FGF18 as a potential biomarker in serous and mucinous ovarian tumors

Tumor Biology - Fibroblast growth factor 18 (FGF18) has been suggested to play important roles in promoting progression of ovarian high-grade serous carcinoma. Our aim was to investigate FGF18...     

Gene expression patterns of chemoresistant and chemosensitive serous epithelial ovarian tumors with possible predictive value in response to initial chemotherapy

Chemotherapy (CT) resistance in ovarian cancer is broad and encompasses diverse, unrelated drugs, suggesting more than one mechanism of resistance. We aimed to analyze the gene expression patterns in primary serous epithelial ovarian cancer (EOC) samples displaying different responses to first-line CT in an attempt to identify specific molecular signatures associated with response to CT. Initially, the expression profiles of 15 chemoresistant serous EOC tumors [time to recurrence (TTR) or =30 months) were independently analyzed which allowed the identification of specific sets of differentially expressed genes that might be functionally implicated in the evolution of the chemoresistant or the chemosensitive phenotype. Our data suggest that the intrinsic chemoresistance in serous EOC cells may be attributed to the combined action of different molecular mechanisms and factors linked with drug influx and efflux and cell proliferation, as possible implications of other molecular events including altered metabolism, apoptosis and inflammation cannot be excluded. Next, gene expression comparison using hierarchical clustering clearly distinguished chemosensitive and chemoresistant tumors from the 25 serous EOC samples (training set), and consecutive class prediction analysis was used to develop a 43-gene classifier that was further validated in an independent cohort of 15 serous EOC patients and 2 patients with other ovarian cancer histotypes (test set). The 43-gene predictor set properly classified serous EOC patients at high risk for early (< or =22 months) versus late (>22 months) relapse after initial CT. Thus, gene expression array technology can effectively classify serous EOC tumors according to CT response. The proposed 43-gene model needs further validation.     

Mosaicism in the expression of tumor-associated carbohydrate antigens in human colonic and gastric cancers

Serial sequential sections from a single tumor were examined by immunohistological staining with several monoclonal antibodies directed, respectively, to different tumor-associated carbohydrate epitopes. Staining patterns were compared with those of conventional staining with hematoxylin-eosin or periodate/Schiff's reagent. Each tumor showed different areas of staining with different antibodies, and the combined staining map shows a clear mosaicism of antigen expression within the same tumor. For example, some areas of a given tumor were stained by FH4 (defining dimeric Le(x)), while other complementary areas were strongly stained, in a mutually exclusive manner, by SH1 (defining Le(x)), AH6 (defining Le(y)), FH6 (defining sialosyl dimeric (Le(x)), or TKH2 (defining sialosyl-Tn). Some areas were stained by two or three of these antibodies. Comparisons of the mosaic-staining patterns with cytohistological properties of tumor cells within specific areas suggested that the pattern of antigen expression is correlated with degree of differentiation; e.g., poorly-differentiated cells with severe dysplasia did not express high levels of Le(x) or Le(y) but did express sialyl-Le(x) or dimeric Le(x); on the other hand, moderately or well-differentiated tumor cells in some areas expressed high levels of Le(x) or Le(y) but lower levels of sialyl-Le(x). Areas showing strong expression of sialyl-Tn in their secretions were consistently correlated with presence of well-differentiated tumor cells, whereas secretions from normal mucosae were consistently characterized by lack of sialyl-Tn expression. It is postulated that the original in situ tumors (which had homogeneous glycosylation patterns) evolved into several spatially discrete cell populations displaying different degrees of glycosylation, reflecting stages of tumor cell differentiation and progression.     

