lewis-y-antigen and Carcinoma--Ovarian-Epithelial

The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics.. This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m(2) intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks).. 26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%-46.71%)]. Median PFS was 8.4 weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3).. Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Drug Resistance, Neoplasm; Fallopian Tube Neoplasms; Female; Humans; Lewis Blood Group Antigens; Middle Aged; Neoplasms, Glandular and Epithelial; Organoplatinum Compounds; Ovarian Neoplasms; Peritoneal Neoplasms; Young Adult

CD147 is a highly glycosylated transmembrane protein expressed on the surface of tumor cells. In the present study, the expression and clinical significance of the Lewis y antigen and CD147 in epithelial ovarian cancer (EOC) were analyzed, and the function and correlation in between the expression of Lewis y and CD147 were evaluated using immunohistochemical staining, reverse transcription‑quantitative polymerase chain reaction analysis, immunocytochemical staining, immunoprecipitation and western blotting. The results showed that the expression of CD147 was higher in EOC tissues and correlated with a higher tumor burden. Lewis y and CD147 exhibited similar expression patterns and their expression was positively correlated. The results of the immunofluorescence and immunoprecipitation experiments showed that Lewis y and CD147 colocalized in the cell membrane and cytoplasm. Lewis y antigen, but not Lewis x or sialyl Lewis x, was predominantly expressed in the highly glycosylated form of CD147. These changes occurred at the post‑transcriptional level. As an important component of CD147, Lewis y promoted CD147‑mediated cell adhesion and the expression of matrix metalloproteinase 2. In conclusion, Lewis y antigen and CD147 were significantly upregulated in ovarian tumors, and the altered expression of Lewis y may cause changes in CD147. The two molecules are associated with carcinogenesis and the development of ovarian cancer, and Lewis y antigen is a component of the CD147 structure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Basigin; Carcinoma, Ovarian Epithelial; Cell Adhesion; Cell Line, Tumor; Collagen Type IV; Disease Progression; Female; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Humans; Laminin; Lewis Blood Group Antigens; Matrix Metalloproteinase 2; Middle Aged; Prognosis; Survival Analysis; Young Adult

MUC1 is a type I transmembrane glycoprotein and is overexpressed in various epithelial tumor tissues. Some researchers have demonstrated that the glycosylation status of MUC1 can affect MUC1-mediated tumor growth and cell differentiation. In our previous study, we proved that the abilities of cell proliferation, adhesion, invasion and metastasis, and drug resistance were enhanced in ovarian cancer cells stably expressing Lewis(y). Therefore, we hypothesized that Lewis(y) antigen may play a central role in regulating MUC1 expression, and MUC1-mediated cell growth and differentiation may be closely associated with Lewis(y) antigen. This study aimed to examine the correlation between MUC1 expression and Lewis(y) antigen levels in ovarian cancer cell lines and tissue samples. A series of techniques, including RT-qPCR, western blot anlaysis, immunoprecipitation, immunohistochemistry and double-labeling immunofluorescence were applied to detect the expression of Lewis(y) and MUC1. In malignant epithelial ovarian tumors, the positive expression rates of Lewis(y) antigen and MUC1 were 88.33 and 86.67%, respectively, which were markedly higher than those in borderline (60.00 and 53.33%, P<0.05), benign (33.33 and 30%, P<0.01) and normal (0 and 25%, P<0.01) ovarian samples. There was no correlation between the positive expression rates of Lewis(y) or MUC1 and clinicopathological parameters in ovarian cancers (P>0.05). The expression levels of Lewis(y) and MUC1 correlated with the clinical FIGO stage (P<0.05). Both MUC1 and Lewis(y) were highly expressed in ovarian cancer tissues, and their expression levels were positively correlated (P<0.01). In α1,2-fucosyltransferase (α1,2-FT)-transfected cells, the gene and protein expression levels of MUC1 were significantly upregulated compared with the cells that did not overexpress α1,2-FT (P<0.05). The ratio of Lewis(y) immunoprecipitated with MUC1 to total MUC1 increased 1.55-fold in α1,2-FT-overexpressing cells (P<0.05). The overexpression of Lewis(y) resulted in the upregulation of MUC1. On the whole, our data indicate that both MUC1 and Lewis(y) are associated with the occurrence and development of ovarian cancers.

