angiogenesis as a chemoattractant for macrophage infiltration. The AII–AT1R axis is also known to be one of the regulators of MCP-1 expression through PI3K/ Akt signaling pathways in vascular smooth muscle cells.106 Our study showed that AII-induced pAkt was accompanied by MCP-1 expression and inhibited by ARB treatment in CRPC cells.107 These pro-angiogenic effects of AII suggest that ARB might protect against cancer by inhibiting angiogenesis. On the basis of the correlation between AT1R expression and angiogenesis in CRPC, we tested the effects of ARB. ARB inhibited VEGF production and MCP-1 expression, leading to dramatically suppressed tumor growth in a mouse xenograft model of human CRPC.42,107 Although androgen deprivation therapy is effective in approximately 80% of cases of metastatic prostate cancer, most such cancers acquire androgen-independent growth ability and show castration resistance, so-called CRPC. Several novel drugs targeting the androgen receptor axis including the CYP17A1 inhibitor, enzalutamide (MDV3100), or chemotherapy are widely used as second-line therapy for CRPC, but the results are not satisfactory, as the prognosis only improves by approximately 3–6 months.108–111 In order to overcome the limited efficacy, other therapeutic modalities are urgently required. These data clearly show the therapeutic potential of RAS blockade in human aggressive prostate cancer. Although the beneficial effects of ACEI in prostate-specific antigen failure after surgery67 and favorable possibility of ARB in the treatment for CRPC have been reported,33 further clinical study will be required to show the prognostic significance of RAS blockade.

Urothelial cancer Using human bladder cancer specimens, bladder tumors with a high grade and/or high stage potentially showed higher AT1R expression in urothelial cancer cells.112 The clinical outcomes after transurethral resection of bladder tumors were also retrospectively investigated in patients who did or did not receive RAS inhibitors, and it was found that the absence of RAS inhibitor administration was an independent risk factor for subsequent tumor recurrence in patients with initially diagnosed non-muscle-invasive bladder cancer.113 In addition, a similar effect of RAS inhibitors was observed in patients with upper-tract urothelial cancer after nephrouretectomy.114 These findings suggested the potential effect of chemoprevention with RAS inhibitors after surgery in patients with urothelial cancer. © 2015 The Japanese Urological Association

In experimental models, Kosugi et al. first reported that a clinically achievable dose of candesartan prevented bladder tumor growth by inhibiting angiogenesis, while its antitumor effect was not a result of direct toxicity.43 In addition, candesaratan was found to enhance CDDP-induced cytotoxicity in mouse xenograft model by inhibiting angiogenesis and inducing apoptosis.115 The mechanism of these synergistic effects has not yet been elucidated; however, clinical specimens from patients who underwent cystectomy after neoadjuvant CDDP-based chemotherapy showed significantly higher AT1R and VEGF expression than corresponding transurethral resection specimens.47 Their in vitro study also showed that CDDP upregulated AT1R expression through ROS generation and enhanced VEGF production. Furthermore, investigating acquired platinum-resistant bladder cancer cells clearly showed a correlation between increased ROS generation and AT1R expression after development of acquired platinum resistance and the significance of RAS inhibition as a new modality for CDDP resistance when bladder tumors progressed after CDDP-based regimens.116 RAS inhibitors could be promising based on the interesting findings that CDDP resistance is related to increased AT1R expression, and RAS inhibitors have synergistic effects with CDDP. However, these findings were reported from a limited number of institutions. Further investigation is warranted from both basic and clinical viewpoints of urothelial cancer and RAS.

Conclusions RAS had been basically only recognized as a regulator of blood pressure and renal hemodynamics. As the concepts of ACE inhibition and AT1R blockade have appeared and spread widely, the mechanisms have been attracting attention scientifically, and research is now being carried out in various other fields in addition to cardiovascular and kidney diseases. Therefore, RAS blockade has shown not only an antihypertensive effect, but also tissue protection, LUTS improvement and antitumor effects. Although some controversy has arisen with regard to its carcinogenicity, the beneficial secondary effects of RAS blockade will remain a focus of research. By elucidating the mechanisms, diverse pathophysiological mechanisms that can be initiated by RAS have been identified. At least one thing is abundantly clear, and that is that RAS blockade has made a contribution clarifying many biological phenomena, which is far greater than we thought when we first met RAS in the textbook.

Acknowledgments The authors thank Dr Tomohiko Asano, Dr Masamichi Hayakawa (Department of Urology, National Defense Medical College) and Dr Masaru Murai (International Goodwill Hospital) for supporting research. The authors also thank Ms Tomomi Genda for editing the manuscript.

Conflict of interest None declared. 727

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