Introduction

Recent evidence suggests that Renin–Angiotensin System (RAS) plays an important role in the development of cancer. Both preclinical and clinical studies show that RAS is active, especially in certain forms of cancer [1,2,3]. While proto-oncogenes, oncogenes, cell signaling, microRNAs and epigenetic factors were demonstrated to play important roles in the relationship between RAS and cancer development [4], there are also conflicting reports showing that RAS blockage may be associated with increased cancer incidence [5]. In this narrative review, we evaluate the relationship between RAS and cancer with respect to epidemiology, pathogenesis and future issues.

Epidemiology of RAS and cancer

In humans, almost every organ was shown to have a functional RAS with varying degrees [6]. Increased RAS activity has been demonstrated in various tumor types including kidney, prostate, bladder, stomach, cervix, brain, pancreas, colon, lung, liver, skin, and hematopoietic cancers [1,2,3]. Although controversial data exist, most experimental studies suggest that Angiotensin-receptor blockers (ARB) have anti-proliferative effects in breast cancer [7], induce cell death in pancreatic cancer [8, 9], ameliorate liver metastases in colon cancer [10], and improve the survival in non-small-cell lung cancer [11]. In addition, angiotensin-converting enzyme (ACE) inhibitors (ACEI) may decrease the risk of developing esophageal cancer [12]. Table 1 shows the summary of meta-analyses regarding the use of ACEI/ARB, various cancers and ACE polymorphisms.

Table 1 The summary of meta-analyses regarding the ACEI/ARB Use and Cancer Risk
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The effect of ARBs on cancer development may depend on the type of ARB. In patients with diabetes mellitus Chang et al. [13]. did not demonstrate any association between ARB use and cancer incidence in general. (OR, 0.94; 95% CI 0.80–1.10). However, findings are heterogeneous among different ARBs. For instance, the risk was decreased with Losartan (OR, 0.78; 95% CI 0.63–0.97) but increased with Candesartan (OR, 1.79; 95% CI 1.05–3.06) and Telmisartan (OR, 1.54; 95% CI 0.97–2.43). The same study did not show any association between ACEI use and cancer incidence. In a population-based study including hypertensive patients, Huang et al. [14]. showed that ARB use was found to be independently associated with a decreased risk for cancer occurrence (HR: 0.66, 95% CI 0.63–0.68, P < 0.001). Interestingly, all types of ARBs (Telmisartan, Candesartan, Irbesartan, Valsartan and Losartan) related to decreased risk of cancer. On the contrary, another nationwide study by Pasternak et al. [15]. did not demonstrate an association between ARB use and the risk of incident cancer development. In a cohort of more than 1 million patients, Rao et al. [16]. showed that ARBs use was protective against lung cancer, independent of the ARB subtype. Wang et al. [17]. followed 85,842 subjects (42,921 ARB users) for a mean duration of nearly 5 years and observed the cumulative incidence of cancer was reported as 4% for ARB users, and 6% for ARB non-users (HR: 0.58, 95% CI 0.55–0.62; P:0.001). All ARB subtypes were significantly correlated with lower cancer rates including liver, lung, colon, rectum, breast prostate and stomach cancers. ACEI/ARB use has been associated with survival outcome in metastatic renal cell carcinoma (MRCC). McKay et al. [18]. in 4736 MRCC patients of whom 783 were taking ACEI or ARB showed that ACEI/ARB regimens had improved overall survival compared to patients using other antihypertensive agents (HR, 0.838, P:0.0105, 26.68 vs. 18.07 months) and compared to patients not taking an antihypertensive drug (HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months).

In spite of the many studies reporting beneficial effects of RAS blockage in the incidence and prognosis of cancer, various others reported contradictory findings. Correspondingly, in an epidemiological study from Denmark did not confirm a protective effect of ACE inhibitors on the development of cancer [19]. Similarly, Connolly et al. [20]. did not report any significant association in the total or specific cancer risk with the use of ARBs (telmisartan, irbesartan, valsartan, candesartan, and losartan) according to the data from 15 trials enrolling nearly 140,000 individuals.

