angiotensin-i and Colonic-Neoplasms

A new arm of the renin-angiotensin system (RAS) has been recently characterized; this includes angiotensin converting enzyme (ACE)2 and angiotensin (Ang)1-7, a heptapeptide acting through the Mas receptor (MasR). Recent studies show that Ang1-7 has an antiproliferative action on lung adenocarcinoma cells. The aim of this study was to characterize RAS expression in human colon adenocarcinoma and to investigate whether Ang1-7 exerts an antiproliferative effect on human colon adenocarcinoma cells.. Gene, protein expression and enzymatic activity of the main components of the RAS were determined on non-neoplastic colon mucosa as well as on the tumor mass and the mucosa taken 5 cm distant from it, both collected from patients with colon adenocarcinoma. Two different human colon cancer cell lines were treated with AngII and Ang1-7.. The novel finding of this study was that MasR was significantly upregulated in colon adenocarcinoma compared with non-neoplastic colon mucosa, which showed little or no expression of it. ACE gene expression and enzymatic activity were also increased in the tumors. However, AngII and Ang1-7 did not have any pro-/antiproliferative effects in the cell lines studied.. The data suggest that upregulation of the MasR could be used as a diagnostic marker of colon adenocarcinoma.

Topics: Adenocarcinoma; Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Caco-2 Cells; Cell Cycle; Colonic Neoplasms; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Intestinal Mucosa; Male; Middle Aged; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled

We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (A)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed A-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in HT29 cells. Reduction of hepatic ATG production by cholesterol-conjugated antisense S-oligodeoxynucleotide suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and A-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated angiotensin activation enhances liver metastasis of CRC and may therefore provide a possible target for antimetastatic therapy in CRC.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Chymases; Colonic Neoplasms; Diabetes Complications; Diabetes Mellitus; Glucose; Glycated Hemoglobin; HT29 Cells; Humans; Hyperglycemia; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Oligoribonucleotides, Antisense; Receptor, Angiotensin, Type 1; Renin; RNA Interference; RNA, Small Interfering