Hemizygous mice for the angiotensin II type 2 receptor gene have attenuated susceptibility to azoxymethane-induced colon tumorigenesis

Abstract

Evidence suggests that the use of angiotensin-converting enzyme inhibitors potentially reduces the risk of cancer, though the mechanism is unclear. To clarify a potential involvement of angiotensin II (Ang II) signaling in cancer risk, we have examined the effect of Ang II receptor deficiency on azoxymethane (AOM)-induced colon tumorigenesis. Male Ang II type 2 receptor gene-disrupted (AT(2)-null) mice with a 129/Ola and C57BL/6J genetic background, AT(2)-null mice with an SWR/J genetic background, and their corresponding control wild type mice were treated once a week with AOM (10 mg/kg, i.p., 4 consecutive weeks) or saline vehicle. All mice were killed 23-26 weeks after the initial injection of AOM, and tumor burdens were examined. AOM treatment caused the development of colon tumors in all wild type control mice regardless of genetic background (100% tumor prevalence), but only one tumor was present in AT(2)-null mice with a 129/Ola and C57BL/6J genetic background (11.1% tumor prevalence). Although the introduction of the AOMsusceptible SWR/J genetic background induced AOM susceptibility in AT(2) null mice, the tumor multiplicity (6.3) and tumor size (19.8 +/- 3.0 mm(3)) were significantly smaller than those in wild type mice (multiplicity, 12.0 and size, 36.8 +/- 3.2 mm(3)). AOM efficiently downregulated cytochrome P450 2E1 (CYP2E1) in the liver of wild type mice significantly more than in AT(2)-null mice. The levels of DNA methyl adducts formed in wild type mouse colon epithelium by AOM treatment were also significantly higher than in AT(2)-null mice. These results imply that the AT(2) receptor functions to augment AOM-induced downregulation of CYP2E1 expression in the liver, and thus increases AOM-induced tumorigenesis in the colon. The AT(2) receptor function in the liver may be a potential determinant of tumor susceptibility in chemical carcinogen-induced colon tumorigenesis.

Specific single chain variable fragment (ScFv) antibodies to angiotensin II AT2 receptor: evaluation of the angiotensin II receptor expression in normal and tumor-bearing mouse lung

“…4-D). This is consistent with our earlier study in which angiotensin II-AT 2 signaling is also associated with carcinogen-induced colon tumorigenesis (Takagi et al 2002). Although expression level of the AT 2 in the adult lung alveolar epithelium is low, the function of AT 2 in alveolar epithelium may be important.…”

“…However, the specific role of AT 2 in carcinogenesis has not been rigorously elucidated. We have previously demonstrated the pro-oncogenic role of AT 2 in carcinogen-induced colon and lung tumorigenesis in the mouse (Kanehira et al 2005;Takagi et al 2002). In the present study we developed several recombinant anti-AT 2 peptide ScFv antibodies by screening a rodent phage-displayed recombinant antibody library using several synthetic peptides of the AT 2 protein and examined AT 2 expression in normal and NNK-induced tumor bearing mouse lung.…”

“…Increasing evidence suggests that angiotensin II signaling plays an important role in carcinogenesis (Fujita et al 2005;Ino et al 2006;Kanehira et al 2005;Suganuma et al 2005;Takagi et al 2002:Egami 2003. However, the specific role of AT 2 in carcinogenesis has not been rigorously elucidated.…”

Angiotensin II Type 2 Receptor Gene Deficiency Attenuates Susceptibility to Tobacco-Specific Nitrosamine-Induced Lung Tumorigenesis: Involvement of Transforming Growth Factor-β-Dependent Cell Growth Attenuation

“…We have previously reported that the AT 2 receptor possesses an oncogenic function through the regulation of the initiation of azoxymethane-induced colon tumorigenesis in mice (28). Because the lung is a major site of angiotensin II generation and also a target tissue for angiotensin II, it is of interest to examine whether angiotensin II signaling is also involved in carcinogen-induced lung tumorigenesis.…”

Angiotensin inhibition and malignancies: a review

“…This suggested that AT 2 receptor activation could be crucial during tumour genesis and growth, representing a potential mechanism of chemoprevention for human colorectal cancer. 37 …”