The Angiotensin II/Angiotensin II Receptor System Correlates with Nodal Spread in Intestinal Type Gastric Cancer

Abstract

We aimed to substantiate the putative significance of angiotensin II receptor type 1 (AT1R) and type 2 (AT2R) for gastric cancer biology by investigating the correlation of their expression with various clinicopathologic variables and patient survival. Local expression of AT1R, AT2R, and angiotensin-converting enzyme (ACE) was investigated by immunohistochemistry in tumor and corresponding nontumor specimens obtained from 100 patients with gastric cancer, and compared with the ACE insertion/deletion gene polymorphism. AT1R and AT2R were found in the tumor epithelial cells of 26 (26%) and 95 (95%) patients, respectively. AT1R was significantly more prevalent (P < 0.001) in intestinal type gastric cancer than in diffuse type gastric cancer. In intestinal type gastric cancer, its expression correlated with the N category (P = 0.009) and the International Union Against Cancer tumor stage (P = 0.024). AT1R + intestinal type gastric cancers had a larger number of lymph node metastases (P = 0.026), a higher International Union Against Cancer tumor stage (P = 0.032), and a shorter survival time (P = 0.009) than AT1RÀ tumors. Multivariate analysis with lymph nodes as a dependent variable showed that AT1R status and ACE-I/D gene polymorphism are independent risk factors. Irrespective of the genotype, AT1R+ gastric cancers had a relative risk of lymph node metastases of 4.40 (95% confidence interval, 1.30-14.86). When the ACE genotype was included, the relative risk of having lymph node metastases increased considerably in AT1R + tumors being heterozygous or homozygous for the ACE D allele (odds ratio, 19.00; 95% confidence interval, 1.45-248.24). Our study shows that AT1R and AT2R are expressed locally in gastric cancer and that the combination of AT1R expression and ACE I/D gene polymorphism correlates with nodal spread in intestinal type gastric cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1206 -12)

Local angiotensin II-generation in human gastric cancer: Correlation with tumor progression through the activation of ERK1/2, NF-κB and survivin

“…This study also showed AT1 receptor protein was overexpressed immnohistochemically in pancreatic ductal cancer cells, whereas the colon cancer cells had extremely weak or negative immunoreactivity for AT1 receptor (7). In gastric caner, it has been also reported that AT1 receptor is overexpressed in cancer tissues (18)(19)(20)(21), little information exists on the local synthesis of angiotensin II. Classically, the physiological activity of angiotensin II has long been recognized to be dependent on conversion of its precursor angiotensin I by angiotensin-converting enzyme (ACE).…”

“…With respect to gastric cancer, several studies have been reported on the local expression of AT1 receptor and have suggested that angiotensin II could play a key factor in tumor growth and metastatic spread via the AT1 receptor (18)(19)(20)(21). These data might indicate that a local tissue RAS is present and is potentially able to supply angiotensin II to the receptors in gastric cancer tissues.…”

The renin-angiotensin system meets the hallmarks of cancer

“…8 For example, in gastric cancer, ACE and AT1R expression in the tumour and the ACE I/D polymorphism (rs1799752) influence metastatic behaviour and, in combination with AT1R expression, positively correlate with nodal spread. 32 AT1R expression is also strongly associated with ovarian tumour invasiveness and with the histological classification: AT1R is expressed in a high proportion of invasive ovarian adenocarcinomas and borderline malignant tumours, but it is expressed in few benign cystadenomas. 33 Recently, Krishnan and colleagues studied the capacity of Ang(1-7) to reduce prostate cancer metastasis in mice.…”

Polymorphisms of Renin Angiotensin System Genes in Uterine Leiomyomas Among Egyptian Females

“…It is also expressed in several cancers such as the breast [12], gastric [13], bladder [14], prostate [15], pancreatic [16], endometrial [17] and renal cancer as well as ovarian carcinoma [18]. AT1R is often upregulated during the progression from normal to malignant phenotypes, indicating at the very least a correlation between the RAS and tumor progression.…”