ABO (H) cell surface antigens in benign and malignant parotid neoplasms

Twenty-two inflammatory, benign, or malignant parotid lesions were studied by means of the specific red cell adherence test (SRCA), a modification of the Coombs' mixed cell agglutination reaction. In 22 normal parotid tissues the acinar structures were devoid of red cell agglutination, but it was present in ductal epithelium. Findings were similar in 2 cases of parotitis, 11 benign mixed tumors, and 1 malignant mixed tumor. All lacked red cell agglutination in areas of neoplastic change. Benign Warthin's tumors (4 cases) demonstrated antigenicity in the columnar epithelial component of the tumor, but lacked red cell agglutination in areas of the lymphoid component. One malignant Warthin's tumor showed agglutination in areas of normal columnar epithelium but not in areas of malignant dedifferentiation. Undifferentiated carcinoma (1 case) and adenoid cystic carcinoma (2 cases) did not possess detectable ABO (H) antigens in neoplastic areas of the gland. The absence of ABO antigens in normal acinar glands supports their suggested myoepithelial or mesenchymal derivation, as the absence of antigen in benign and malignant mixed tumors supports their proposed mesenchymal derivation. Ductular epithelium and the epithelial components of benign Warthin's tumors have ABO (H) antigens, while the loss of antigen in the epithelial portion of the malignant Warthin's tumor is characteristic of epithelial neoplastic dedifferentiation. Loss of antigen in adenoid cystic and undifferentiated carcinomas of the parotid supports the concept that antigen is absent in epithelially derived malignant neoplasms.     

Immunohistochemical study of the expression of S-100 protein,epithelial membrane antigen,cytokeratin and carcinoembryonic antigen in thyroid lesions

The diagnosis of papillary carcinoma of the thyroid is based on the two morphological features that best characterize this tumor, the papillae and the nuclear changes. However, both the architectural and cytological hallmarks may be encountered in other conditions such as multinodular goiter, Grave's disease, thyroiditis and hyperplastic areas of follicular neoplasms and thus produce problems in the histopathological interpretation. The distinction of these lesions from papillary carcinoma has important implications for clinical management. Thus the availability of supportive diagnostic evidence would be helpful. In the present study we compared the immunoreactivity for S-100 protein, epithelial membrane antigen (EMA), cytokeratin (Ck) and carcynoembryonic antigen (CEA) in different thyroid pathologies. We conclude that the strong expression of S-100 protein, in combination with EMA expression, is of value in identifying papillary neoplasia and distinguishing it from papillary hyperplasia.     

Heterogeneity of cytokeratin expression as revealed using monoclonal antibodies in salivary adenocarcinomas

Numerous neoplastic lesions of the salivary glands often share a number of similar histopathological features and different areas of the same tumor specimen, not infrequently, may show a diverse histomorphology. The present study evaluates expression of single keratin proteins recognized by monoclonal anti-K7, K8, K18, K19 and keratins recognized by monoclonal KL1 and K8.12 in tubular-duct-like or cribriform structures, solid nests, clear cells, microcystic, basaloid cells and squamous metaplastic histomorphology present in tissue specimens of adenoid cystic carcinoma (n=11), acinic cell carcinoma (n=5), polymorphous low grade adenocarcinoma (n=1) and adenocarcinoma, not otherwise specified (NOS, n=5) of salivary glands. Expression of vimentin in the epithelial tumor cells was further evaluated using an anti-vimentin monoclonal antibody. A great heterogeneity of keratin expression was observed in the luminal and abluminal cells forming the tubular-duct-like and cribriform structures. The abluminal cells in more than half of the instances of adenoid cystic carcinoma had immunoreactive vimentin. In addition, heterogeneity was more pronounced in tumor cells forming the solid nests, comedo-necrosis, microcysts, clear cells or squamous metaplasia. A heterogeneity of keratin profile in different histomorphologies of different tumor types and even in different areas of the same tumor specimen, in the present study, and the available evidence so far limits the use of cytokeratin immunostaining in the differential diagnosis of neoplastic salivary lesions and characterization of a particular histomorphology which, in many instances, are ubiquitous in different tumor subtypes.     

