A close relationship is assumed to exist between the renin–angiotensin system (RAS) and cancer. Angiotensin II directly induces cell proliferation and angiogenesis, and all RAS components are expressed in various types of cancer [1]. It has also been suggested that angiotensin II plays an important role in tumor metastasis by contributing to tumor adhesion to vascular endothelial cells, migration, invasion, and angiogenesis [2]. Therefore, RAS inhibitors are expected to be beneficial for inhibiting tumor metastasis. Indeed, several reports have indicated that RAS inhibitors can inhibit cancer metastasis in some malignant tumors. For example, Miyajima et al. [3] reported that among postoperative patients with kidney cancer, metastasis-free survival was significantly better in patients treated with RAS inhibitors (93.7%) than in patients in the control group (83.9%). Sun et al. [4] conducted a meta-analysis and found a nonsignificant trend toward better metastasis-free survival among RAS inhibitor users (hazard ratio [HR] = 0.63; 95% confidence interval [CI] = 0.40–1.01). Conversely, Asgharzadeh et al. [5] conducted a meta-analysis of the association between use of RAS inhibitors and survival rates among patients with kidney cancer and revealed significantly higher mortality rates in patients treated with RAS inhibitors than in those who did not receive RAS inhibitors (HR = 0.723, 95% CI = 0.568–0.921). These reports suggest that RAS inhibitors may reduce cancer metastasis, which leads to better prognosis. However, there are also contradictory reports on the effects of RAS inhibitors on metastasis-free survival [6], making it difficult to draw a definite conclusion regarding this issue.

In this study, Hirata et al. [7] analyzed the impact of RAS inhibitors on cancer metastasis using a database of patients with cancer. Multivariate analyses revealed that rates of metastasis for skin cancer (HR = 5.81, 95% CI = 1.07–31.57) and kidney cancer (HR = 4.24, 95% CI = 1.71–10.53) were significantly higher in patients treated with RAS inhibitors. For pancreatic cancer, the risk of metastasis was higher in patients prescribed antihypertensive drugs other than RAS inhibitors (HR = 3.31, 95% CI = 1.43–7.69). Overall, this study is novel in that a large database of electronic medical records was utilized to examine the association between antihypertensive drugs and cancer metastasis in a cross-sectional manner, and it raises the possibility that RAS inhibitor use can increase the risk of cancer metastasis. Although several reports have analyzed the association between antihypertensive drugs and cancer development [7] and the association between antihypertensive drug use and cancer progression or prognosis [8] using large-scale databases, the association between antihypertensive drug use and cancer metastasis has not been sufficiently studied. Because RAS inhibitors are recommended as first-line therapies for cancer survivors, especially for hypertension patients with cancer and proteinuria [8], the possible higher risk of metastasis associated with RAS inhibitors is noteworthy, and further validation is needed.

Conversely, studies of the association between antihypertensive drug use and the development or progression of malignant tumors can easily be affected by various types of bias, which were not fully resolved in the current study. In particular, hypertension is known to be a risk factor for renal cell carcinoma [9], and the possibility that blood pressure itself also affects the occurrence of renal cell carcinoma metastasis could not be dismissed because accurate blood pressure data were not obtained. Indeed, ACE inhibitors, ARBs, beta-blockers, Ca antagonists, and diuretics have all been reported to be associated with a risk of renal cell carcinoma [10], suggesting that the underlying hypertension itself may have influenced the results. Although it has been recently reported that 5-year metastasis-free survival was significantly better in hypertension patients with renal cell carcinoma (84.6% vs. 73.0%) [11] and that such patients had significantly lower rates of lymph node and distant metastasis [12], further validation is needed. It was recently proposed that use of thiazide diuretics is associated with the occurrence of various types of skin cancer, including squamous cell carcinoma, basal cell carcinoma, and melanoma [13, 14]. Although an association between thiazide diuretic use and skin cancer metastasis has not been indicated, it cannot be dismissed that the non-RAS inhibitor users included patients taking thiazide diuretics, which might have influenced the results. It should also be noted that this was a retrospective study based on electronic medical records and does not necessarily indicate a causal relationship between antihypertensive drug use and cancer metastasis.

At present, RAS inhibitors, Ca blockers, and thiazide diuretics are empirically recommended for antihypertensive management among cancer survivors, and beta-blockers are recommended for patients receiving cardiotoxic anticancer agents [15]. Nevertheless, these recommendations are not based on clear evidence. Recently, it has been reported that the risk of cardiovascular diseases such as heart failure is significantly higher in hypertension patients with cancer [16]. In the future, hypertension should not only be regarded as an adverse event in patients with cancer, but we should study the association between hypertension and cancer comprehensively within the new academic field “Onco-Hypertension” to clarify the complicated association and pathophysiology of these diseases [17]. Based on such concepts, the effects of antihypertensive drugs on cancer incidence, metastasis, and prognosis should be analyzed using large-scale databases, such as electronic medical records or health insurance databases, as well as new technologies, such as artificial intelligence. Based on these data, evidence should be accumulated on the most suitable antihypertensive drugs for use in each cancer type.