子宫内膜癌中CXCR2的表达及其与血管生成的关系

目的:研究IL-8受体CXCR2在子宫内膜腺癌组织中的表达及其与血管生成的关系。方法:应用免疫组化SP法,检测45例子宫内膜腺癌、8例增生过长组织、8例不典型增生组织、16例正常内膜组织中CXCR2的表达,并检测子宫内膜癌中微血管密度。结果:(1)相对于非腺癌组织,CXCR2在子宫内膜癌细胞腔侧表达明显减少(P<0.05),非腔侧表达明显增加(P<0.05),并出现胞浆表达;(2)子宫内膜癌期别越晚,CX-CR2非腔侧及胞浆表达越强,与病理分级无关;(3)子宫内膜癌组织中,CXCR2非腔侧及胞浆表达与微血管密度呈正相关(P<0.05)。结论:CXCR2在癌细胞非腔侧、胞浆的表达与子宫内膜癌发生、发展相关,并在促血管生成中有重要作用。     

Loss of Smad4 protein expression occurs infrequently in endometrial carcinomas.

Smad4 is a member of the Smad proteins, which are needed for mediating signals of transforming growth factor beta from the cell surface to the nucleus. Smad4 is also a tumor suppressor gene for cancers of the pancreas, colon, and lung. The aim of this study was to investigate the expression and prognostic significance of this gene product in endometrial cancer. Immunohistochemical staining for Smad4 was performed on formalin-fixed, paraffin-embedded specimens of endometrial tumors with an anti-Smad4 monoclonal antibody (clone B8): 97 primary endometrial carcinomas, 20 cases of endometrial hyperplasia, and 26 cases of metastases from endometrial carcinoma. The immunoreactivity of each tumor was correlated with the clinical and histopathologic parameters of the patients. Diffusely positive expression of Smad4 protein was detected in all 20 cases of endometrial hyperplasia and in most of the primary and metastatic endometrial cancers. The frequency of positive expression decreased progressively with tumor grade. Clinically, however, it was not associated with tumor progression, nor did it predict patient outcome. Although loss of heterozygosity at chromosome 18q21 (the location of the Smad4 gene) is frequent in endometrial carcinomas, the authors show in this immunohistochemical study that inactivation of this gene occurs infrequently in this tumor.     

Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression

OBJECTIVES: Chemokine CXCL12 and its unique receptor CXCR4 have been recently implicated in cancer metastasis. Our goal was to explore expression of CXCL12 and CXCR4 protein in normal ovarian surface epithelium, primary tumors and paired metastases of epithelial ovarian cancer as well as its association with clinicopathological features. We also wanted to test if expression of CXCR4 has prognostic value in epithelial ovarian cancer patients. METHOD: Sections from 6 normal ovarian surface epithelium, 44 primary epithelial ovarian tumors and 30 paired metastatic tumors in omentum were evaluated for CXCL12 and CXCR4 expression using immunohistochemistry (IHC). RESULTS: All samples of normal ovarian surface epithelium were negative for CXCL12 and CXCR4 protein. Ovarian cancer cells mainly showed cytoplasmic staining of CXCL12 and CXCR4. CXCL12 and CXCR4 staining were detected in 40/44 (91%) and 26/44 (59%) patients with primary epithelial ovarian tumors respectively. CXCR4 expression in primary tumors had no significant correlation with lymph nodes metastasis. However, if we combined CXCR4 expression in primary tumors with metastatic tumors, a significant correlation with lymph nodes metastasis was found (P = 0.018). The intensity of CXCL12 staining correlated with ascites (P = 0.014). The rate of CXCR4 expression in refractory and recurrent group (81% versus 28%, P = 0.0008) was significantly higher than that in no-recurrent group. After a median follow-up of 37 months, CXCR4 expression was found associated with an unfavorable prognosis with significantly reduced median disease progression-free survival and overall survival of 15 and 27 months (P = 0.0004, P = 0.017) respectively. Median time-to-event was not reached in patients with negative CXCR4 staining. In multivariate analysis, CXCR4 expression and residual tumor size emerged as independent prognostic factors in epithelial ovarian cancer patients. CONCLUSIONS: This article provides the first evidence that CXCR4 expression could be an independent prognostic factor for epithelial ovarian cancer patients.     

