Increasing evidence suggests that Mets is involved in the development of CRC, and this continues to be a growing health problem worldwide, especially in developed countries [1
]. Recent epidemiological studies have suggested that patients with hypertension, a component of Mets [1
], comprise a high-risk group for CRC [3
]. However, appropriate animal models to evaluate hypertension-related colorectal carcinogenesis have not yet been generated.
To our knowledge, the present study provides the first evidence that after administration of AOM, SHRSP and SHRSP-ZF rats, both of which present with hypertension, more readily develop colonic preneoplastic lesions than normotensive WKY rats. In particular, we found that SHRSP rats experience accelerated development of ACF. This is significant because these rats did not exhibit insulin resistance, hyperleptinemia, or dyslipidemia and did not have increased adipose tissue, which are involved in the pathophysiology thought to link Mets to CRC [5
]. These findings, therefore, suggest that hypertension per se
might play a critical role in the early events of colorectal carcinogenesis. We have found that the angiotensin converting enzyme inhibitor captopril, an anti-hypertensive drug, significantly prevents the development of ACF in SHRSP-ZF rats [19
]. These findings also support our hypothesis that blood pressure elevation per se
might be directly involved in the early stage of colorectal carcinogenesis. However, in order to test this hypothesis, further studies are needed to establish whether other anti-hypertensive agents, such as AT-II type 1 receptor blockers and calcium channel blockers, can suppress the development of ACF by lowering blood pressure.
Among the pathophysiological disorders associated with hypertension, an increased level of oxidative stress is thought to be particularly important in CRC development [5
]. Oxidative stress, defined as the overproduction of oxygen species combined with inadequate anti-oxidative defense mechanisms, can result in DNA damage and, consequently, mutations associated with colorectal carcinogenesis [5
]. In the present study, the hypertensive SHRSP and SHRSP-ZF rats had significantly elevated urine 8-OHdG levels and serum d-ROM levels, which are associated with increased oxidative stress [21
]. However, they also had reduced GPx
mRNA levels, both of which encode antioxidant enzymes, in the colonic epithelium. These findings indicate that both SHRSP and SHRSP-ZF rats are subjected to strong oxidative stress, which might contribute to the development of ACF.
In addition to oxidative stress, the induction of chronic inflammation is also considered to play a critical role in obesity-, diabetes-, and hypertension-related colorectal carcinogenesis [5
]. In the present study, serum levels of TNF-α and IL-6, as well as colonic expression of MCP-1
mRNA, were markedly elevated in SHRSP-ZF obese and diabetic rats. These changes might have been associated with the increase in adipose tissue in SHRSP-ZF rats because excess adipose tissue plays an important role in the exacerbation of systemic inflammation [22
]. Furthermore, colonic epithelial expression of TNF-
α mRNA and serum levels of COX-2 were significantly higher in both the hypertensive SHRSP and SHRSP-ZF rats, although the former did not become obese or develop diabetes. These findings are also significant because the dysregulation of TNF-α, a central mediator of chronic inflammatory diseases, and COX-2 have key roles in the stimulation of tumor growth and the progression of carcinogenesis in several tissues, including the colon and rectum [24
Why did the SHRSP rats, which did not exhibit obesity and insulin resistance, experience an acceleration of oxidative stress, exacerbation of chronic inflammation, and development of ACF to the same extent as SHRSP-ZF rats that are both obese and diabetic? One possible explanation is that the dose of AOM (20 mg/kg body weight) used in the present protocol was considerably greater than that needed to induce ACF development in these hypertensive rats. A lower dose of AOM may therefore result in differences in both the number and size of ACF between SHRSP and SHRSP-ZF rats. It is also possible that an increase in the serum level of AT-II, which is the main effector peptide of the renin-angiotensin system [12
], might contribute to these phenomena because renin-angiotensin system activation has been implicated in the increase in oxidative stress and the induction of inflammation [11
]. Renin-angiotensin system activation induces adipocyte inflammation, as demonstrated by the increased expression of TNF-α and IL-6 in adipose tissue, which in turn is implicated in hypertension [28
]. In prostate cancer, treatment with AT-II stimulates the secretion of IL-6 and MCP-1 from prostate stromal cells and is associated with the increased proliferation of prostate cancer cells [30
]. AT-II also induces the expression of iNOS, an inflammatory marker, along with 8-OHdG in prostate cancer cells [31
], suggesting a crosslink between renin-angiotensin system-related inflammation and oxidative stress in cancer tissue.
To date, there is no definitive evidence demonstrating the effectiveness of renin-angiotensin system inhibitors in preventing human malignancies, including CRC, in hypertensive patients [32
]. However, our findings suggest that targeting hypertension-related metabolic abnormalities, including oxidative stress and chronic inflammation caused by renin-angiotensin system activation, may be an effective strategy to prevent CRC development in patients with Mets, especially those with hypertension. In malignant tissue such as CRC, dysregulation of the renin-angiotensin system is implicated in cancer cell migration, invasion, and metastasis [10
]. A recent study also showed that treatment with renin-angiotensin system inhibitors could inhibit chemically induced colorectal carcinogenesis in obese and diabetic mice by attenuating chronic inflammation and oxidative stress [37
]. In order to test the potential efficacy of renin-angiotensin system inhibitors in preventing CRC development in patients with Mets, additional long-term experiments to evaluate whether these agents can prevent colorectal carcinogenesis in hypertensive rats should be conducted.