Immunohistochemical analysis of integrin αvβ3 expression on tumor-associated vessels of human carcinomas

Expression of the αvβ3 integrin is upregulated on sprouting endothelia. Systemic application of antibody or peptidic inhibitors of αvβ3 function disrupts tumor angiogenesis and reduces growth and invasiveness of human tumors in animal models. We systematically investigated αvβ3 expression on tumor-associated vessels of 4 different human epithelial tumors and the corresponding normal tissues by means of immunohistochemistry on frozen sections using the αvβ3-complex specific monoclonal antibody LM609. Variable levels of LM609 staining were found in all carcinoma lesions. A considerable number of tumor tissues (35/50) expressed αvβ3 on more than 50% of their vessels. Inflammatory infiltrates and the possibly hypoxic conditions near necrotic areas of tumors were accompanied by an increased αvβ3 expression. Remarkably, the vasculature in apparently normal tissue also stained for αvβ3. However, the percentages of stained vessels and their staining intensity were lower than in neoplastic tissues. Besides the vascular αvβ3 expression, several extravascular cell types stained positive, in both normal and tumor specimens. Taken together, our findings show a considerable number of colon, pancreas, lung and breast carcinoma lesions with many αvβ3-expressing vessels that could be targets for anti-αvβ3-therapy. Int. J. Cancer 71:320-324, 1997. © 1997 Wiley-Liss Inc.     

Neuropilin-1 is differentially expressed in myoepithelial cells and vascular smooth muscle cells in preneoplastic and neoplastic human breast: a possible marker for the progression of breast cancer

The expression and distribution of neuropilin-1 (NRP-1) was examined in the samples of normal human breast tissues and in non-neoplastic and neoplastic areas of breast tissue removed for carcinoma using RT-PCR as well as conventional and tissue microarrays immunohistochemical analyses. The NRP-1 mRNA expression was significantly higher in neoplastic tissues as compared to normal breast samples. Immunohistochemically, the myoepithelial cells of the mammary ducts and lobules display positive reactions for NRP-1, whereas the inner ductal and lobular epithelial cell layers failed to react. The myoepithelial cells of ducts and lobules in both neoplastic and non-neoplastic tissue specimens displayed a stronger positive reaction for NRP-1 than those in the normal breast. A positive reaction for NRP-1, but with a gradual reduction in intensity, was observed in the myoepithelial cells of ducts with atypical epithelial hyperplasia and ductal carcinoma in situ (DCIS). The reaction was undetected or minimally detected in the areas of invasive carcinoma. NRP-1 positive immunolabeling was also localized in the vascular smooth muscle cells and in some endothelial cells of the blood vessels in normal, non-neoplastic and neoplastic breast tissue samples. In areas of breast carcinoma, NRP-1 immunolabeling was more prominent in both vascular smooth muscle cells and in some endothelial cells than in similar cells in normal breast. The specificity of the newly developed antibody for NRP-1 was confirmed by in situ hybridization with DIG-labeled PCR generated probe. These results suggest that NRP-1 may be a multiple function protein in human breast and may be involved in the induction of local invasiveness of neoplasia and angiogenesis and have direct relevance to the progression of breast cancer.     

Aminopeptidase A expression in cervical neoplasia and its relationship to neoplastic transformation and progression

Aminopeptidase A (AP-A) is a cell surface metallopeptidase which specifically cleaves the amino-terminal acidic residue from peptide substrates such as angiotensin II. AP-A is identical to the differentiation-related antigen, murine BP-1 or human kidney gp160, and is involved in regulating cell differentiation and/or neoplastic transformation of certain normal and transformed cells. We examined expression of AP-A in premalignant and malignant lesions of the uterine cervix, and investigated whether its expression was related to disease progression and neoplastic transformation. Formalin-fixed, paraffin-embedded tissue sections including 14 cervical intraepithelial neoplasms (CIN) and 23 invasive squamous cell carcinomas (SCC) were immunohistochemically evaluated. AP-A was localized in the basal cell layer in normal squamous epithelium. In CIN, AP-A expression was found on dysplastic cells, and increased with the severity of the precancerous lesions. In invasive cancer, 18 of 19 non-keratinizing-type SCCs and none of 4 keratinizing-type SCCs expressed AP-A. In addition, AP-A immunoreactivity was significantly correlated with proliferating cell nuclear antigen expression in both CIN and SCC cases. Furthermore, angiotensin II type 1 receptor was present in all AP-A-positive SCCs. These results indicate that AP-A is upregulated as the lesion progresses toward carcinoma in the cervical epithelium, and suggest that AP-A may play a regulatory role in neoplastic transformation and disease progression in cervical neoplasms and may serve as a potential tumor marker during cervical neoplasia development.     