Comparison of epidemiological factors between serous and mucinous borderline ovarian tumors: therapeutic implications

The goals of this multicenter French retrospective study were to compare epidemiological factors within borderline ovarian tumors (BOT) according to their serous (SBOT) or mucinous (MBOT) type and according to the presence of pejorative histological criteria. We analysed 224 SBOT and 164 MBOT diagnosed between 1990 and 2009. The patients mean age was not different according to serous or mucinous type (46.9 ± 16.7 years and 44.6 ± 17.6 years). Women with SBOT, had more frequently history of infertility (17.2% versus 3.9%, P < 0.0001) than women with MBOT. SBOT were more often asymptomatic (52.3% versus 33.5%, P < 0.001), bilateral (26.4% versus 4.3%, P = 0.0001), smaller (9.1 cm versus 14.5 cm, P = 0.0001) and diagnosed at advanced stage (81.2% of stage I versus 95.1%, P < 0.0001) than MBOT. The micropapillary pattern found in 10.3% of SBOT was observed at younger age (38 ± 15.4 years versus 47.9 ± 16.6 years, P = 0.007) and was more often associated with peritoneal implants (26.1% versus 6.5%, P = 0.02). The intraepithelial carcinoma found in 6.7% of MBOT, was more often associated with micro-invasion (36.4% versus 4.6%, P = 0.003). The existence of epidemiologic differences between SBOT and MBOT underlines that the BOT series analysis can not be considered without taking into account this parameter.     

Variation in gene expression patterns in effusions and primary tumors from serous ovarian cancer patients

Background

While numerous studies have characterized primary ovarian tumors, little information is available regarding expression patterns of metastatic sites of this cancer. To define sets of genes that distinguish primary and metastatic ovarian tumors, we used cDNA microarrays to characterize global gene expression patterns in 38 effusions (28 peritoneal, 10 pleural) and 8 corresponding primary ovarian tumors, and searched for associations between expression patterns and clinical parameters.

Results

We observed multidimensional variation in expression patterns among the cancers. Coordinate variation in expression of genes from two chromosomal regions, 8q and 19q, was seen in subsets of the cancers indicating possible amplifications in these regions. A set of 112 unique genes of known function was differentially expressed between primary tumors and effusions using supervised analysis. Relatively few differences were seen between effusions isolated from the pleural and peritoneal cavities or between effusions from patients diagnosed with stage III and stage IV cancers. A set of 84 unique genes was identified that distinguished high from lower grade ovarian cancers. The results were corroborated using immunocytochemistry, mRNA in situ hybridization, and immunoblotting.

Conclusion

The extensive variation in expression patterns observed underscores the molecular heterogeneity of ovarian cancer, but suggests a similar molecular profile for ovarian carcinoma cells in serosal cavities.     

Retinoid receptor alpha and Beta expression in serous ovarian tumors

The expression of retinoid acid receptors alpha (RARalpha) and beta (RARbeta) and estrogen receptor alpha (ERalpha) was assessed by immunohistochemistry and Western blotting in normal ovaries, serous cystadenoma (n = 20), serous borderline (n = 14), and serous ovarian cancer (n = 47) and was correlated in cancer cases with stage, grade, progress-free survival (PFS), and survival. RARalpha was increasingly expressed in benign cystadenomas, borderline, and low-stage and advanced-stage neoplasms (p < 0.001). In stage III, G3 serous carcinoma, increased RARalpha expression was an independent prognostic factor associated with lower chemoresponse to first-line chemotherapy (taxol and carboplatin) and shorter PFS (p < 0.002).RARbeta and ERalpha expression did not correlate with RARalpha tumor characteristics or PFS and survival.     

BMPER在卵巢浆液性肿瘤中的表达及临床意义

目的:检测BMPER在卵巢浆液性肿瘤组织中的表达,分析其与卵巢浆液性癌临床病理参数及预后的关系,探讨BMPER表达的临床意义.方法:应用免疫组织化学方法检测59例卵巢浆液性癌、21例卵巢浆液性交界性肿瘤、23例卵巢浆液性良性肿瘤和28例正常卵巢组织中BMPER的表达,分析其与卵巢癌患者临床病理参数及预后的关系.结果:B...     