There are also reports of increased cancer risk with RAS blockage (Table 1). Hicks et al. [21]. compared the incidence of lung cancer in ACEI vs. ARB users and showed that, ACEIs were associated with an increased risk of lung cancer compared with ARBs (HR: 1.14, 95% CI 1.01–1.29). The hazard ratios increased gradually with longer durations of use, and were higher after 5 years and even higher after 10 years.

Bearing all these issues in mind, a specific mention is needed regarding sartans and cancer. In July 2018, some sartan products were discovered to have been contaminated with N-nitrosodimethylamine (NDMA) which is “probably carcinogenic to human. Soon after another carcinogenic nitrosamine, N-nitrosodiethylamine (NDEA) was found in valsartan, irbesartan and losartan [22]. Thus, there is a concern of increased cancer risk with the use of these products, not due to the carcinogenic effects of RAS blockage but due to these contaminants. Pottegård et al. [23]. assessed the cancer risk associated with exposure to NDMA through contaminated valsartan products, using nationwide registries involving 6000 patients. Results showed no increased risk of cancer in patients using the contaminated tablets of valsartan. The principal weakness of the study was the limited median follow-up. On the other hand, there have been reports of a possible association of valsartan, with melanoma [24].

ACE polymorphism is needed to be considered in cancer epidemiology. Various meta-analyses with ACE polymorphisms is showed inconsistent results (Table 1). ACE polymorphisms, which change the expression level of ACE, have been associated with various cancers. The most studied ACE polymorphisms are the insertion/deletion (I/D) polymorphism. ACE levels of D/D carriers are higher than I/I carriers. D/D polymorphism is associated with the number of lymph node metastases in gastric cancer [25]. D/D polymorphism is also associated with worse prognosis in prostate cancer [26].

All these conflicting results of observational studies could be explained by study design, poor reporting and patient characteristics. It is obvious that more studies are needed with the use of specific ACEI/ARBs to assess the development of cancer.

Pathogenesis

As suggested above, RAS system is suggested to be involved in many types of cancer while the findings are not uniform and conflicting data exist among different studies. This may be due to the fact that RAS system is composed of various receptors, namely Angiotensin Type 1 and type 2 receptors (ATR1 and ATR2), pro-renin receptor (PRR) and Mas receptors and different kinds of effectors such as Angiotensin 2, Ang 1–9, Ang 1–7. Regarding cancer development these effectors and receptors have opposite actions with various aspects (Fig. 1). Classical data focuses on the processing of angiotensinogen to the active peptide angiotensin II (AngII) and the interactions of Ang II with its receptors primarily ATR1. However, the homologue of ACE, known as ACE2, is more recently discovered and functions to cleave the carboxy-terminal amino acid from Ang II and generate angiotensin 1–7 (Ang 1–7). Ang 1–7 interacts with its Mas receptor (MASR) to antagonise the actions of Ang II [27]. ATR1 signaling appears to be the major component of RAS that is involved in tumor growth by inducing angiogenesis and tumor proliferation by promoting VEGF or epidermal growth factor receptor (EGFR) expression [6, 28,29,30]. Angiotensin II can also promote cell growth and proliferation via transforming growth factor-beta [31], tyrosine kinase [32] and activating mammalian target of rapamycin (mTOR) pathways [33] (Fig. 2). In addition, activation of AT1R in LNCaP, DU145, and PrSC cells resulted in increased mitogen-activated protein kinase (MAPK) activation, janus kinase signal transducers and activators of transcription (JAK-STAT) signaling, and cell proliferation [34, 35], ARBs, including candesartan and telmisartan, have been reported to inhibit AT1R expression, suppress cell proliferation, and augment apoptosis in prostate cancer [36,37,38]. Indeed, in many cancer types including breast, pancreas and lung cancer, ATR1 is upregulated [28] and studies have shown that ACEI/ARB blockage results in amelioration of cancer by a variety of mechanisms [28].

