Increased ACE in extrahepatic cholangiocarcinoma as a clue for activated RAS in biliary neoplasms

Cholangiocarcinoma (CCA) is a primary neoplastic tumor of the epithelial lining of the biliary tree which carries a poor prognosis despite combined therapeutic strategies. Although the exact etiology remains obscure, it has been suggested that locally produced Angiotensin II (Ang II) in intrahepatic CCA tissues plays a key role in the proliferation and activation of CCA. In the present study, we aimed to analyze the relationship between the levels of circulating angiotensin converting enzyme (ACE), an important molecule of the renin-angiotensin system (RAS), and biliary disorders.

The study group comprised 19 extrahepatic cholangiocarcinoma (EHCC) (16 patients with hilar, three patients with distal CCA), and 15 choledocolithiasis (CL) patients, with 15 controls. Median age of EHCC, CL and healthy controls were 67 (48-82), 65 (29-87) and 56 (23-74) respectively. ACE was measured by monitoring the alteration in absorbance at 340 nm of the hydrolysis of furylacrylolylphenylalanylglycylglycine (FAPGG) to FAP and GG on an analyzer. The ACE activity in the sample was determined by comparing the sample reaction rate to that obtained with the ACE calibrator.

Serum mean ACE levels were 56.6±27.4 U/L, 32.9±14.6 U/L and 28.6±10.6 U/L for patients with EHCC, CL and healthy controls, respectively. Serum ACE levels were significantly higher in patients with EHCC compared to CL and control groups. No significant differences with respect to ACE levels were observed between CL and control groups.

Circulating ACE in the context of RAS might be associated with EHCC development by creating a local environment enriched with cytokines and other growth factors that may promote cholangiocyte turnover.