Abstract
BackgroundPulmonary vascular endothelium is the main metabolic site for Angiotensin I-Converting Enzyme (ACE)-mediated degradation of several biologically-active peptides (angiotensin I, bradykinin, hemo-regulatory peptide Ac-SDKP). Primary lung cancer growth and lung cancer metastases decrease lung vascularity reflected by dramatic decreases in both lung and serum ACE activity. We performed precise ACE phenotyping in tissues from subjects with lung cancer.MethodologyACE phenotyping included: 1) ACE immunohistochemistry with specific and well-characterized monoclonal antibodies (mAbs) to ACE; 2) ACE activity measurement with two ACE substrates (HHL, ZPHL); 3) calculation of ACE substrates hydrolysis ratio (ZPHL/HHL ratio); 4) the pattern of mAbs binding to 17 different ACE epitopes to detect changes in ACE conformation induced by tumor growth (conformational ACE fingerprint).ResultsACE immunostaining was dramatically decreased in lung cancer tissues confirmed by a 3-fold decrease in ACE activity. The conformational fingerprint of ACE from tumor lung tissues differed from normal lung (6/17 mAbs) and reflected primarily higher ACE sialylation. The increase in ZPHL/HHL ratio in lung cancer tissues was consistent with greater conformational changes of ACE. Limited analysis of the conformational ACE fingerprint in normal lung tissue and lung cancer tissue form the same patient suggested a remote effect of tumor tissue on ACE conformation and/or on “field cancerization” in a morphologically-normal lung tissues.Conclusions/SignificanceLocal conformation of ACE is significantly altered in tumor lung tissues and may be detected by conformational fingerprinting of human ACE.
Highlights
Pulmonary vascular endothelium is the main site of metabolism of vasoactive peptides -angiotensin I and bradykinin [1] and likely hemoregulatory peptide Ac-SDKP [2] by Angiotensin I-Converting Enzyme (ACE) as 100% of lung capillaries express ACE whereas only 5–15% of systemic capillaries express ACE [3,4]
The conformational fingerprint of ACE from tumor lung tissues differed from normal lung (6/17 monoclonal antibodies (mAbs)) and reflected primarily higher ACE sialylation
Primary lung cancer growth and lung cancer metastases decrease lung vascularity reflected by dramatic decreases in both lung and serum ACE activity. [5,6] and preoperative serum ACE activity was suggested as a useful prognostic indicator in lung cancer [7] or as a tool for monitoring serum ACE levels–for the management of patients with lung malignancies [8,9,10]
Summary
Pulmonary vascular endothelium is the main metabolic site for Angiotensin I-Converting Enzyme (ACE)-mediated degradation of several biologically-active peptides (angiotensin I, bradykinin, hemo-regulatory peptide Ac-SDKP). Primary lung cancer growth and lung cancer metastases decrease lung vascularity reflected by dramatic decreases in both lung and serum ACE activity. We performed precise ACE phenotyping in tissues from subjects with lung cancer
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