Immunohistochemical study of the expression of a Mr 34,000 human epithelium-specific surface glycoprotein in normal and malignant tissues

Monoclonal antibody HEA125 was used to study the tissue distribution of an epithelial cell surface glycoprotein of Mr 34,000 (Egp34). A large panel of normal and neoplastic tissues was examined for immunoreactivity with HEA125 by means of a sensitive immunoperoxidase technique. HEA125 labeled most epithelial cell types throughout the body but did not label any nonepithelial tissue. Major exceptions were epidermal keratinocytes, gastric parietal cells, hepatocytes, thymic cortical epithelial, and myoepithelial cells. Normal mesothelial cells were unreactive. In normal glandular epithelia and tubular adenocarcinomas exclusively the basolateral cell membranes were stained. HEA125 intensely reacted with all tested carcinoma specimens derived from colorectum, stomach, pancreas, liver, lung, mammary gland, ovary, thyroid, kidney, urinary bladder, and prostate including a number of anaplastic, diffusely infiltrating carcinomas. Metastatic lesions of these tumors were consistently positive. Generally, the staining of tumor cells was very homogeneous. The majority of squamous cell carcinomas were less strongly labeled than adenocarcinomas; keratinizing areas of the tumor masses were negative. Germ cell tumors and mesotheliomas of epithelioid type focally expressed the antigen. Egp34 was found to be absent from sarcomas, lymphomas, melanomas, and neurogenic tumors. Hence, HEA125 is a useful reagent for the distinction of carcinomas from nonepithelial neoplasms, even at very low degrees of histological differentiation. Furthermore, HEA125 allows the immunohistochemical detection of micrometastases originating from carcinomas. The antigen is detectable in formalin-fixed paraffin sections.     

Secretion of plasminogen activator by normal,reactive and neoplastic human tissues cultured in vitro

Plasminogen activator secretion by 39 primary or early-passage cultures of malignant human neoplasms has been compared with that of 16 similar cultures of benign neoplasms and 39 cultures of normal or reactive tissue. While normal cells of mesenchymal or neural origin secreted considerably less plasminogen activator than did cells from frankly malignant tissues, elevated levels of enzyme secretion were also encountered in cultures of benign neoplastic or reactive cells. In the case of epithelial tissue, no consistent relationship between plasminogen activator secretion and neoplasia could be documented. Our failure to observe, for any particular cell type, a reproducible correlation between malignancy and plasminogen activator secretion may be attributable to the artificial conditions of in vitro culture, where normal in vivo regulatory mechanisms do not obtain.     

Investigation of expression of 5T4 antigen in cervical cancer

A monoclonal antibody detecting amniotrophoblastic antigen 5T4 has shown reactivity against various neoplastic cell lines and tumour specimens but with a relatively restricted normal tissue expression. This antibody has been investigated as a potential indicator of premalignant changes identified as cervical intra-epithelial neoplasia and malignant cervical lesions using immunohistochemistry on frozen tissue biopsies. The basal cells of normal cervical stratified epithelium exhibited faint staining, but a general increase in intensity and extent of specific labeling of this tissue was seen from the first premalignant stage through to carcinoma. In most cases, this was in accordance with the distribution of dysplastic cells, and was accompanied by increased specific staining of the stromal tissue. All invasive squamous carcinomas of the cervix were 5T4 antigen positive. Common inflammatory non-malignant diseases did show a certain degree of epithelial and stromal reactivity. These results, showing 5T4 reactivity with neoplastic and pre-neoplastic lesions, may provide a quantitative basis for its potential use as a tumour marker in the immunochemical detection on immunoassay of cervical cancer.     

The role of monoclonal antibodies to the epithelial membrane antigen in the diagnosis of human tumors]

The paper discusses the possibility of the use of the Soviet-made ICO 25 monoclonal antibodies to membrane antigen of lipid globules of the human milk for differential diagnosis of human tumors. ICO 25 monoclonal antibodies reliably detected the above antigens in normal epithelial and breast cancer cells. However, these antigens cannot be considered strictly specific for breast tissue. They were found in various human epithelial tissues, in the majority of epithelial tumors and lymph node metastases. Staining for ICO 25 monoclonal antibodies was negative in non-epithelial tumors. The above antibodies proved a useful marker for the identification of epithelial origin of primary tumors and their metastases showing unclear histology. They can be used to differentiate between epithelial and non-epithelial malignancies as well as to detect micrometastases and areas of microinvasion. Paraffin-embedded samples can be used for immunohistochemical examination.     