CXCR7及其配体在子宫内膜癌中的表达与意义

目的:检测趋化因子受体CXCR7(chemokine receptor 7)及其配体在子宫内膜癌组织和子宫内膜癌细胞中的表达,并研究雌激素对该受体的调控作用。方法:首先通过RT-PCR分析20种趋化因子受体在子宫内膜癌细胞株Ishikawa(ERα阳性)和AN3CA(ERα阴性)的转录水平,筛选出子宫内膜癌细胞株高表达的趋化因子受体,以免疫细胞化学染色法测定该受体及其相应配体在子宫内膜癌组织和细胞中的表达,并用蛋白质印迹法观察雌激素对该受体蛋白水平表达的影响。结果:(1)CXCR7 mRNA在子宫内膜癌细胞株Ishikawa、AN3CA均呈高表达,免疫细胞化学示子宫内膜癌组织和Ishikawa、AN3CA细胞表达CXCR7及其配体SDF-1,不表达I-TAC;(2)在Ishikawa中,雌激素在一定浓度范围内上调细胞中CXCR7蛋白水平的表达,而在AN3CA中,雌激素对CXCR7蛋白并无明显的调节作用。结论:CXCR7/SDF-1高表达于子宫内膜癌组织和子宫内膜癌细胞中,且雌激素上调CXCR7的表达,表明CXCR7/SDF-1可能在子宫内膜癌中发挥调控作用。     

细胞角蛋白、CA125对子宫内膜癌淋巴结微转移的诊断价值

目的　研究细胞角蛋白 (cytokeratin ,CK)、CA12 5对子宫内膜癌淋巴结微转移的诊断价值 ,及其作为子宫内膜癌复发危险因素的临床意义。方法　采用免疫组化链霉菌抗生物素蛋白 过氧化物酶连接 (SP)法检测 5 0例子宫内膜癌患者的原发灶组织 5 0份和淋巴结 2 98枚中CK、CA12 5的表达情况 ,采用多元回归分析法对影响子宫内膜癌复发的危险因素进行分析。结果　 (1)CK、CA12 5在子宫内膜癌组织中的阳性表达率分别为 10 0 % (5 0 / 5 0 )和 78% (39/ 5 0 )。 (2 )HE染色检查有转移的淋巴结中 ,CK和CA12 5均呈强阳性表达的阳性表达率均为 10 0 % (16 / 16 )。HE染色检查无转移的淋巴结中 ,CK、CA12 5的阳性表达率分别为 15 % (4 3/ 2 82 )和 12 % (35 / 2 82 ) ,且均为弱阳性表达。 (3)Ⅰ、Ⅱ期子宫内膜癌患者淋巴结中 ,CK阳性与CK阴性表达者的复发率分别为 38%、0 ,两者比较 ,差异有显著性 (P <0 0 5 ) ;CA12 5阳性与CA12 5阴性表达者的复发率分别为 39%、4 % ,两者比较 ,差异也有显著性 (P <0 0 5 )。 (4 )多元回归分析结果显示 ,淋巴结中CK表达是影响Ⅰ、Ⅱ期子宫内膜癌复发的独立危险因素 ,而淋巴结中CA12 5表达和肌层浸润深度均为影响Ⅰ、Ⅱ期子宫内膜癌复发的相关因素。结论　在HE染色检查无转移的淋巴     

Heparanase expression in both normal endometrium and endometrial cancer

The aim of this study was to investigate the relationship between heparanase expression and prognostic factors in endometrial cancer, as well as the relationship between heparanase expression during phases of the normal endometrial cycle. Immunohistochemical analysis of 166 endometrial cancers and 34 normal endometria in various phases of growth was performed. The heparanase expression in the late-proliferative phase of normal endometria was found to be significantly higher than in either the early-proliferative or the secretory phases (P= .012 and P= .044, respectively). Heparanase expression was also significantly higher in endometrial cancer patients with tumors of an advanced FIGO stage (P= .0003) and high FIGO grade (P= .004) and with cancers showing either deep myometrial invasion (P= .023), lymph node metastasis (P= .006), lymphvascular space involvement (P= .048), or positive peritoneal cytology (P= .010). The disease-free and overall survival rates of patients with intense heparanase expression were significantly lower than those of patients with absent or moderate heparanase expression (P= .004 and P= .002, respectively). Heparanase may participate in normal endometrial remodeling and can serve as an indicator of the aggressive potential and poor prognosis of endometrial cancers.     