Fig. 1
figure 1

The Contradictory Actions of Receptors and Effectors of Renin-Angiotensin System in Tumor Development. Renin-Angiotensin System has different receptors and effectors. Classic data focuses on the processing of angiotensinogen to the active peptide AngII and the interactions of Ang II with its receptors primarily ATR1. Binding of AngII to ATR1 increases inflammation, fibrosis angiogenesis, tumor invasion and metastasis. PRR has also similar action with AngII. On the other hand, when AngII binds to ATR2 the effects are opposite to ATR1 binding. Ang 1–7 when binds to its receptor Mas, causes anti-inflammatory, anti-fibrotic anti-proliferative and anti-migratory function. RAS inhibitors are mostly beneficial in cancer due to augmentation of ATR2 and Ang 1–7 mediated Mas signaling. AngII angiotensin 2, ATR1 angiotensin type 1 receptor, ATR2 angiotensin type 2 receptor, PRR pro-renin receptor, Ang 1–7 angiotensin (1–7), RAS renin-angiotensin system

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Fig. 2
figure 2

RAS Receptor Signaling Pathways Related with Cancer Biology. Different RAS receptors either activate or inactivate various signaling pathways related to cancer development. ATR1 and PRR receptor signaling activate MAPK, PI3K/AKT/mtor, NF-κB and JAK/STAT pathways and increase in VEGF, TGFβ1, EGFR and fibronectin which ultimately lead to increased cellular proliferation, angiogenesis, fibrosis, tumor invasion and metastasis. These pathways are inhibited by ATR2 and Ang 1–7 mediated Mas signaling. RAS renin-angiotensin system, ATR1 angiotensin type 1 receptor, PRR pro-renin receptor, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositol 3-kinase, Akt a serine/threonine kinase, mTOR mammalian target of rapamycin, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, JAK Janus kinase, STAT signal transducer and activator of transcription, VEGF vascular endothelial growth factor, TGF-β1 transforming growth factor-beta 1, EGFR epidermal growth factor receptor

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Pro-renin receptor (PRR) is another receptor that plays an important role as a regulator of the RAS. The major role of PRR is Ang II formation. In addition, the PRR is involved in Wnt signalling, function of the vacuolar H+adenosinetriphosphatase (V-ATPase), the Par3 system, and tyrosine-phosphorylation-dependent signalling pathways [39]. In general, PRR has been upregulated in prostate cancer [40], leukemia [41], and in pancreas cancer [42], thus both ATR1 and pro-renin receptors are suggested to have meaningful roles in oncogenesis (Fig. 1). As mentioned above, ATR2 and other RAS related peptides, such as Ang 1–7, should also be considered. During ARB blockage, AngII levels cannot bind to ATR1 thus limiting proliferation capacity. In contrast to the proliferative effects of ATR1, ATR2 and MASR have anti-proliferative effects [43, 44]. Unlike AngII, Ang (1–7) inhibits both angiogenesis and cell proliferation [45, 46]. The dominance of Ang (1–7) and ATR2 over AngII and ATR1 may provide an explanation to the beneficial effects of ARB on cancer development. Indeed, it was shown that downregulation of ACE2/Ang-(1–7)/Mas axis [47], as well as decreased Ang (1–7) levels were found in breast cancer [48]. Moreover, Ang (1–7) inhibits the growth of tumors cells in several types of cancer including lung cancer [49], prostate cancer [50], nasopharyngeal carcinoma [51] and esophageal squamous cell carcinoma [52].

Many studies have now shown that Ang (1–7) exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms via Mas receptor [53]. In general, Ang1-7/ Mas axis has been reported to be protective in various cancer by a variety of mechanisms including inhibition of cell proliferation, invasion and metastasis and inhibiting epithelial to mesenchymal transition [54]. In contrast, it was also suggested that MASR was significantly up-regulated in colon cancer [55] and was associated with colorectal cancer metastasis [56].

To sum up, various components of RAS seem to play different roles in oncogenesis. The contradicting findings in the literature may be related to different patterns of activation of distinct RAS components, in addition to different levels of tissue expressions and the low selectivity and sensitivity of the antibodies assays used, which poses a limitation for precise measurement of the protein expression levels.

RAS and cell signaling

RAS has interactions with various intracellular signaling pathways that also play substantial roles in carcinogenesis (Fig. 2). Although an extensive review of RAS signaling is beyond the scope of this review, we should remember that RAS system can couple with cell signaling pathways including MAPKs (extracellular-regulated kinases, extracellular signal-regulated kinase (ERK) 1 and ERK2, p38 MAPK and Jun N-terminal kinase and the Jak-STAT pathway which may have a role in tumor development [27].