Topics: Adolescent; Adult; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Lewis Blood Group Antigens; Middle Aged; Mucin-1; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Ovary; Up-Regulation; Young Adult

Aberrant regulation of BCL6 plays crucial oncogenic roles in various malignant tumors; howbeit, the function of BCL6 in tumorigenesis of ovarian cancer remains unclear. The aim of this study is to investigate the role of BCL6 in ovarian cancer. The methods of immunohistochemical staining, quantitative real-time polymerase chain reaction, immunocytochemical staining, and gene expression profile enrichment analysis were performed to identify the possible role of BCL6 in ovarian cancer. We observed that the expression of BCL6 was significantly higher in ovarian cancer tissues and correlated with higher tumor burden including advanced International Federation of Gynecology and Obstetrics stages, poor differentiation, Type II ovarian cancer, the presence of >1 cm residual tumor size, and appearance of recurrence or death (all p < 0.05). The expression patterns of Lewis y were similar to these of BCL6. Multivariate Cox analysis demonstrated that advanced International Federation of Gynecology and Obstetrics stage, lymph node metastasis, residual tumor size >1 cm, as well as high expressions of BCL6 and Lewis y antigen were independent factors of worse progression-free survival and overall survival (all p < 0.05). There was a positive correlation of the expressions of BCL6 and Lewis y antigen. The associated genes with BCL6 in response to Lewis y antigen were identified, including four upregulated genes ( SOCS3, STAT1, PPARG, and GADD45A) and three downregulated genes ( ACAN, E2F3, and ZBTB7B). In conclusion, the high expressions of BCL6 and Lewis y antigen are associated with development, high tumor burden, and worse prognosis of ovarian cancer and targeting BCL6 could be a novel therapeutic strategy for ovarian cancer treatment.

Topics: Adolescent; Adult; Aged; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Lewis Blood Group Antigens; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Proto-Oncogene Proteins c-bcl-6; Tumor Burden; Young Adult

Autophagy is modulated by multiple factors including CD147, but little is know about the effects and mechanism by which the modification of CD147 by Lewis y antigen regulates autophagy of ovarian cancer cell. Here, we reported that Lewis y antigen can promote basic autophagy activity and restrain autophagic cell death in ovarian cancer cells. Furthermore, human whole genome expression profile microarrays and massage pathway analysis revealed that during early stages of autophagy in ovarian cancer cells with highly expressing Lewis y antigen, PI3K/Akt-mTOR activity was reduced, in contrast, the PI3K/Akt-mTOR signaling pathway was activated as the length of amino acid deprivation increased, which inhibited eIF4G2 expression, further decreased the transcription of autophagy-related genes, suppressed autophagic cell death. we also elaborated that co-regulates protein degradation in cells via the ubiquitin-proteasome system and the autophagy-lysosome pathway. These findings suggested that the modification of CD147 by Lewis y antigen enhanced the survival ability by promoting basic autophagy activity and restraining autophagic cell death in ovarian cancer , thus playing an important role in ovarian cancer malignant progression.

Topics: Autophagy; Basigin; Beclin-1; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Disease Progression; Eukaryotic Initiation Factor-4G; Female; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Humans; Lewis Blood Group Antigens; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Phosphatidylinositol 3-Kinase; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Proteolysis; Proto-Oncogene Proteins c-akt; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Ubiquitination