CD24 expression is a poor prognostic marker in endometrial carcinoma

OBJECTIVE: CD24 is a cell adhesion molecule that has been implicated in metastatic tumor progression of various solid tumors. Its expression is known to be related to the prognosis of several kinds of tumors. This study was designed to examine the prognostic significance of CD24 in endometrial cancer patients. METHODS: Forty-four endometrial carcinoma tissues were immunostained for CD24 antibody (Ab2, clone 24 C02). Cytoplasmic and membranous immunoreactivity were scored semiquantitatively by Fisher's exact test. RESULTS: CD24 expression was detected in 34 (77.3%) out of 44 cases. Membranous and cytoplasmic staining of CD24 was significantly associated with the International Federation of Gynecology and Obstetrics (FIGO) grade (p = 0.011 and p = 0.002, respectively) and nodal status (p = 0.002 and p = 0.000, respectively). CONCLUSION: Our data suggests that CD24 expression in endometrial carcinoma as detected by immunohistochemistry might be a new marker for a more aggressive endometrial cancer biology. CD24 is commonly up-regulated in endometrial cancer and this corroborates the importance of CD24 in tumor progression among these cases.     

Endokrine Therapie des Endometriumkarzinoms

Endometrial cancer originates from the endometrium which is hormone dependent. In addition, many endometrial cancers express receptors for progestagens and/or estrogens, therefore, endocrine therapy for this malignancy has been studied for many decades. High dose progestagens are the backbone of fertility sparing conservative treatment of atypical endometrial hyperplasia and of very early stages of well differentiated endometrial cancers in women wishing to preserve child bearing capability. In many studies it has been shown that adjuvant therapy with high dose progestagens after primary surgical treatment is of no benefit. In the palliative situation, when recurrent tumor and/or metastases are no longer amenable to surgery and/or radiotherapy, patients with grade 1 or 2 tumors or with expression of progesterone and/or estrogen receptors should be treated with high dose progestagens if tumor manifestations are not life-threatening. If tumors first respond to this endocrine therapy and then become resistant, a second endocrine therapy using either tamoxifen or fulvestrant (off-label use!) can be considered.     

Oxygen regulates human cytotrophoblast migration by controlling chemokine and receptor expression

IntroductionPlacental development involves the variation of oxygen supply due to vascular changes and cytotrophoblast invasion. Chemokines and their receptors play an important role during placental formation. Herein, the analysis of the chemokine/receptor pair CXCL12/CXCR4 and further chemokine receptors, such as CCR1, CCR7 and CXCR6 expression in human cytotrophoblasts was conducted.MethodsHuman cytotrophoblasts were examined directly after isolation or after incubation with different oxygen tensions and a chemical HIF-stimulator for 12 h with realtime PCR, immunoblot, immunohistochemistry. Conditioned media of placental villi, decidua, and endothelial cells was used for ELISA analysis of CXL12. Cytotrophoblast migration assays were conducted applying conditioned media of endothelial cells, a CXCL12 gradient, and different oxygen level. Endometrial and decidual tissue was stained for CXCL12 expression.ResultsAn upregulation of CXCL12, CXCR4, CCR1, CCR7 and CXCR6 was observed after cytotrophoblast differentiation. Low oxygen supply upregulated CXCR4, CCR7 and CXCR6, but downregulated CXCL12 and CCR1. In contrast to the HIF associated upregulation of the aforementioned proteins, downregulation of CXCL12 and CCR1 seemed to be HIF independent. Cytotrophoblast migration was stimulated by low oxygen, the application of a CXCL12 gradient and endothelial cell conditioned media. CXCL12 was detected in endometrial vessels, glands and conditioned media of placental and decidual tissue, but not decidual vessels.Discussion/conclusionTaken together, oxygen supply and cytotrophoblast differentiation seem to be regulators of chemokine and receptor expression and function in human cytotrophoblasts. Therefore, this system seems to be involved in placental development, directed cytotrophoblast migration in the decidual compartment and a subsequent sufficient supply of the growing fetus.     

Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma

OBJECTIVE: To investigate the consequences of IGF proteins dysfunction in development of endometrial adenocarcinomas. METHODS: The expression of IGF 2 and IGF 1R was correlated with the expression of IGF 2R and apoptosis rate in 59 human endometrial adenocarcinomas, 10 endometrial hyperplasias and 7 normal tissues. The presence of mutations in the IGF 2R gene was followed in 46 adenocarcinomas. We also examined the effect of IGF 1 receptor blockage on cancer cell proliferation. In groups of either IGF 2-positive or IGF 2-negative tumors (stages III and IV) the expression of IGF 1 and IGF 1R was correlated with cell proliferation index and telomerase activity. RESULTS: The expression of IGF 2 and IGF 1R was much higher in malignant tissue of stages III and IV than in tumors of stages I and II and normal or hyperplastic endometrium. This correlated with a decreased apoptosis rate and IGF 2R expression. Eight adenocarcinomas expressed biallelic mutation of the IGF 2R gene. The specific inhibition of IGF 1R and IGF 2 decreased tumor cell proliferation in IGF 2/IGF 1R-positive tumors. Furthermore, the positive correlation between increased expression of IGF 1 and IGF 1R proteins and increased telomerase activity and cell proliferation index was found in both IGF 2-negative and IGF 2-positive tumors. CONCLUSION: Our data suggest that IGF 1, IGF 2 and their receptors are involved in the progression of endometrial adenocarcinomas. As cancer cell proliferation can be abrogated by blocking mRNA or protein products of these genes, tumors with extensive involvement of the IGF 2 pathway would be candidates for the therapeutics strategies aimed at interference with this pathway.     

Apolipoprotein D expression in endometrial carcinomas

BACKGROUND: Apolipoprotein D is a protein component of the human plasma lipid transport system but is also associated with a more favorable prognosis in breast cancer and ovarian cancer women. This study was undertaken to examine the tumoral expression of apolipoprotein D in endometrial cancer and to analyze the possible correlation with tumor and patients characteristics as well as androgen receptors and its prognostic significance. METHODS: Immunohistochemical evaluation was used to examine apolipoprotein D expression in paraffin blocks from 58 endometrial carcinomas. RESULTS: A total of twenty (34%) tumors stained positively. Staining was localized in tumor cells. No significant correlation was found between apo D expression and patients or tumor characteristics and androgen receptor status. In addition, apolipoprotein D expression was not associated with patient prognosis. CONCLUSIONS: Apolipoprotein D is expressed by a significant percentage of endometrial carcinomas without apparent association with other clinicopathologic parameters or with outcome of patients.     