PKP4在卵巢上皮性浆液性囊腺癌组织中的表达及其临床意义

目的:检测PKP4（plakophilin 4,又称p0071）在卵巢上皮性浆液性囊腺癌组织中的表达,探讨PKP4参与肿瘤发生发展的机制及其临床意义。方法:利用免疫组化SP法检测PKP4在55例卵巢上皮性浆液性囊腺癌,12例卵巢上皮性交界性肿瘤,13例卵巢上皮性良性肿瘤,15例正常卵巢组织中表达情况,分析其与卵巢上皮性浆液性囊腺癌患者临床病理参数及预后的关系。结果:PKP4以细胞膜、细胞质着色为主,PKP4在卵巢上皮性浆液性囊腺癌组织中阳性表达率(94.55%)明显高于正常卵巢组织(26.67%)、卵巢上皮性良性肿瘤组织(46.15%)及卵巢上皮性交界性肿瘤(75.00%)(P＜0.05)。PKP4表达随FIGO分期增加而增高(P＜0.05),是影响卵巢上皮性浆液性囊腺癌患者总生存时间和预后的独立危险因素。结论:PKP4与卵巢癌的发生、发展和预后相关,有望在卵巢癌的早期诊断及预后评估方面发挥重大意义。     

Rab23在卵巢上皮性浆液性囊腺癌组织中的表达及临床意义

目的:探讨Rab23在卵巢上皮性浆液性囊腺癌组织中的表达情况及其与卵巢癌患者临床病理参数及预后的相关性。方法:利用免疫组化SP法检测Rab23在59例卵巢上皮性浆液性囊腺癌、10例卵巢上皮性交界性肿瘤组织、13例卵巢上皮性良性肿瘤组织以及20例正常卵巢组织中表达情况,进一步分析其与卵巢癌患者临床病理参数及预后的关系。结果:Rab23主要以细胞质、细胞膜着色。Rab23在卵巢上皮性浆液性囊腺癌中阳性表达率（84.7%,50/59）明显高于良性组（30.8%,4/13）及正常卵巢组织（25%,5/20）（P均<0.05）。在卵巢上皮性浆液性囊腺癌中,Rab23阳性表达与FIGO分期晚期（P<0.01）和分化程度（P<0.05）具有相关性,是影响卵巢癌患者总生存时间和预后的独立危险因素。结论:Rab23与卵巢癌的发生、发展及预后有关,有望成为卵巢癌患者评估预后、靶向治疗的分子标志物。     

WT1 gene expression as a prognostic marker in advanced serous epithelial ovarian carcinoma: an immunohistochemical study

Background  

WT1 is a tumor suppressor gene responsible for Wilms' tumor. WT1 reactivity is limited to ovarian serous carcinomas. Recent studies have shown that WT1 plays an important role in the progression of disease and indicates a poorer prognosis of human malignancies such as acute myeloid leukemia and breast cancer. The aims of this study were to determine the survival and recurrence-free survival of women with advanced serous epithelial ovarian carcinoma in relation to WT1 gene expression.     

Intracellular antigens as targets for antibody based immunotherapy of malignant diseases

This review discusses the potential use of intracellular tumor antigens as targets of antibody‐based immunotherapy for the treatment of solid tumors. In addition, it describes the characteristics of the intracellular tumor antigens targeted with antibodies which have been described in the literature and have been identified in the authors'' laboratory. Finally, the mechanism underlying the trafficking of the intracellular tumor antigens to the plasma membrane of tumor cells are reviewed.     

Non-polarized expression of Basal-cell adhesion molecule B-cam in epithelial ovarian cancers

The basal cell adhesion molecule (B-CAM) is a M(r) 90,000 cell surface glycoprotein identified by two monoclonal antibodies (mAbs), F8 and G253, raised against human tumor cells. Cloning and sequence analysis of a B-CAM cDNA has revealed a characteristic immunoglobulin domain structure of the B-CAM polypeptide, most closely related to MUC18, a cell surface protein of invasive human melanomas. The pattern of B-CAM expression in cultured cells suggests that the molecule is associated with a substrate-adherent growth pattern in some lineages. Moreover, B-CAM expression is upregulated following malignant transformation in some cell types. In the present study, we have used immunohistochemical methods to examine S-CAM expression in normal and neoplastic tissues, including over 200 tumors of diverse histological type. B-CAM was detected in several normal tissues, including polarized expression in several epithelia and expression in vascular endothelium and smooth muscle. Among the tumors tested, B-CAM was found most uniformly and with a non-polarized pattern in epithelial cancers of the ovary (27 of 31 tumors B-CAM-positive), By contrast, only small subsets of epithelial cancers of other organs, including some neuroendocrine, breast, and lung carcinomas, showed uniform or polarized B-CAM expression. Most non-ovarian carcinomas, lymphomas, sarcomas, and neuroectodermal tumors tested were B-CAM-negative. Immunoprecipitation studies with ovarian carcinoma cell lines showed that B-CAM in these cells is a M, 90,000 glycoprotein, composed of M(r) 65,000-75,000 polypeptides with abundant, N-linked carbohydrate side chains. These findings identify B-CAM as a characteristic cell surface protein of epithelial ovarian cancers. The availability of B-CAM-specific mAbs and cDNAs may help identify the role of B-CAM in normal endothelial and epithelial cells and ovarian cancers.     