One of these pathways is adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway which is involved in oncogenesis. AMPK has a tumor suppressor function via cell cycle arrest with stabilization of p53 and the cyclin-dependent kinase inhibitors p21WAF1 and p27CIP1. This pathway also inhibits the synthesis mTOR-1 and hypoxia-inducible factor-1α (HIF-1α) along with fatty acids, triglycerides, cholesterol, glycogen, ribosomal RNA and proteins, resulting inhibition of cell growth [57].

Yang et al. [58]. investigated the relationship between RAS and AMPK signaling pathway in carcinogenesis using the uninephrectomized (UNX) rat model. 96 rats were equally randomized into four groups: sham operation, left uninephrectomy, left uninephrectomy plus treatment with lisinopril or left uninephrectomy with losartan. After 10 months, UNX rats had decreased expression of AMPK compared to sham. There were atypical proliferation and carcinoma of tubular epithelia in UNX rats along with glomerulosclerosis and casts. Treatment with ACEI and ARB increased the AMPK expression by 41.7% and 50.0%, respectively. Moreover, a decrease in AMPK expression was associated with over-expressions of Ki-67. and mutant p53 and morphologic transformations of malignancy in the UNX rat model. These alterations were significantly decreased by RAS blockage, highlighting the interaction of RAS and AMPK signaling pathway in the carcinogenesis of UNX rats.

As mentioned above, Ang II acts on various types of receptors including AT2R. It is accepted that AT2R antagonizes the effects of the AT1R and generates anti-inflammatory, anti-proliferative and anti-migratory responses [59]. AT2R receptor-interacting proteins (ATIP) are important proteins for these responses and ATIP1 was the first reported ATIP member which constitutively interacts with AT2R at the cell membrane. ATIP1 plays a dominant role fort he inhibitory action of AT2R on cell proliferation, receptor tyrosine kinase activation and ERK phosphorylation [60]. ATIP-1 also contributes to AT2R receptor transport and signaling. ATIP-3 is another protein interacting with AT2R with tumor suppressor action. In invasive breast cancer, decreased levels of ATIP-3 are observed and restoration of ATIP3 expression in breast cancer cells reduces tumor cell proliferation [61]. Under those circumstances, AT2R may possibly have beneficial effects in cancer pathogenesis. Indeed, some experimental studies have shown that AT2R expression and activation ameliorate tumor growth, vascularization and/or metastasis progression in different models of cancer [62, 63].

PRR also plays important roles in various pathways, such as the Wnt/β-catenin, MAPK/ERK and PI3K/AKT/mTOR pathways that are involved in a wide range of physiological and pathological processes including tumorigenesis. It is shown that PRR activates transforming growth factor β (TGFβ), activates MAPK/ERK signaling and PI3K/AKT/mTOR signaling pathways [64] while silencing of these pathways down regulates the expression of ERK1/2, AKT and NF-κB (32) in pancreatic cancer cells [42]. Furthermore, Lin et al. [51]. found that Ang (1–7) downregulated PI3K/Akt/mTOR signaling in human nasopharyngeal carcinoma xenografts and inhibited tumor growth via autophagy. Similar findings were also observed in breast cancer, as Ang (1–7) decreased PI3K/AKT pathway activation as well as VEGF expression, epithelial-mesenchymal transition, matrix metalloproteinase MMP-9 activity [65].

The AT1R, the major receptor of Ang II, has extensively modulates many cellular signaling pathways. Du et al. [66]. investigated the downstream effects of the activation and silencing of AT1R using RNA interference in breast cancer. The cancer cells had significantly upregulated levels of AT1R expression. Angiotensin II significantly increased the expression of p-Ras, p-Erk, NF-κB-P65, p-CREB, PCNA, and cyclin D1 and decreased p53 expression in AT1R ( +) cell lines, while AT1R(−) cell line created by RNA interference was not affected by AngII. Irbesartan, an ARB, blocked the effects of AngII on cell growth, cell cycle, and downstream signaling events, including the stimulation of MAPK pathway and NF-Κb. These findings implied that the pro-proliferative effects of AngII may be dependent on its interaction with AT1R in certain cancer types.