Hypoxia contributes to development of recurrent endometrial carcinoma

Tumor hypoxia can trigger the induction of angiogenesis. High microvessel density (MVD) as well as hypoxia-inducible factor-1alpha (HIF-1alpha) have been related to recurrent disease and tumor aggressiveness, respectively. In this study, MVD and hypoxic status were investigated in primary and recurrent endometrial carcinomas. A total of 65 primary tumors of patients with recurrent endometrial carcinoma (n = 40), and without recurrent endometrial carcinoma (n = 25) were studied. Immunohistochemical analysis was performed on paraffin-embedded tumor tissue. MVD was determined by quantitative analysis of CD31/FVIII positive vessels. Tumor hypoxia was estimated by evaluating the expression of the hypoxia-regulated gene HIF-1alphaand its target gene carbonic anhydrase IX (CA-IX). An additional 23 recurrent tumors were available for determination of MVD and HIF-1alpha expression. Effects of hypoxia on tumor protein p53 (TP53) expression were evaluated in the endometrial cancer cell lines (ECC-1), Ishikawa (derived from adenocarcinomas), and AN3CA (derived from a lymph node metastasis). MVD, CA-IX, and HIF-1alpha expression were not significantly different in primary tumors of patients with recurrence compared to the control tumors. The MVD was significantly lower, and HIF-1alpha expression was significantly higher in recurrent tumors when compared with their primary tumors (paired t test, P < 0.05). HIF-1alpha expression correlated well with TP53 expression levels in primary tumors, but not in recurrences. TP53 protein levels were highest in AN3CA cells. Hypoxic conditions induced TP53 protein in ECC-1 and Ishikawa, but not AN3CA cells. We conclude that MVD, CA-IX, and HIF-1alpha expression are not independent prognostic markers for recurrent endometrial carcinoma. The low MVD, increased HIF-1alpha protein levels, dissociation of hypoxia, and TP53 protein induction in the metastatic tumor cells (AN3CA) support a role for hypoxia in the development of recurrent endometrial carcinoma.     

Correlation of androgen receptors with histological differentiation in human endometrial carcinomas

Primary endometrial carcinomas from 35 non-treated patients were investigated by measurement of androgen receptors in the tumor cytosols. Receptor analysis was done with a labelled synthetic androgen, methyltrienolone 3H-R1881 and triamcinolone acetonide, and dextran-coated charcoal absorption. The concentrations of androgen receptors in the endometrial carcinomas were, in decreasing order: highly-differentiated tumors, 15.7 +/- 1.8 (fmol/mg protein, mean +/- SE) (number of cases, 21); moderately differentiated tumors, 4.6 +/- 1.6 (n = 7); poorly differentiated tumors, undetectable in 7 out of 8 cases. Highly-differentiated tumors contained a much greater concentration of receptors than the two less differentiated ones. One highly-differentiated endometrial carcinoma with pyometra virtually lacked the receptor. The moderately differentiated endometrial carcinomas contained very low levels of the receptors. The poorly differentiated tumors virtually lacked the receptors. Metastatic lymph nodes from primary endometrial carcinomas with moderate differentiation had a very low receptor level. From these results, it is concluded that human endometrial carcinomas, particularly with histologically high differentiation, contain a considerable amount of androgen receptor and that the receptor concentrations appear to correlate with the histologic grade of tumor differentiation.     

B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration

OBJECTIVES AND METHODS: B7-H4 (DD-O110), a member of the B7 family, negatively regulates T cell-mediated immune response. Previous studies have shown that B7-H4 is highly expressed in endometrioid ovarian cancers with relatively low levels of expression in normal ovary which was confirmed by Western blot. The present study was designed to localize B7-H4 expression by immunohistochemistry (IHC) in normal endometrium, endometrial hyperplasia and uterine endometrioid adenocarcinoma. The pattern of B7-H4 localization was compared with the IHC detection of CD3 and CD8-positive T lymphocytes and CD14 positive macrophages to investigate the role of B7-H4 in the regulation of tumor immune surveillance. B7-H4 expression was evaluated in apoptotic tumor cells. RESULTS: The proportion and intensity of B7-H4 staining were increased in the progression from normal, hyperplastic and malignant endometrial glandular mucosa. B7-H4 showed a predominantly apical membranous staining (pattern 1) in normal and hyperplastic endometrial epithelium but showed intense circumferential membranous and cytoplasmic staining (pattern 2) in a majority of endometrioid carcinoma cases (p=0.018). The proportion of B7-H4 positive tumor cells and staining intensity was also higher in high risk tumors than in low risk tumors (p=0.001 and p=0.032, respectively). The proportion of B7-H4 positive tumor cells was inversely related to the number of CD3-positive and CD8-positive tumor-associated lymphocytes (TALs). There was a positive correlation between B7-H4 pattern 2 staining and both CD3-positive and CD8-positive tumor-infiltrating lymphocytes (TILs) (p=0.039 and p=0.031, respectively). CONCLUSIONS: B7-H4 is overexpressed in hyperplastic and malignant endometrial epithelium and is correlated with the number T cells associated with the tumor. These results suggest that B7-H4 overexpression may reflect a more aggressive biologic potential and may play a role in tumor immune surveillance mechanisms.     

