Physiologic pathway of RAS

The novel function of the renin-angiotensin system (RAS) is cardiovascular homeostasis. Classic functions of vasoconstriction and salt retention occur through the main effector angiotensin II (ANG II); an octapeptide, converted from angiotensin I by angiotensin-converting enzyme (ACE) [1, 2]. Numerous receptors of angiotensin II that have been identified and cloned, with the two thought to provide most of the physiological responses, are angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R). A majority of the actions responsible for cardiovascular homeostasis is through AT1R, identified and functioning in the blood vessels, liver, adrenal cortex, kidney, and brain. AT1R also has been shown in several studies to be pro-inflammatory, promote angiogenesis, and to be anti-apoptotic. AT2R is usually found to be expressed in fetal life, but there are some remaining receptors which studies have shown to antagonize the functions of AT1R [3, 4].

ANG II can be further converted via angiotensin-converting enzyme II (ACE II) to a mediator ANG 1–7. This mediator acts primarily on Mas, a G-coupled protein receptor. Contrary to the primary physiologic effects of ANG II on AT1R, ANG 1–7 decreases inflammation, increases apoptosis, and is anti-angiogenic and anti-proliferating [3–5]. Further investigation is currently underway in understanding the physiological and pathological implications of ANG 1–7 (please see Figure 2 of Fyhrquist and Saijonmaa 2008 [2]).

Angiotensin and malignancy

Angiogenesis is vital to the process of tumor growth and development. The activation of AT1R via ANG II has been shown to stimulate the expression of vascular endothelial growth factor (VEGF), angiopoietin 2, fibroblast growth factor, nitric oxide, and platelet-derived growth factor [6–9]. The pro-angiogenic and proliferative nature of these endogenous compounds have been linked to solid tumor development. RAS components have been identified to be upregulated in numerous malignant tissues: breast [10], prostate [11], pancreas [12], skin [13], cervix [14], and ovaries [15]. Blockade with perindopril showed a decrease in murine hepatocellular carcinoma in vitro growth and angiogenesis. There was a significant reduction in VEGF concentration, implying a direct correlation with ANG II and VEGF concentration [16]. As both receptors, AT1R and AT2R have been studied; but there is more focus on AT1R being involved in the inflammatory, remodeling, and angiogenic process [17]. Studies have demonstrated that blocking angiogenesis will inhibit solid tumor growth past 2–3 mm and the potential propagation of metastasis [18, 19]. Thus, angiotensin inhibition may potentially be used as a chemo-preventative mechanism in solid tumor development and metastasis.

The physiologic function of ACE in the colon

Novel physiologic functions of the RAS have been well established in the cardiovascular and renal system, with the primary functions of blood pressure control, electrolyte balance, and fluid volume. Recently, studies have examined and identified receptors and mediators of the RAS in other tissue and organs of the body. Angiotensin II receptors have been identified in the normal colon of human, rat, and guinea pig [20]. Localization via immunohistochemistry identified AT1 receptors in the surface epithelium, crypt bases, and in the lamina propria. AT2 receptors were identified mainly in the mesenchymal cells of the lamina propria and weakly in the surface epithelium. Components of the RAS system were also identified in the lamina propria, supporting the evidence of RAS also exhibiting paracrine function. With evidence of the presence in normal tissue, identification of physiologic function within in the colon has not been completely elucidated. Varying serum concentrations of Angiotensin II (Ang II) have demonstrated to have different effects based on which receptor is predominantly activated. At low Ang II concentrations, AT2R is predominantly stimulated, which stimulate the absorption of water and sodium from the colon. At high Ang II concentrations, AT1R mediated pathway is predominantly activated and inhibit sodium reabsorption and/or stimulate sodium secretion [20].

Colonic motility may also be influenced by the activation of AT1 receptors [21]. With knowledge of the angiotensin receptors in vascular smooth muscle, the longitudinal smooth muscle of the colon has also been speculated to have some of the multivariable colonic contractile input from activation of AT1. In a mouse colon, concentration-dependent contractile effects in the presence of Ang II were present in the proximal and distal colon. The AT1 receptor inhibitor, Losartan, competitively inhibited these effects, requiring a greater concentration to observe the same contractile effect. Conversely, AT2 receptor inhibitors did not affect the contractile property of Ang II.

Studies involving ACE-I/ARB and colorectal cancer

The use of ACE-Is or ARBs have demonstrated a decrease in mortality and an increase in survival in studies of different malignancies, including lung cancer, pancreatic cancer, and metastatic renal carcinoma [22]. Of relevance, a case-control study involving over 480,000 patients at the Overton Brooks VA looked at the incidence of newly diagnosed pancreatic, esophageal, and colorectal cancer (CRC) in patients taking ACE-I prior to diagnosis (38% were ACE-I users). A statistically significant decrease was demonstrated in all three cancers: pancreatic (OR 0.48; 95% CI 0.39–0.61) [23], esophageal (OR 0.55; 95% CI 0.45–0.66) [24], and colon (OR 0.47; 95% CI 0.45–0.50) [25] in patients taking ACE-Is.

