Urologic Oncology: Seminars and Original Investigations
Original articleRenin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice☆
Introduction
Renal cell carcinoma (RCC) is the most common kidney cancer and represents approximately 3% of all adult malignancies [1], [2], [3]. There has been an increase in the incidence of RCC in recent years. More than one-third of patients with RCC have evidence of metastases at the time of diagnosis, and approximately 33% develop systemic recurrence after primary tumor resection [4], [5]. The lung is the most common site of distant recurrence. Lung metastases are found in 50% to 60% of patients [6].
RCC is not responsive to conventional radiotherapy and chemotherapy [7]. In the case of localized disease, RCC is curable with surgery. However, the prognosis is poor for patients presenting with distant metastases [8]. The treatment of metastatic RCC (mRCC) has significantly improved with a better understanding of the disease pathogenesis. Recently, some multitarget-oriented drugs have shown impressive activity in mRCC, with a high percentage of patients exhibiting a partial response or disease stabilization or both; additionally, these drugs have had a significant effect on survival [9], [10], [11], [12]. Nevertheless, the outcomes are far from optimal, and novel therapeutic strategies are needed in order to help overcome this disease.
The renin-angiotensin system (RAS) regulates normal kidney blood flow and fluid homeostasis and also plays a key role in blood pressure control [13], [14]. Angiotensin II (Ang II) is a crucial component of RAS, and its actions are mediated through its specific cell surface membrane receptors, AT1R, and AT2R. A potential role of Ang II in promoting tumor growth is through hormonal actions and vasoconstrictive effects [15]. Lever et al. [16] reported the first clinical evidence that long-term Ang II blockade may have a protective effect against cancer and suggested that it could prevent carcinogenesis. There have been several reports that Ang II can induce neovascularization in experimental models via AT1R [17], [18]. AT1R is also expressed frequently in various human tumors [19], [20]. Several studies have shown that RAS blockade inhibits tumor growth both in vitro [21], [22], [23] and in vivo [24], [25], [26], [27], [28], [29], and some suggest that this inhibition is due to the suppression of angiogenesis. Vascular endothelial growth factor (VEGF) is the most important angiogenic factor associated with inducing and maintaining neovasculature in tumors, thereby exerting its mitogenic effect by binding to its receptors, mainly VEGF receptor 2 [30].
In this study, we investigated the effects of Ang II blockade on a murine model of RCC.
Section snippets
Cell line and culture
Renca, a murine cell RCC line of spontaneous origin derived from a BALB/c mouse, was purchased from the American Type of Culture collection (CRL-2947). The cells were maintained in RPMI supplemented with 10% fetal bovine serum (Life Technologies) and supplemented with fresh 2-mM l-glutamine (Life Technologies), 100-U/ml penicillin, and 100-mg/ml streptomycin. Cells were maintained in a humid chamber at 37°C and 5% CO2.
Animals
All experimental procedures were conducted according to the National
Tumor growth
Inoculation of the left kidney of BALB/c mice (8 wk) resulted in the development of large tumors (Fig. 1A) with a mean increase in kidney weight of 4.30±0.78-fold in relation to the contralateral kidney (Fig. 1B). In the course of the experiments, 2 animals in the control group, 1 animal in the ARB group and 1 animal in the group ARB+ACEI died. Tumor growth was significantly reduced in treated mice when compared with the controls. However, the animals treated with ARB or ACEI alone had
Discussion
RCC is relatively resistant to conventional cancer treatments, such as radiation and chemotherapy, and despite new treatment options for advanced and metastatic disease, radical nephrectomy remains the mainstay for the treatment of disease [7].
Recent studies have identified a high expression of AT1R in primary RCC and metastases, as well as the involvement of Ang II in tumor angiogenesis and metastasis [26], [31], [32].
Therefore, we decided to investigate whether the blockade of Ang II with
Conclusions
We conclude that the Ang II/AT1R axis plays an important role in the progression and metastatic potential of RCC and that suppression of tumor angiogenesis may be one of the mechanisms by which ACEI and ARB attenuate the growth and metastases of RCC. It is evident that further studies on this subject should be conducted to strengthen these data. However, these drug classes may represent a potentially promising strategy as an ancillary therapy to angiogenesis control in RCC.
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2020, European Urology FocusCitation Excerpt :Lower expression of Ang II receptors yielded better survival in patients with clear cell RCC, and increased ACE activity has been associated with higher tumor grades [57,58]. While the decrease in degradation of bradykinin by ACEis may stimulate growth, survival, and migration of cancer cells, these effects must ultimately be offset by the decrease in angiogenic effects through the decreased VEGF expression due to decreased Ang II [55,56]. There is also the potential for Ang 1–7, increased with the use of ACEis, to have antitumor effects by decreasing cell migration and invasion of cancer cells and reducing tumor growth by decreasing VEGF [59–61].
Therapeutic potential of renin angiotensin system inhibitors in cancer cells metastasis
2020, Pathology Research and PracticeCitation Excerpt :It was showed that overexpression of ACE2 suppress the invasion and angiogenesis of non-small cell lung cancer [13]. In other hand, several studies have shown that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blocker (ARBs), known renin-angiotensin system inhibitors (RASIs) reduce cancer metastasis by targeting various involved mechanisms in different cancer [14–16] (Fig. 1). The expression of RAS has been observed in several tissues and is correlated with tumor development through the regulation of cell proliferation [17–19].
Modifiable risk factors to reduce renal cell carcinoma incidence: Insight from the PLCO trial
2018, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Shapiro et al. [19] noted that diuretic antihypertensive medications did not have an influence of incident RCC. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have seem to peak some interest in reducing cancer specific death in other cancers including kidney cancer [20–22]. However, other studies have refuted that any one antihypertensive medication increases or decreased the risk of RCC, but it is whatever provides the best patient-specific hypertension control [23].
Kidney Toxicities Associated With Novel Cancer Therapies
2017, Advances in Chronic Kidney DiseaseCitation Excerpt :Finally, hypertension usually occurs rapidly after the first cycle of VEGF inhibitors and resolves with cessation of treatment.25 Because angiotensin II increases VEGF expression and promotes angiogenesis, RAS blockade may have antitumor effect.32,33 In a retrospective study of 4736 patients with metastatic kidney cell carcinoma, the use of angiotensin system inhibitors in patient on VEGF inhibitors was associated with an increased overall survival compared with other antihypertensive drugs.34
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This work was supported by institutional Grants (no 2010/52180-A) from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.