Up-regulation of DNA methyltransferase 3B expression in endometrial cancers

OBJECTIVE: To understand the role of epigenetic regulation in the pathogenesis of endometrial cancer, we have characterized DNA methyltransferase 3B (DNMT3B) gene expression in normal, Grade I and Grade III endometrioid cancers, and examined DNMT3B promoter activities in endometrial cancer cell lines. METHODS: DNMT3B expression was measured in normal, Grade I, and Grade III endometrioid cancer samples. Real-time PCR and Western blot analysis were performed to compare DNMT3B mRNA and protein levels. DNMT3B levels were also compared among endometrial cell lines including those for Ishikawa, KLE, AN3, RL-95, HEC-1A, and HEC-1B. DNMT3B promoter reporter plasmids were constructed. Promoter activities in well and poorly differentiated cell lines were compared by in vitro reporter gene transfection. RESULTS: DNMT3B was significantly up-regulated in both Grade I and Grade III cancers as compared to normal controls. Western blot analysis confirmed the increased DNMT3B protein expression in cancer tissues. It was also found that the well-differentiated endometrial cell line, Ishikawa, expressed lower levels of DNMT3B than the poorly differentiated KLE cells, the expression patterns similar to those observed in tumor specimens. CONCLUSION: The results suggest that DNMT3B overexpression may play a significant role in endometrial cancer development. In addition, the transfection experiments indicated that DNMT3B promoters are more active in the poorly differentiated endometrial cancer cell lines, suggesting that the in vitro assay provides a useful model for studying the DNMT3B transactivation mechanism related to tumor transformation.     

Differential mRNA expression of urokinase-type plasminogen activator, plasminogen activator receptor and plasminogen activator inhibitor type-2 in normal human endometria and endometrial carcinomas

OBJECTIVE: Extracellular proteolytic degradation is an essential part of cellular invasive processes. The increased proteolytic activity observed in invasive cancers, mediated through the activitation of components of the plasminogen activation system, has been demonstrated in various human tumors. The aim of this study was to determine the level of mRNA expression for the genes encoding urokinase (uPA), urokinase receptor (uPAR), and plasminogen activator inhibitor (PAI-2) in endometrial carcinomas. METHODS: In this study, the expression of uPA, uPAR, and PAI-2 mRNA was examined in normal endometrial tissue (n = 16) and endometrial carcinoma tissues (n = 34) by Northern blot analysis. RESULTS: Compared to the controls, the relative abundance of uPAR was significantly elevated in all of the clinical stages of malignancy examined, with a 33-fold increase in mRNA expression from normal endometria to advanced clinical stage carcinomas (Stage III, P < 0.0001). Similarly, uPA was significantly elevated in all clinical stages examined when compared to the normal group, with a 16-fold increase in mRNA expression in advanced stage carcinomas (P < 0.0005). The expression of both uPA and uPAR mRNA also increased with each progression in clinical stage. Expression of the inhibitor, PAI-2, was significantly up-regulated by 5-fold in only the late stages of endometrial tumor development (P < 0.001), while Stage IB and IC carcinomas did not express high levels of PAI-2 mRNA. CONCLUSION: These data indicate that components of the plasminogen activation cascade are up-regulated in progressive stages of invasive endometrial cancer and are consistent with their role in determining invasive potential of endometrial carcinomas.     

Aberrant expression and mutations of TGF-beta receptor type II gene in endometrial cancer

