Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients

Abstract

The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme-2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease.

Expression of the Components of the Renin-Angiotensin System in Oncological Diseases

“…Consequently, changes in topology and ACE expression levels in cancer may serve as a marker localization effects proonkogennyhA-2 and other humoral factors, the metabolism of which is associated with the functions of RAS components. For example, in cancer of the kidneys, a regular change in protein expression and activity of ACE topology (Errarte P. et al, 2017;. Sobczuk P. et al, 2017).…”

“…Sobczuk P. et al, 2017). Normally cortical epithelium tubule of the nephron segments, in particular, epithelium proximal demonstrates high expression indicators ACE that is not in clear cell renal cell carcinoma (CCRCC) and is detected only in the tumor blood vessels (Errarte P. et al, 2017). The authors have shown that the protein expression level in the tumor and the magnitude of its enzymatic activity in blood plasma may be a marker CCRCC aggressiveness and overall survival of CCRCC patients.…”

“…et al, 2012.;Shibayama Y. et al, 2015.;Yue Z. et al, 2016). Conversely, under certain oncological diseases cells gradually lose their inherent ability to express normal RAS proteins (Errarte P. et al, 2017;.. Sobczuk P. et al, 2017). Secondly, there is a regular ).…”

Tissue synthesis of some components of the renin-angiotensin system in hypertensive patients with localized kidney cancer

“…Метаболический дисбаланс компонентов внутрипочечной РАС при опухолях почек показан в нескольких исследованиях [11,12]. При изучении экспрессии АПФ и АПФ2 продемонстрирована значительная корреляция их повышенной активности с агрессивностью светлоклеточного почечно-клеточного рака [13]. Однако в другом исследовании установлено, что ферментативная активность и экспрессия АПФ и АПФ2 в основном подавляются в тканях почечно-клеточного рака и хромофобного РП, а также при почечной онкоцитоме, а уровни АПФ2 и матричной РНК снижены только при хромофобном и онкоцитарном РП, а при почечно-клеточном раке не коррелируют [14].…”

The Conjugation of Tumor and Systemic Expression of the Components of the Renin-Angiotensin System in Hypertensive Patients With Kidney Cancer

“…Однако показано, что нарушения локальной экспрессии компонентов РАС сопряжены с опухолевым ростом в почках [5,6]. Так, повышенная тканевая экспрессия ангиотензинрегулирующих ферментов (АПФ и АПФ2) сопряжена с агрессивностью почечно-клеточного рака [7].…”