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

https://doi.org/10.1016/j.clinre.2011.06.008Get rights and content

Summary

Aim

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.

Patients and methods

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.

Results

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.

Conclusion

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.

Introduction

Cholangiocarcinoma (CCA) is an uncommon malignant cancer that arises from the neoplastic transformation of cholangiocytes anywhere along the intrahepatic and extrahepatic biliary tree, excluding the papilla of Vater and the gall bladder [1]. CCA can be classified as intra-hepatic (IHCC) or extrahepatic (EHCC), the latter being further subdivided into hilar, middle and distal carcinomas, based on the location of the tumor within the extrahepatic biliary tract. Despite novel advances in diagnosis and pathogenesis, in the majority of cases the etiology of CCA still remains obscure. However, several conditions associated with inflammation and cholestasis have been defined as risk factors for CCA. Furthermore, CCA likely results from neoplastic transformation of cholangiocytes, although transformation of epithelial cells within the peribiliary glands and/or biliary stem cells may also contribute to its development [2], [3], [4].

The circulating renin-angiotensin system (RAS) is known to play a crucial role in regulating blood pressure, blood flow, fluid volume and electrolyte balance [5], [6]. In addition to these well-known physiologic effects on cardiovascular and renal systems, local tissue RAS has been described to exist in tissues such as kidneys, gonads, adipose tissue, liver, pancreas and bone marrow from which it can elicit various specific responses for individual tissue functions [7], [8], [9], [10], [11], [12], [13], [14]. Angiotensin-converting enzyme (ACE), an important molecule of the RAS, is also considered to be a regulatory molecule in systemic and local circulation in distinct disorders. ACE catalyzes the conversion of Angiotensin I (Ang I) to Angiotensin II (Ang II) and is known to play a pivotal role in RAS [7], [15]. Although there is a considerable amount of data reporting the inevitable role of RAS in a variety of inflammatory and neoplastic disorders, there is only one study in the literature demonstrating the role of Ang II in the context of RAS that induces tumor progression and fibrosis in IHCC through an interaction with hepatic stellate cells [16]. The aim of the present study was to assess circulating ACE concentrations in biliary disorders including EHCC and choledocholithiasis (CL). Elucidation of the associations between ACE in the context of RAS and EHCC may help provide a better understanding of the enigmatic pathogenesis of EHCC.

Section snippets

Patients and methods

The present study was carried out in our tertiary reference center (Turkiye Yuksek Ihtisas Training and Research Hospital, Department of Gastroenterology) between July 2010 and February 2011. The study groups comprised 19 cases with EHCC (16 patients with hilar, three patients with distal CCA), 15 CL patients and 15 healthy controls. The diagnosis of CL was based on clinical and biochemical features of CL and also confirmed by radiological tools (ultrasonography, magnetic resonance

Results

The median age of patients with EHCC, CL and healthy controls were 67 (48–82), 65 (29–87), and 56 (23–74) respectively. There were no statistically significant differences between the ages of the study participants. Clinical characteristics and complete blood cell count values of study participants are summarized in Table 1. Biochemical tests of the cases with biliary disorders and the control group are summarized in Table 2. With respect to routine biochemical tests between the study groups,

Discussion

In the present study, we demonstrated that patients with EHCC have elevated circulating ACE concentrations in comparison with CL patients and healthy controls. The results of this study added a clue to the hypothesis that elevated ACE levels in the context of RAS could be linked to pathological biliary epithelial events in the microenvironment of the cholangiocytes that line the biliary tree (Fig. 2). Furthermore, elevated ACE levels are considered to have a role in the cytokine network of the

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgement

We would like to thank Dr. Sureyya Altunay, who helped us to prepare the Fig. 2 in this manuscript.

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