The main aim of this study was to explore the molecular structural relationship between annexin II (ANXA2) and Lewis y antigen by determining their expression patterns and clinical significance in ovarian epithelial carcinoma. The structural relationship between ANXA2 and Lewis y antigen was examined using immunoprecipitation and confocal laser scanning microscopy in two ovarian caner cell lines ES-2 and CaoV-3. We also constracted the stably transfected cell lines with low ANXA2 gene expression in order to detect the expression level between ANXA2 and Lewis y. ANXA2 and Lewis y were detected in tissues from malignant, borderline, benign, and normal ovarian tissues using immunohistochemical analysis. ANXA2 and Lewis y were present in both two ovarian cancer cells and ANXA2 contained Lewis y antigen. Moreover, expression of Lewis y antigen in ANXA2 from cell after transfection was higher than that before. Our immunohistochemistry data revealed significantly higher positive expression rates of ANXA2 in malignant ovarian tissues, compared to benign tumor and normal tissue, similar to Lewis y antigen levels in ovarian cancer. Notably, tissues displaying marked expression of ANXA2 simultaneously expressed high levels of Lewis y antigen. A linear correlation between the expression patterns of ANXA2 and Lewis y antigen was evident. Consistently, double-labeling immunofluorescence experiments illustrated co-localization of ANXA2 and Lewis y antigen within the same area. In conclusions, ANXA2 contains Lewis y antigen. Our results further demonstrate a close correlation between the expression levels of the two antigens, which are significantly high in ovarian cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Annexin A2; Carcinoma, Ovarian Epithelial; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lewis Blood Group Antigens; Microscopy, Confocal; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms

To measure Lewis y antigen and CD44 antigen expression in epithelial ovarian carcinoma and to correlate the levels of these antigens with clinical response to chemotherapy.. The study cases included 34 cases of ovarian carcinoma with resistance to chemotherapeutic drugs, 6 partially drug-sensitive cases, and 52 drug-sensitive cases (92 total).. The rates of expression of Lewis y antigen and CD44 antigen were significantly greater in the drug-resistant group than that in the partially-sensitive or sensitive groups. Surgical stage, residual tumor size and expression of CD44 and Lewis y antigen in ovarian carcinoma tissues were independent risk factors for chemotherapeutic drug resistance.. Over-expression of Lewis y and CD44 antigen are strong risk factors for chemotherapeutic drug resistance in ovarian carcinoma patients.

Topics: Carcinoma, Ovarian Epithelial; Drug Resistance, Neoplasm; Female; Humans; Hyaluronan Receptors; Immunohistochemistry; Lewis Blood Group Antigens; Middle Aged; Multivariate Analysis; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms

The aim of this study was to analyze the correlation and clinical significance between the expression of Mucin-1 (MUC1) and the Lewis y antigen with chemoresistance in ovarian epithelial cancers.. Ovarian cancer patients (n = 92) treated at our hospital from May 2005 to July 2009 were divided, according to their treatment and follow-up outcomes, into a resistant group (n = 37) or sensitive group (n = 55). The expression of MUC1 and Lewis y antigen in ovarian cancer tissues was detected using immunohistochemistry and correlated with chemoresistance.. The positive rates of MUC1 and Lewis y antigen in the resistant group were both 91.89%, significantly higher than their positive rates in the sensitive group (65.45% and 69.09%, respectively, and both p < 0.05). MUC1 or Lewis y expression and the pathological stage of the tissue were independent risk factors for chemoresistance (all p < 0.05).. The increased expression of MUC1 and the Lewis y antigen is a significant risk factor for chemoresistance in patients with ovarian epithelial cancer.

Topics: Carcinoma, Ovarian Epithelial; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Lewis Blood Group Antigens; Mucin-1; Multivariate Analysis; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Proportional Hazards Models; Risk Factors

The main aims of this study were to explore the molecular structural relationship between Human epididymis protein 4 (HE4) and Lewis y antigen by determining their expression patterns and clinical significance in ovarian epithelial carcinoma.. The structural relationship between HE4 and Lewis y antigen was examined using immunoprecipitation and confocal laser scanning microscopy. HE4 and Lewis y were detected in tissues from malignant (53 cases), borderline (27 cases), benign (15 cases) and normal ovarian tissues (15 cases) using immunohistochemical analysis.. HE4 was present in ovarian cancer, benign tumor tissues, ovarian carcinoma cells, and culture medium, and contained Lewis y antigen. Moreover, expression of Lewis y antigen in HE4 from ovarian cancer was higher than that from benign tumor (P<0.05). HE4 possibly exists as two protein isoforms, both containing Lewis y antigen. Our immunohistochemistry data revealed significantly higher positive expression rates of HE4 in malignant ovarian tissues, compared to benign tumor and normal tissue (P<0.05), similar to Lewis y antigen levels in ovarian cancer (P<0.05). Notably, tissues displaying marked expression of HE4 simultaneously expressed high levels of Lewis y antigen. A linear correlation between the expression patterns of HE4 and Lewis y antigen was evident. Consistently, double-labeling immunofluorescence experiments illustrated co-localization of HE4 and Lewis y antigen within the same area.. HE4 contains Lewis y antigen. Our results further demonstrate a close correlation between the expression levels of the two antigens, which are significantly high in ovarian cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Ovarian Epithelial; Female; Gene Expression Regulation, Neoplastic; Humans; Lewis Blood Group Antigens; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Ovary; Proteins; WAP Four-Disulfide Core Domain Protein 2; Young Adult

