The Expression of Angiotensin Converting Enzyme (ACE) in Tumor Cells may Increase Invasive Ability and Promote Lymph Node Metastases

Aims: ACE cleaves angiotensin I to form angiotensin II, which is involved in the regulation of growth and differentiation via the angiotensin II receptors, Type 1 (AT1) and Type 2 (AT2). ACE is up-regulated in gastric cancer, and the increased mRNA expression associated with the ACE polymorphism significantly correlates with the development of lymph node metastases in gastric cancer. Methods: Using immunohistochemistry, we investigated the expression of ACE in lymph node metastases of gastric cancer. Gastric cancer cell lines were evaluated for the mRNA expression of ACE, AT1, and AT2, and in vitro cell proliferation and invasion assays were carried out after treatment with cytokines, and inhibition of ACE, AT1 and AT2. Results: ACE was expressed in 26 of 45 (58%) lymph node metastases, occasionally exhibiting a very localised expression directly surrounding the lymph node. The proliferation and invasive ability of the cell lines, which all expressed varying levels of ACE, AT1 and AT2, was influenced by the cytokines, and inhibition of ACE and AT1 resulted in significant upregulation of proliferation combined with a significant reduction in the extent of invasion in the NCI-N87 cell line. The MKN28 cells showed only significantly increased invasive ability. Conclusions: The effect of ACE and AT1 inhibition on cell proliferation and invasive ability seems to depend on the balance of expression of ACE, AT1 and AT2, and may also be related to the local presence of cytokines.

Keywords: angiotensin, cytokines, gastric cancer, invasion, metastasis