Expression of the local angiotensin II system in gastric cancer may facilitate lymphatic invasion and nodal spread

Abstract

Purpose: In this study we investigated the putative pathophysiological mechanism, by which angiotensin converting enzyme (ACE), and angiotensin II receptor (ATR) type 1 and 2 might contribute to cancer progression and lymph node metastasis in gastric cancer.Materials and Methods: Local expression of ACE, AT1R, and AT2R was investigated immunohistochemically in non-lesional tissue, primary tumors and lymph node metastases from 45 gastric cancer patients. The distribution of the ACE genotypes was studied in gastric cancer cell lines. In vitro cell proliferation, apoptosis and invasion assays were carried out in the presence of ACE, AT1R and AT2R inhibitors.Results: ACE and AT2R were significantly up-regulated in tumors and metastases, and expressed in the lymph node metastases of 26 (58%) and 40 (89%) gastric cancer patients, respectively. AT1R expression was higher in all tissues of metastatic cancers than in previous investigations. ACE, but not AT1R or AT2R, occasionally exhibited an increased expression in tumor cells directly surrounding lymph follicles. All three possible combinations of the ACE gene insertion/deletion polymorphism were found in gastric cancer cell lines, i.e. the DD- (AGS, MKN28), the II- (MKN45), and the ID-genotype (N87). ACE, AT1R and AT2R inhibition resulted in a significantly increased proliferation and a significant reduction in invasive ability of the N87 and MKN45 cell lines, with N87 exhibiting reduced apoptosis.Conclusions: Our study provides evidence of the expression of the local angiotensin II system in lymph node metastases, and that ACE-, AT1R- and AT2R-activity promotes tumor cell invasion.