Lewis y is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface. Elevation of Lewis y is frequently observed in epithelial-derived cancers. This study aimed to detect the expression and clinical significance of the Lewis y antigen and TGF-β1 (transforming growth factor β1) in ovarian epithelial tumors, and to evaluate the correlation between them. Immunohistochemical staining was used to detect the expression of Lewis y antigen and TGF-β1 in 60 cases of ovarian epithelial malignant tumors, 20 cases of borderline ovary tumors, 20 cases of benign ovary tumors and 10 cases of normal ovarian tissues. An immunofluorescence double labeling method was also used to detect the correlation between Lewis y antigen and TGF-β1. The positive rates of Lewis y antigen in ovarian epithelial cancer tissues was 88.33%, significantly higher compared to those of borderline ovarian tumors (60.00%) (P<0.05), benign ovarian tumors (35.00%) (P<0.01) and normal ovarian tissues (0%) (P<0.01). Its expression was not associated with clinical parameters; the positive rates of TGF-β1 in ovarian epithelial cancers were 78.33%, significantly higher compared to those of benign ovarian tumors (65.00%) (P<0.05) and normal ovarian tissues (40.00%) (P<0.05); the positive rates of the TGF-β1 and Lewis y were not associated with metastasis of lymph nodes and histological types, differentiation degree and clinical stage (P>0.05). Expression of Lewis y antigen and TGF-β1 was significantly positively associated with epithelial carcinoma. Close correlation between Lewis y, TGF-β1 and ovarian cancer was observed. Altered expression of Lewis y antigen may cause changes in TGF-β1 expression. Lewis y can increase the growth of ovarian cancer cells and the invasion ability by promoting TGF-β1 abnormal expression and by promoting angiogenesis and a change in its signal transduction pathway. This study provides theoretical evidence for the development of ovarian cancer biological treatments.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Case-Control Studies; Cell Differentiation; Cell Proliferation; Chi-Square Distribution; China; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Lewis Blood Group Antigens; Linear Models; Lymphatic Metastasis; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Risk Assessment; Risk Factors; Transforming Growth Factor beta1; Up-Regulation; Young Adult

To detect the expression and clinical significances of Lewis y antigen and integrin αv, β3 in epithelial ovarian tumors, and to explore the expression correlation between Lewis y antigen and integrin αv, β3.. Immunohistochemical staining was performed in 95 cases of epithelial ovarian cancer, 37 cases of borderline tumors, 20 cases of benign tumors, and 20 cases of normal ovarian tissue, for the detection of Lewis y antigen and integrin αv, β3 expressions, and to analyze the relationship between Lewis y antigen and integrin, and the relationship between clinical and pathological parameters of ovarian cancer. In addition, immunofluorescence double labeling was utilized to detect the expression correlation between Lewis y antigen and integrin αv, β3 in ovarian cancer.. In epithelial ovarian tumors, the expression rate of Lewis y antigen was 81.05%, significantly higher than that of borderline (51.53%) (P < 0.05) and benign (25%) (P < 0.01) tumors, and normal ovarian tissues (0) (P < 0.01). The expression rate of integrin αv, β3 in malignant epithelial ovarian tumors was 78.95% and 82.11%, respectively, significantly higher than that of the borderline (45.94%, 40.54%) (both P < 0.05), benign group (10.00%, 15.00%) (both P < 0.01) and normal ovary group (5%, 15%) (both P < 0.01).. Lewis y and integrins αv, β3 are relevant to pelvic and abdominal diffusion and metastasis of ovarian cancer cells, suggesting that these two molecules mediate a boosting function for tumor metastasis.