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA and plays an active role in oncogenesis by promoting proliferation, transformation, angiogenesis, invasion, metastasis, chemo and radio resistance [67]. Angiotensin II plays a synergistic role with NF-κB in cancer development. Zahaoet et al. showed that AngII affected cell migration in breast cancer. In addition, AngII induced phosphorylation ofPI3K/Akt and resulted in increased NF-κB activity. Thus AngII activates the AT1R/PI3K/Akt pathway, which further activates IKKα/β and NF-κB, resulting in enhanced expression of matrix metalloproteinase (MMP)-2, MMP-9 and in increased cell migration in human breast cancer cells [68]. Bakhtiari et al. [69]. assessed the effect of angiotensin II and NF-κB blockage in breast cancer cell line. Both angiotensin II and NF-κB blockage resulted in decreased cell viability and increase apoptosis separately, while, these affects were more pronounced when angiotensin II and NF-κB blockage were combined. Saber et al. [70]. studied the effects of RAS inhibitors, using losartan (10 mg/kg), perindopril (1 mg/kg) or fosinopril (2 mg/kg) in hepatocellular carcinoma. RAS inhibitors improved liver function and histology and reduced Alpha-Fetoprotein levels, by the inactivation of NFкB pathway through the inhibition of NFĸB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of NFĸBia. Additionally, NFкB-induced tumor necrosis factor alpha (TNF-α) and TGF-β1 levels were reduced, leading to lower levels of MMP-2 and VEGF.

Another signaling pathway involving both RAS and oncogenesis is mitogen-activated protein kinase (MAPK) pathway. Indeed, Ang (1–7), decreased the proliferation of human lung cancer cells via a reduction in MAPK signaling [71]. Major on–off switches of MAPK signaling are MAPK kinases and MAPK phosphatases, which activate and inactivate MAPK via phosphorylation and dephosphorylation, respectively. It was also shown that Ang (1–7) reduces MAPK activity by upregulating MAPK phosphatase named dual-specificity phosphatase 1 (DUSP1). This, in turn, inactivates ERKs1 and 2, potent mitogenic signaling proteins implicated in cell viability, growth, and proliferation in breast tumors. Furthermore, the upregulation of DUSP1 was blocked by Ang (1–7) receptor antagonist, indicating that DUSP1 induction by Ang (1–7) was a receptor-mediated process. Ang (1–7) also prevented the production of TGF-β1, an ERK1/2 activator, and fibronectin synthesis, thus reducing fibrosis in the tumor environment [72].

Correspondingly, AngII has been shown to stimulate ERK1/2 with a resultant increase in monocyte chemoattractant protein (MCP)-1 in pancreatic ductal adenocarcinoma (PDA). In addition, AngII induced MCP-1 transcription was inhibited by AT1R blocker but was unchanged by an AT2R blocker. Inhibition of ERK1/2 activation also reduced the AngII induced MCP-1 synthesis [73, 74].

Overall, evidence suggests that various signaling pathways including protein kinases, NF-κB, ERK1/ERK2, and molecules including VEGF, MCP1, inhibitors of metalloproteinases and HIF1α are involved in RAS activation and tumor behaviour.