OBJECTIVE: Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that strongly inhibits epithelial cell growth. Disabling of TGF-beta signaling is thought to be involved in development of a variety of tumors in which abnormal expression or function of TGF-beta receptor plays critical roles. In the present study, we examined aberrant expression and mutation of the gene TGF-beta receptor type II (TbetaRII) in endometrial cancers of endometrioid subtype. METHODS AND RESULTS: Real-time PCR analysis using surgical tissue specimens of 27 endometrial cancers and 24 normal endometria revealed that endometrial cancers had significantly decreased levels of TbetaRII mRNA expression (mean level 2.44 +/- 2.65), compared to normal endometria (mean level 7.23 +/- 6.07) (P < 0.001). Methylation status of TbetaRII promoter containing 30 CpGs was examined by bisulfite sequencing analysis, and 98% (51/52) of the patients were found to have unmethylated TbetaRII promoter, indicating that promoter hypermethylation is not the major cause of decreased expression of TbetaRII in endometrial cancers. Mutational analysis revealed that 15.1% (8/53) of endometrial cancers had frameshift mutations at polyadenine repeats in exon 3 of the TbetaRII gene. Notably, these mutations were preferentially accumulated in patients with MSI-H phenotype (7/19:37%) (P < 0.001) or with those with methylated MLH1 promoters (6/16:38%) (P < 0.01). Thus, it appears that the TbetaRII gene is a target of mismatch repair deficiency. CONCLUSION: Taken together, we found that the decreased expression of TbetaRII as well as frameshift mutation of TbetaRII via mismatch repair deficiency frequently occurs in this tumor type, possibly causing loss of receptor function and unresponsiveness of TGF-beta signaling that may lead to endometrial carcinogenesis.     

Expression of estrogen receptors alpha and beta in two uterine mesenchymal tumors after prolonged tamoxifen therapy. Report of two cases

INTRODUCTION: Tamoxifen therapy is associated with an increased risk of endometrial carcinoma, and possibly uterine sarcomas. Little is known about hormone receptor expression in mesenchymal tumors of the uterus after tamoxifen therapy. CASES: The cases of two patients with uterine mesenchymal tumors after prolonged tamoxifen therapy due to breast cancer are presented. The expression of estrogen receptors alpha (ERalpha) and beta (ERbeta) and progesterone receptors (PR) was studied immunohistochemically in both cases. Both tumors were negative for ERalpha and positive for ERbeta. In the first case the tumor was negative for PR, while in the second only 20% of nuclei were PR-positive. CONCLUSIONS: Consistent with previous studies, uterine mesenchymal tumors after tamoxifen therapy do not express ERalpha. The results of the present report provide for the first time evidence that tamoxifen might exert a stimulatory effect on the uterus, at least during tumor progression, through ERbeta but not through ERalpha.     

Immunoexpression of B7-H3 in endometrial cancer: relation to tumor T-cell infiltration and prognosis

Objective

B7-H3, a member of the B7 family of immune regulatory ligands regulates T cell-mediated peripheral immune response. The purpose of this study was to correlate the expression of B7-H3 and number of lymphocytes in patients with endometrial cancer.

Material and methods

A total of 107 patients with primary endometrial carcinoma (type I/endometrioid, n = 81; type II, n = 18) and endometrial hyperplasia (n = 8) were investigated. Expression of B7-H3 in endometrial hyperplasia, endometrial carcinoma, and the endothelium of tumor-associated vasculature was assessed using immunohistochemistry from paraffin-embedded tissue blocks. Detection of CD8-positive tumor-infiltrating lymphocytes (TIL) and CD8-positive tumor-associated lymphocytes (TAL) was correlated with the expression of B7-H3.

Results

Patients with high grade tumors and patients with type II carcinomas expressed significantly more B7-H3 than low grade and endometrioid tumors (p = < 0.0001 and p = 0.0001, respectively). The expression of B7-H3 in the endothelium of identified vasculature in the tumor specimens showed similar results with strong relation to high grade tumors (p = 0.001) and type II carcinomas (p = 0.004). We found a significant correlation between B7-H3 expression on cancer cells and tumor T-cell infiltration (TIL) (p = 0.017). In a univariate survival analysis, overexpression of B7-H3 in tumor cells was associated with shortened overall survival (p = 0.005).

Conclusions

B7-H3 is overexpressed on cancer cells and in the endothelium of tumor-associated vasculature in high grade tumors (G3) and type II carcinomas. B7-H3 expression on cancer cells is correlated with the number of T cells infiltrating the tumor. Endometrium tumor development and progression may be associated with downregulation of T-cell-mediated antitumor immunity through B7-H3.