Topics: Abdominal Neoplasms; Adult; Aged; Carcinoma, Ovarian Epithelial; Female; Fluorescent Dyes; Humans; Immunohistochemistry; Integrin alphaVbeta3; Lewis Blood Group Antigens; Middle Aged; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms

This study aimed to measure and correlate the expression of insulin-like growth factor receptor-1 (IGF-1R) and the Lewis(y) antigen in ovarian cancer cell lines and tissue samples.. Reverse transcriptase PCR (RT-PCR), Western blotting, immunoprecipitation, immunohistochemistry, and immunofluorescence double-labeling techniques were applied to detect and measure the expression of Lewis(y) and IGF-1R.. In α1,2-fucosyltransferase (α1,2-FT)-transfected cells, IGF-1R expression was significantly upregulated compared with cells that do not overexpress α1,2-FT (P < 0.05). The amount of Lewis(y) expressed on IGF-1R increased 1.81-fold in α1,2-FT-overexpressing cells (P < 0.05), but the ratio of Lewis(y) expressed on IGF-1R to total IGF-1R was unaltered between two cells (P > 0.05). In malignant epithelial ovarian tumors, the positivity rates of Lewis(y) and IGF-1R detection were 88.3% and 93.33%, respectively, which is higher than the positivity rates in marginal (60.00% and 63.33%, all P < 0.05), benign (33.00% and 53.33%, all P < 0.01), and normal (0% and 40%, all P < 0.01) ovarian samples. No correlations were detected in positivity rates of Lewis(y) or IGF-1R expression with respect to clinicopathological parameters in ovarian cancers (all P > 0.05). Both IGF-1R and Lewis(y) were highly expressed in ovarian cancer tissues, and their expression levels were positively correlated (P < 0.05).. Overexpression of Lewis(y) results in overexpression of IGF-1R. Both IGF-1R and Lewis(y) are associated with the occurrence and development of ovarian cancers.

Topics: Adolescent; Adult; Aged; Blotting, Western; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Female; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Humans; Immunohistochemistry; Lewis Blood Group Antigens; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Receptor, IGF Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation; Young Adult

Epithelial carcinomas of the ovary exhibit the highest mortality rate among gynecologic malignancies. Studies found that the metabolism of glycolipids or carbohydrates is associated with acquirement of anticancer drug-resistance by cancer cells. This study was to characterize possible involvement of Lewis Y (Le(Y)) antigen in the drug-resistance of cancer cells. We transfected the α1,2-fucosyltransferase gene into human ovarian carcinoma-derived RMG-1 cells and established RMG-1-hFUT cells with enhanced expression of Le(Y). We determined the effects of docetaxel on the survival of cells by MTT assaying and observed the apoptosis of cells in the presence of docetaxel by flow cytometric analysis and by transmission electron microscopy. Plasma membranes and intracellular granules in RMG-1-hFUT cells were stained with anti-Le(Y) antibody, the intensity of the staining was higher than that in control cells. The RMG-1-hFUT cells exhibited higher resistance to docetaxel than the control cells with regard to the docetaxel concentration and time course. After treatment with 10 μg/mL docetaxel for 72 h, the control cells, but not RMG-1-hFUT, contained abundant positively stained cell debris due to disintegration of the cytoskeleton. On transmission electron microscopy, although the control cells treated with docetaxel as above showed the following morphology, i.e., absence of villi, cells shrunken in size, pyknosis, agglutinated chromatin and cell buds containing nuclei in the process of apoptosis, the RMG-1-hFUT cells showed only agglutinated chromatin and vacuoles in the cytoplasm. In summary, cells with enhanced expression of Le(Y) were shown to acquire docetaxel-resistance, indicating the possible involvement of glycoconjugates in the drug-resistance.

Topics: Apoptosis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Survival; Docetaxel; Drug Resistance, Neoplasm; Female; Flow Cytometry; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Gene Expression Regulation, Neoplastic; Humans; Lewis Blood Group Antigens; Microscopy, Electron, Transmission; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Taxoids; Transfection