Apoptosis, cell proliferation and RAS

The relationship of RAS with apoptosis also deserves special attention. Ang II stimulated ATR1 signaling effects p53 and influences Bcl-2/Bax ratio and decrease apoptosis (Fig. 3). In a study of non-small cell lung cancer (NSCLC), telmisartan, an AT2R receptor antagonist, was found to significantly inhibit cellular invasion and migration, while also increasing pro-apoptotic proteins caspase-3 and Bcl-associated expression. Additionally, levels of phosphorylated RAC serine/threonine-protein kinase (p-AKT), p-mechanistic target of rapamycin, p70-S6 kinase and cyclin D1 were decreased in the telmisartan-treated group. The findings of this study imply that telmisartan-induced apoptosis may be regulated via the phosphoinositide 3-kinase/AKT signaling pathway [75]. On the contrary, RAS inhibitors have been reported to have anti-apoptotic effects as well. It was shown that proapoptotic changes were associated with upregulation of cardiac RAS activity and ACEI treatment was effective in counteracting apoptotic tendency in ovariectomized spontaneously hypertensive rats (SHRs). In response to ovariectomy, Bcl-2/Bax ratio was decreased, leading to a proapoptotic microenvironment in the cardiomyocytes. At the same time, ACE and ATR1 genes were upregulated. Treatment with ramipril effectively reduced apoptosis by downregulation of ACE and ATR1. Similarly, other studies found that AngII could induce apoptosis via inhibition of PI3K/Akt [76] and activation of Janus kinase and signal transducers and activators of transcription (STAT) [77].

Fig. 3
figure 3

The impact of ATR1 signaling on apoptosis. RAS system influences apoptosis. AngII by binding to ATR1 receptor suppress p53 which in turn changes the Bax/Bcl ratio leading to decreased apoptosis

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These findings provided insight into the proapoptotic effects of RAS while suggesting the possibility of an undesirable anti-apoptotic milieu after RAS inhibition which should be investigated in cancer tissue. P53, the major regulator of apoptosis and one of the major defense mechanisms against abnormal cellular proliferation, is a key element in the relationship between RAS and apoptosis. It is well appreciated that the ratio of Bcl-2 to Baxplays a major role in determining the apoptotic fate of the cell [78] and is decreased by p53 signaling, leading to apoptosis [79]. It was shown that p53 and resultant RAS activation increases apoptosis during ischemia reperfusion in heart tissue [80]. Indeed it was shown that ACEI enarapril decreased the p53 expression and cardiac hypertrophy after aortic stenosis [81]. However, there is also conflicting data regarding the relationship of RAS and p53.

For example, in one study the effect of RAS blockage on p53 was investigated in UNX rats. After 10 months, mutant p53 were markedly increased. Treatment with ACEI or ARB attenuated the inhibition of AMPK signaling pathway as well as carcinogenesis, signifying an interaction between RAS p53 in carcinogenesis. These alterations were significantly decreased by RAS blockage, highlighting the interaction of RAS and AMPK signaling pathway in the carcinogenesis of UNX rats [58].

In dysplastic Barrett's esophagus (BE), ACE inhibitor enalapril increased the levels of p53 and possibly apoptosis, suggesting that AngII inhibits p53 expression in dysplastic BE [82]. Currently, consistent evidence is lacking on whether the primary effect of RAS blockage is pro-or anti-apoptotic and whether such an effect is dependent on the tissue type.

RAS activity is shown to modulate cell growth by interacting with protooncogenes and oncogenes as well as apoptosis (explained above). Gopi et al. [4]. reported that cardiac myofibroblast cells exposed to angiotensin II showed increased expression of proto-oncogenes c-fos, (seven-fold), c-myc (five-fold), and c-jun (three-fold), compared with control cells. Correspondingly, losartan reduced the expression of these proto-oncogenes. Inigo et al. [83]. Compared the effects of ACEI/ARB in leukemic myeloid cell lines positive and negative for renin expression. The authors showed that captopril and trandolapril inhibit cell growth in these cell lines independent of their renin expression, while growth arrest was reversed when the agents were removed from the medium. Furthermore, ACEI treatment also decreased the c-myc expression. Losartan had similar anti-proliferative effects, which seemed to be associated with AngII induced Smad activation. Therefore, ACEI/ARB treatment seems to decrease cell growth and c-myc, an important proto-oncogene in hematologic malignancies.

While these studies primarily focused on Ang II and its associated receptor ATR1, PRR may also be responsible for stimulating the downstream factors that contribute to oncogenesis during RAS activation [84].