NGAL在卵巢上皮性肿瘤中的表达及临床意义

目的探讨中性粒细胞明胶酶相关载脂蛋白（NGAL）在卵巢上皮性肿瘤中的表达及其临床意义。方法应用免疫组织化学方法检测NGAL在60例卵巢癌、30例卵巢交界性肿瘤、10例卵巢良性肿瘤和10例正常卵巢组织中的表达,分析其与病变类型的关系及其在卵巢癌组的表达率与临床病理特征的联系。结果 NGAL在卵巢癌和卵巢交界性肿瘤中的阳性表达率分别为81.7%、60.0%,明显高于卵巢良性肿瘤（20.0%）和正常卵巢组织（10.0%）（P〈0.05）。NGAL表达与卵巢癌的病理分级、病理分期和淋巴结转移有关（P〈0.05）。结论 NGAL蛋白促进肿瘤的形成、浸润与转移。NGAL可能是卵巢癌早期诊断和预后的潜在生物学参考指标。     

Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors.

PURPOSE: Ovarian serous borderline tumors (SBT) are characterized by arborizing papillae lined by stratified epithelial cells, varying atypia, and absence of stromal invasion. Originally, these tumors have been classified as borderline because they behaved in a remarkably indolent manner, even with widespread tumor deposits called implants and the presence of lymph node involvement. The molecular biology of these lesions has just begun to be explored. High prevalence of B-RAF/K-RAS mutations in SBTs in contrast to serous carcinomas (SCAs) indicates that the mitogenic RAS-RAF-MEK-ERK-MAP kinase pathway is crucial for the pathogenesis of SBTs. The purpose of this study was to further unravel the genetic pathways through which SBTs develop, with a special focus on explaining the generally benign SBT behavior.Materials and METHODS: We generated RNA expression profiles of 38 ovarian serous neoplasms. Global Test pathway analysis and significance analysis of microarrays (SAM) of the expression profiles was performed. RESULTS: SAM and Global Testing showed that although the mitogenic pathway is activated in SBTs, activation of downstream genes involved in extracellular matrix (ECM) degradation is absent, suggesting an uncoupling of both events. In addition, we show that two genes involved in regulating this uncoupling, ERK-inhibitor Dusp 4 and uPA-inhibitor Serpina 5, are downregulated in SCAs in contrast to SBTs. In SCAs, this was associated with downstream MMP-9 activation at both mRNA and protein level. CONCLUSION: We propose that the putative tumor suppressor genes Dusp 4 and Serpina 5 provide a major clue to the indolent behavior of SBTs.     

Classification of human ovarian tumors using multivariate data analysis of polypeptide expression patterns

Large amounts of data on quantitative gene expression are generated by procedures such as 2-DE analysis of proteins or cDNA microarrays. Quantitative molecular variation may potentially be used for the development of methods for the classification of tumors. We used here the statistical concepts of principal components analysis (PCA) and partial least square analysis (PLS) in an attempt to type ovarian tumors. Using a set of 170 polypeptides, 22 tumors were used to establish a model ("learning set") for classification into 3 groups (benign/borderline/malignant). Eighteen tumors were then used to test the model. Six of 8 carcinomas and 3 of 4 borderline tumors were correctly classified. Two of 6 benign lesions were correctly classified, 3 were classified as borderline and 1 as carcinoma. We conclude that it may be possible to classify tumors according to their constitutive protein expression profile using multivariate analysis, thus making classification by artificial intelligence a future possibility.