Keratin immunoreactivity in the benign and neoplastic human prostate

Keratin immunoreactivity in the benign and neoplastic human prostate was examined immunohistochemically using two monoclonal antibodies with differing specificities. One of these antibodies stained only the basal cells of the normal and hyperplastic prostatic epithelium, with no reactivity in tumor cells of prostatic adenocarcinoma. The other monoclonal antibody recognized a keratin protein present in all normal and hyperplastic columnar (secretory) epithelial cells, as well as in all cancer cells regardless of degree of tumor differentiation. In addition, the second antibody stained acinar and ductal epithelial cells exhibiting premalignant changes. Our findings indicate that keratin immunoreactivity differs among the epithelial cell populations of the human prostate, probably reflecting expression of different keratin proteins. The distinctive patterns of staining obtained with these two antibodies may assist in distinguishing hyperplastic from neoplastic prostatic epithelium, as well as in the recognition of basal cell hyperplasia, transitional cell metaplasia, and premalignant changes.     

Nerve growth factor receptor immunoreactivity in breast cancer patients

Nerve growth factor receptor (NGF-R) has been shown to have antiproliferative, differentiative, or apoptotic effects on some types of tumor cells, whereas in others it may have mitogenic activity. The immunohistochemical distribution of NGF-R was analyzed in a series of tissue samples from breast cancer patients and its relationship with other clinical and pathological parameters was studied. The distribution of NGF-R was evaluated by immunohistochemistry in frozen tissue samples of 46 breast cancer patients (ME20-4 monoclonal anti-NGF-R). NGF-R immunoreactivity was localized in the plasma membrane of myoepithelial cells, differentiated ducts, neoplastic cells, blood vessels, and nerve fibers in 26 patients (57%). Less differentiated neoplastic tissues were usually NGF-R negative. NGF-R immunoreactivity was associated with estrogen receptor (ER) status (p = 0.02), small tumor dimension (pT) (p = 0.04), low histologic grade (G1-G2) (p < 0.05), old age (p = 0.02), menopause (p = 0.02), and long disease-free survival (DFS) (median follow up 86 months; p = 0.03; independently from ER, pT, age, menopause by multivariate analysis, p = 0.0078). The expression of NGF-R immunoreactivity by breast cancer patients with long DFS may represent a crucial step both in the differentiation status of neoplasia and in the host immune mechanism controlling tumor growth and metastasization.     

Differential expression of e-cadherin in normal, metaplastic and dysplastic esophageal mucosa - a putative biomarker

Barrett's mucosa is a potentially premalignant columnar lined metaplastic epithelium in the oesophagus about which little is known regarding maintenance of cell adhesion. In this regard E-Cadherin (E-cad) is a 120 kDa polypeptide present in all epithelial tissues and it is the prime mediator of cell-cell interactions. An immunohistochemical technique utilised the monoclonal antibody HECD-1 to evaluate E-cad expression in microwave treated, paraffin embedded sections from 120 patients. The phenotype of the specimens from the patients were metaplastic [41] and dysplastic mucosa [24], invasive squamous carcinoma [15] and adenocarcinoma [18] and corresponding metastatic lesions [10] as well as 12 specimens of normal oesophageal mucosae. Surface expression was high in non-metaplastic tissue and in non-dysplastic metaplasia but was reduced extensively in dysplasia. In addition in squamous carcinoma and adenocarcinoma E-cad was characteristically expressed in the cytoplasm and this was associated with poor morphological differentiation. SDS-PAGE gel protein analysis revealed the characteristic 120 kDa sized protein in normal squamous oesophageal tissue. In Barrett's metaplastic tissue and carcinoma, however, stronger bands at 108 kDa and 45 kDa were also present, suggesting either decreased glycosylation or a truncated protein in the metaplastic and neoplastic tissue, respectively. In conclusion changes in E-cad immunoreactivity and cellular localisation occur in premalignant metaplastic epithelium of the oesophagus. Further studies are in progress to evaluate whether the abnormal E-cad protein reflects both loss of function and may be used as a biomarker in pre-malignant lesions.     