Micro RNA, RAS And cancer

A microRNA (miRNA) denotes for a small non-coding RNA molecule that functions in RNA silencing and post-transcriptional regulation of gene expression [85]. miRNAs are involved in cell proliferation, cell death, and apoptosis and are known to be up or down regulated in different types of cancer [86, 87]. There is accumulating evidence that miRNAs are involved in the regulation of RAS [88]. For instance, miR-155 is shown to dysregulate the expression of AT1 gene mRNA, which was strongly associated with the malignant transformation of B cells [89]. A miRNA that deserves specific attention is miRNA21, a major player in lung cancer. Previously, a positive correlation between EGF receptor (EGFR) and miRNA-21 was demonstrated in lung carcinoma celllines. In addition, EGFR-tyrosine kinase inhibitors (EGFR-TKI) suppressed miRNA-21, suggesting that the EGFR positively regulates miRNA-21expression [90]. Indeed, the higher miRNA-21 expression is associated with the acquired resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC) [91]. It was suggested that angiotensin II-induced micro RNA-21 can be the culprit for non-small-cell lung adenocarcinoma [6]. Different from the proto-oncogenic miRNA, miRNA 205 is a tumor-suppressing miRNA [92]. Yue et al. [93]. investigated the effect of olmesartan, a AT1R antagonist, on the expression of miRNA-205 and VEGF-A. Olmesertan caused overexpression of miRNA-205 and decreased VEGF-A, which contributed to olmesartan-induced anti-tumor effect on cervical cancer cells. The effects of miRNA-155 on AngII induced vascular smooth muscle cell (VSMC) proliferation were also explored in mice. Cultured cells from the aorta were incubated with AngII and miR-155. While angiotensin II enhanced the viability of VSMCs in a dose-dependent fashion, miRNA-155 prevented this effect of AngII on VSMC and further decreased the expression of ATR1 gene and protein [94]. The anti-proliferative effects of miRNA-155 have been also shown in human extravillous trophoblast-derived HTR-8/SVneo cells via reducing cyclin D1 pathway [95] and by inducing apoptosis [96]. Other miRNAs such as miRNA-221 and miRNA-222 are involved in cell proliferation by the inhibition of the cell cycle regulator, p27kip1 [97]. Enhanced expression of miR-141 and miR-200a mimic p38α deficiency and increases tumor growth in mouse models, but it also improves chemotherapeutic response. Higher miR-200a was found in high grade human ovarian adenocarcinomas along with low concentrations of p38α and an increased oxidative stress [98]. As miRNA biology is evolving, more studies are needed reveal the role of specific miRNAs in a variety of cancers and its corresponding interaction with RAS, keeping in mind that RAS blockage may be a therapeutic option under certain circumstances.

Future Perspectives

The RAS is complex with regard to cancer biology and their knowns, unknowns and future issues are of concern (Table 2). RAS has various receptors and effectors that have contrasting effects in cancer development. Although most studies have shown that RAS activation is associated with cancer, minor studies showed contrasting findings. Currently, we do not know fully whether RAS is activated or inhibited in tumors of different origins. There is also no data regarding the role of the other components of RAS such as angiotensin IV and its receptor, the insulin-regulated amino peptidase (IRAP). Equally important, there is much to investigate the relationship of RAS with intracellular signaling pathways, oncogenes and tumor suppressor genes. Another area of uncertainty is the role of epigenetic regulation of cancer [99]. Although the epigenetic reorganization of the expression of RAS components is a relatively new and little studied area in oncology, epigenetic alterations RAS components in cancer pathogenesis has been suggested [100]. Some data suggest that the renin gene expression in normal and malignant hematopoiesis can be controlled by epigenetic mechanisms [101]. Besides, Ang (1–7) has important epigenetic effects via limiting the mobility of cancer cells and their ability to metastasize [102]. However the research regarding epigenetics RAS and cancer is at its infancy and further research is necessary regarding epigenetics, RAS system and cancer development.

Table 2 The knowns, Unknowns and Recommendations Regarding RAS System and Cancer Biology
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Conclusion

It is now clear that RAS is related to cancer. Mostly, RAS blockage is protective in cancer but fewer studies have also shown contradictory data. These discordant findings may be due to opposite actions of different types of receptors and effectors which are found in RAS. These actions may impact various cell signaling pathways, oncogenes, tumor suppressor genes and epigenetic mechanisms differently. Future research will show the exact cellular mechanisms and their association with different RAS elements with regard to cancer development and pathogenesis.