To decrease the development of CRC from benign or pre-cancerous polyps, the use of colonoscopy has provided not only a screening benefit, but a therapeutic technique as well. A majority of patients with colon cancer may present very subtle signs and symptoms of malignant disease. One of the more common symptoms is anemia, secondary to blood loss from a colorectal malignancy. Another study examined the incidence of malignancy diagnosed during colonoscopy after a positive occult blood stool test. In patients who were on ACE-Is prior to colonoscopy were less likely to have an advance neoplasia (OR 0.71; 95% 0.57–0.89) [26]. In another colonoscopy screening retrospective study, patients who had an adenomatous polyp removed at initial screening were followed and evaluated at their follow colonoscopy at the time interval of 3 to 5 years. The patients were categorized as patients who used ACE-I between initial screening and follow and those who did not use an ACE-I. Of the patient who took ACE-I, there was a 41% reduction in the incidence of advance adenomatous polyps (OR 0.59; 95% 0.49–0.69). There was also a statistically significant decrease in right sided polyps, and a decrease in the polyp size (smaller in ACE-I users), which was dose dependent [27].

Of patients who have known colorectal cancer, metastatic spread can be of devastating consequence. A small study demonstrated an inverse relationship between history of hypertension and the risk of distant metastasis (OR 4.5, p = 0.006) in stage 2 CRC patients. As this inverse correlation was of interesting significance, the investigators further evaluated the data set and noticed the majority of patients with the diagnosis of hypertension were prescribed ACE-Is. Twenty-five percent of patients with metastasis were using ACE-Is, compared with 64% of patients using ACE-Is and who did not have metastasis [28]. This implication of ACE-Is as a potential chemo-preventative option deserves further evaluation.

Colorectal cancer metastases in the liver and RAS

The most common location of CRC metastasis is the liver. Over 70% of deaths from CRC occur from metastasis to the liver. The normal liver is responsible for the physiologic production of angiotensinogen, the precursor to angiotensin I (ANG I). Components of the renin-angiotensin system can be distinctly characterized between normal liver and metastatic CRC. CRC metastases have high levels of ACE and MasR expression but low AT1R and angiotensin mRNA levels compared to normal liver [29]. The high levels of ACE from CRC take full advantage from normal liver production of angiotensinogen and convert it to the physiologically active ANG II. ANG II proceeds as the functional mediator to the proliferative, angiogenic, and invasive qualities of CRC. AT1R expression is found to be lower in CRC metastasis compared to surrounding normal liver. Through staining, the most likely location of increased AT1R expression is in the Kupffer cells (KCs) or hepatic macrophages. Contrary to progression of pathological processes like atherosclerosis, where macrophage involvement is a progressive step in the disease process, KCs increase in quantity and have anti-tumor invasive qualities when Captopril is infused during in vitro studies. KCs have been identified to express ACE and AT1R. In the mice model, when KCs are depleted, there is an increase seeding of metastases. Captopril and Irbesartan increased the anti-tumor effect of Kupffer cells and inhibited the number and volume of metastatic liver CRC tumors [30, 31].

Interestingly, the mediator ANG 1–7 exhibits similar results as Captopril on CRC liver metastasis. ANG 1–7 is believed to target the Mas R receptor, which has also been shown to mediate a number of potentially anti-angiogenic and anti-proliferative effects. With the combination of Captopril, there is a perceived synergistic effect of ACE inhibition, which leads to an increase in ANG 1–7 production. The decrease in ANG II and increase in ANG 1–7 lead to an anti-proliferative mediation through two distinct intracellular mechanistic pathways. Captopril not only inhibits ACE, but it reduces the ACE level and angiotensinogen expression in the host liver, leading to a further inhibitory mechanism [29].

Glycemic control, RAS and liver metastasis

Diabetes is a progressive disease with numerous identified comorbid conditions. There is recent evidence that diabetes may contribute to the progression of some cancers. A meta-analysis composed of 15 studies showed that diabetes is associated with an increased risk of colorectal cancer when compared to patients without diabetes (RR 1.30; 95% CI 1.20–1.40) [32]. Though the influence of diabetes in primary CRC has been established, implications of glycemic control and diabetes and its influence of CRC metastasis to the liver have yet to be explored. Recent studies have identified a relationship between diabetes and renin concentration in CRC liver metastasis [33, 34].

In the mice models, hyperglycemia in diabetic mice resulted in an increase in renin expression. This relationship was found to be dose dependent with glucose concentration in CT26 cells. The relationship between hyperglycemia and renin may potentially have synergistic effects. An upregulation of renin will ultimately lead to an increase of circulating Ang II, and therefore, the proliferating and pro-angiogenic effects associated with activation of AT1R [34]. An increase in liver metastasis in hyperglycemic mice was also observed, concluding the potential of liver metastasis being associated with angiotensin activation. A reduction of liver metastasis was observed when angiotensin inhibitors and hypoglycemic medication were introduced in separate arms of the experiment. A synergistic effect was observed with both angiotensin inhibitors, and hypoglycemic medications were used simultaneously [33].

Conclusion

Colorectal cancer is currently the number three most common cancer, and the number two cancer with the highest mortality in combined males and females. The use of routine screening for colorectal cancer through colonoscopy may identify colon cancer in earlier stages, however, the number of new cases each year continues to keep colorectal cancer in the top three of the most diagnosed cancers. Recent implications of using a common anti-hypertensive medication as a chemo-preventative medication may have remarkable results in the colorectal cancer community. Studies exhibiting the decreased incidence, decreased diagnosis after bleeding symptom, and decreased rate of recurrence have already been published. The potential of a randomized clinical trial may further establish the potential clinical significance of ACE-Is and ARBs in preventing colorectal cancer in different stages of the cancer timeline.