Cellular expression of growth hormone and prolactin receptors in human breast disorders

Growth hormone (GH) and prolactin (PRL) exert their regulatory functions in the mammary gland by acting on specific receptors. Using isotopic in situ hybridization and immunohistochemistry, we have localized the expression of hGH receptor (hGHR) and hPRL receptor (hPRLR) in a panel of human breast disorders. Surgical specimens from adult females included normal breast, inflamatory lesions (mastitis) benign proliferative breast disease (fibroadenoma, papilloma, adenosis, epitheliosis), intraductal carcinoma or lobular carcinoma in situ, and invasive ductal, lobular or medullary carcinoma. Cases of male breast enlargement (gynecomastia) were also studied. In situhybridization analysis demonstrated the co-expression of hGHR and hPRLR mRNA in all samples tested. Epithelial cells of both normal and tumor tissues were labelled. Quantitative estimation of receptor mRNA levels was regionally measured in areas corresponding to tumor cells and adipose cells from the same section. It demonstrated large individual variation and no correlation emerged according to the histological type of lesion. Receptor immunoreactivity was detected both in the cytoplasm and nuclei or in the cytoplasm alone. Scattered stromal cells were found positive in some cases, but the labeling intensity was always weaker than for neoplastic epithelial cells. Our results demonstrate the expression of the hGHR and hPRLR genes and their translation in epithelial cells of normal, proliferative and neoplastic lesions of the breast. They also demonstrate that stromal components express GHR and PRLR genes. Thus the putative role of hGH or hPRL in the progression of proliferative mammary disorders is not due to grossly altered levels of receptor expression. Int. J. Cancer (Pred. Oncol.) 79:202–211, 1998.© 1998 Wiley-Liss, Inc.     

Expression of platelet-derived growth factor beta-receptors on stromal tissue cells in human carcinoid tumors

Carcinoid tumors of the midgut type are slowly growing neoplasms which often present clinically and histologically pronounced fibrosis around the tumors. Cryosections from 41 neuroendocrine tumors (31 midgut carcinoid tumors, 8 endocrine pancreatic carcinomas, 1 parathyroid carcinoma, and 1 pheochromocytoma) and 22 nonneuroendocrine carcinomas were examined for the presence of platelet-derived growth factor (PDGF) beta-receptor by immunohistochemistry using the monoclonal antibody PDGFR-B2. Twenty midgut carcinoid tumor tissues (66%) and 4 endocrine pancreatic carcinomas (50%) and the parathyroid carcinoma stained positively with the antibody. In contrast, only 2 nonneuroendocrine tumor tissues (10%) were stained, and the staining in these cases was weak. The immunoreaction in the carcinoid tumors was observed in connective tissue cells adjacent to tumor cell clusters but not in the tumor cells themselves. The degree of positive PDGF beta-receptor expression in the carcinoid tissues seems to correlate positively with the presence of macrophages as determined by the monoclonal antibody anti-Leu-M5, but not with other infiltrated lymphocytes identified with the monoclonal antibody anti-Leu-4, or with anti-HLA-DR antibodies. Stromal cells adjacent to tumor cells, including small capillaries, stained more strongly than the stromal cells which were distant from tumor cell clusters. Furthermore, carcinoid tumor metastases from lymph nodes as well as from liver showed stronger immunoreactivity in the stromal cells with the PDGF beta-receptor antibody than the corresponding primary tumors. Our data suggest that carcinoid tumor cells may directly or indirectly induce expression of PDGF beta-receptor on adjacent stromal cells in the tumor tissue, which may contribute to the fibrosis that is often seen around carcinoid tumors.     

Categorization of pediatric neoplasms by immunostaining with antiprekeratin and antivimentin antisera

Forty-six tumors in children were examined using light microscopy and subsequently frozen sections were stained with antiprekeratin and antivimentin antisera, so that the tumors could be classified by tissue of origin. Except for two adrenal cortical carcinomas and four liver tumors, most epithelial neoplasms continued to produce prekeratin filaments, a characteristic of normal epithelial cells. Tumors and cells of epithelial origin did not produce vimentin filaments, whereas normal and neoplastic mesenchymal cells did. Tumors with both epithelial and mesenchymal components produced vimentin filaments in mesenchymal areas and prekeratin in epithelial areas. Tumors of lymphoid origin showed variable production of vimentin filaments, depending on the amount of cell cytoplasm, but did not contain prekeratin filaments. Of the neuroectodermal tumors, only the ganglioneuroma contained vimentin filaments and none contained prekeratin filaments. Thus, antibodies to both prekeratin and vimentin filaments are useful in diagnosing childhood neoplasms and studying their histogenesis.     

