Possible Involvement of Adipocyte-Derived Leucine Aminopeptidase via Angiotensin II in Endometrial Carcinoma

Abstract

Objective: It has recently been appreciated that a local autocrine or paracrine renin-angiotensin system (RAS) may exist in a number of tissues. Angiotensin II (AngII) is a potent RAS-derived vasoconstrictor peptide, and it is involved in tumor angiogenesis. We have cloned human adipocyte-derived leucine aminopeptidase (A-LAP), which degrades Ang II. This study investigated whether the expression of A-LAP, Ang II, angiotensin type I receptor (AT1R) and vascular endothelial growth factor (VEGF) correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma. Methods: Histologic sections of formalin-fixed, paraffin-embedded specimens from 94 primary endometrial carcinomas were stained for A-LAP, AngII, AT1R and VEGF using each antibody. Disease-free survival (DFS) and other clinicopathologic characteristics were analyzed according to the intensity of each staining. Results: Of 94 cases, 91 (96.8%) showed specific A-LAP immunostaining. A-LAP expression demonstrated negative correlations with myometrial invasion (p = 0.01) and vascular infiltration (p = 0.01). Of 94 cases, 77 (81.9%) showed specific AngII immunostaining. We found a positive correlation between AngII expression and surgical stage (p = 0.01). Of 94 cases, 56 (59.6%) showed specific AT1R immunostaining and 73 (77.7%) specific VEGF immunostaining. We found a positive correlation between VEGF expression and lymph node metastasis (p = 0.05). AngII and AT1R expression predicted a significantly poorer prognosis. Contrarily, A-LAP expression indicated a significantly more favorable prognosis in endometrial endometrioid adenocarcinoma patients. Multivariate analysis demonstrated that A-LAP expression (odds ratio, 0.12; 95% confidence interval, 0.025–0.618; p = 0.01) was an independent prognostic factor. Conclusions: In this study, we demonstrated the existence of local RAS and A-LAP in endometrial endometrioid adenocarcinoma as prognostic predictors of clinical outcome. These findings suggest that the assessment of RAS and A-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma.

The Renin Angiotensin System in the Regulation of Angiogenesis

“…Based upon measurements of ATII and ACE in fresh surgical specimens of pancreatic carcinoma, Ohta et al suggest that ATII is produced at significant levels in this form of carcinoma by an ACEindependent mechanism [195]. In a retrospective immunohistochemical study of endometrial carcinomas, Shibata et al found that ATII and AT1 expression were correlated with a significantly worse prognosis [196]. Interestingly, expression of adipocyte-derived leucine aminopeptidase, which degrades ATII, was inversely correlated with prognosis [196].…”

LAP3 promotes glioma progression by regulating proliferation, migration and invasion of glioma cells

“…In mammals, LAP3 is exopeptidase which can catalyze the peptide substrates or the amino termini of protein hydrolysis [8]. Altered LAP3 expression pattern and/or catalytic function could induce the peptide activation change, the cell cycle progression change in gynecologic malignancy [11,18], could adjust the insulin receptor of diabetic patients [19,20]. Recently, it has shown that LAP3 is overexpressed at human esophageal squamous cell carcinoma and could regulate proliferative and migration of esophageal squamous cell [21].…”

Angiotensin converting enzyme: the antigenic properties of the domain, role in alzheimer's disease and tumor progression

“…Имеются данные, что РАС вовлечена в злокачественную трансформацию и опухолевую прогрессию при некоторых видах гинекологического рака [53]. При раке эндометрия в образцах опухолевых тканей экспрессия АТ1Р и АII обнаруживалась параллельно с гиперэкспрессией VEGF; экспрессия АТ1Р и АII имела положительную корреляцию со снижением выживаемости пациентов и без признаков рака эндометрия [61][62]. Данные, касающиеся опухолей яичников, показывают, что повышенная экспрессия АТ1Р сопутствует переходу пограничной формы цистаденомы в инвазивную злокачественную форму и положительно коррелирует с экспрессией VEGF и плотностью микрососудов в опухолевой ткани яичников, а также со снижением выживаемости пациентов [63][64].…”