Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma.
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.
Shibata
Kiyosumi
K
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan. shiba@med.nagoya-u.ac.jp
Kikkawa
Fumitaka
F
Mizokami
Yayoi
Y
Kajiyama
Hiroaki
H
Ino
Kazuhiko
K
Nomura
Seiji
S
Mizutani
Shigehiko
S
D017667:Adipocytes / Q000201:enzymology; D000804:Angiotensin II / Q000032:analysis / Q000096:biosynthesis*; D018269:Carcinoma, Endometrioid / Q000098:blood supply / Q000378:metabolism* / Q000628:therapy*; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000628:therapy*; D005260:Female; D006801:Humans; D007931:Leucyl Aminopeptidase / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis / Q000096:biosynthesis; D012084:Renin-Angiotensin System; D042442:Vascular Endothelial Growth Factors / Q000032:analysis / Q000096:biosynthesis*
D044140:Receptor, Angiotensin, Type 1; D042442:Vascular Endothelial Growth Factors; D000804:Angiotensin II; D007931:Leucyl Aminopeptidase