Expression and prognostic significance of urokinase and plasminogen activator inhibitor type-1 in endometrial hyperplasia and cancer

Proteolytic enzymes, like urokinase (uPA) and plasminogen activator inhibitor type-1 (PAI-1), are involved in remodelling tissues during invasion and metastasis of tumor cells. The purpose of the study is to evaluate the expression and the prognostic significance of these enzymes in endometrial hyperplasia and cancer. We used immunohistochemical staining to localize uPA and PAI-1 antigens and evaluate their expression, and the enzyme-linked immunosorbent assay (ELISA) to measure their levels during the progression of endometrial carcinoma. The results show that the levels of uPA and PAI-1 detection are systematically weak in simplex hyperplasia and are moderate in complex hyperplasia. In the endometrial carcinoma a very strong reaction was observed in the most aggressive variant of epithelial tumors. A positive signal for uPA was found only in the cytoplasm of normal and hyperplastic cells while, in tumors, uPA was present also in the cellular areas surrounding the neoplastic glands and at the apex of the malignant cells. The PAI-1 immunoreactivity was weak to moderate in 95.4% of carcinomas, with a diffuse signal mostly distributed in the cytoplasm of neoplastic cells and tumor stroma. UPA antigen concentrations were significantly higher in endometrial carcinoma than in endometrial hyperplasia (p<0.05) and in normal endometrium (p<0.001). PAI-1 antigen concentrations in carcinoma samples were significantly higher than in normal endometrium (p=0.002), but the difference was not statistically significant with respect to that in endometrial hyperplasia. We did not find any correlation between uPA and PAI-1 concentrations and the standard prognostic parameters for evaluating endometrial carcinoma. In conclusion, this study demonstrates that in hyperplastic endometria and in endometrial carcinoma there is a progressive increase in expression of uPA and PAI-1 than in normal endometrial tissue. In carcinoma tissues, the high expression of uPA is unregulated in the surrounding stroma tissue, particularly in the most aggressive histopathologic variants. UPA and PAI-1 may be factors associated with invasive behavior in endometrial carcinoma independent of other clinicopathological parameters.     

Imbalance between neutral endopeptidase 24.11 and endothelin-1 expression in human endometrial carcinoma

OBJECTIVES: Neutral endopeptidase 24.11 (NEP)/CD10 is a cell-surface peptidase that degrades various bioactive peptides including endothelin-1 (ET-1). This enzyme is known to play a role in maintaining ET-1-regulated vascular homeostasis in the normal human endometrium. The purpose of the present study was to investigate the expression and localization of NEP and ET-1 in neoplastic endometria, and also to clarify the correlation of their expression with the tumor grade of endometrial carcinoma. METHODS: Immunohistochemical analysis for NEP and ET-1 expression was performed on paraffin-embedded tissue sections of 7 normal endometria (after menopause), 5 atypical endometrial hyperplasias (AEH), and 32 endometrial endometrioid adenocarcinomas. RESULTS: In normal endometrium and AEH, NEP immunoreactivity was detected in stromal cells, but not in glandular cells. In contrast, ET-1 immunoreactivity was detected in both glandular and stromal cells. In the stromal cells of grade 1 endometrial adenocarcinoma, NEP was detected at high or moderate quantities. However, significantly decreased NEP immunoreactivity was observed in the stromal cells of grade 2 and 3 adenocarcinomas. However, NEP was not immunostained in adenocarcinoma cells except for the lesions of squamous differentiation. ET-1 immunoreactivity was weakly detected in the stromal cells of grade 1 adenocarcinoma, but the intensity of ET-1 staining increased with advancing tumor grade. The ratio of the staining scores of stromal ET-1 to stromal NEP was positively correlated with the tumor grade. CONCLUSIONS: These findings demonstrate that NEP expression in the stromal cells of endometrial adenocarcinoma is downregulated, while stromal ET-1 is upregulated, with increasing tumor grade. The present findings also suggest that NEP may play a role in the regulation of neoplastic transformation, tumor progression, and differentiation in endometrial neoplasms, possibly by degrading certain peptide growth factors such as ET-1.