Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated the presence of the 55- and 75-kDa receptor for tumor necrosis factor (TNF) and lymphotoxin (LT) (TNF-R) in serum, and ascites from women with ovarian cancer. The present studies were initiated to begin to examine the possible cellular source of these receptors in women with ovarian cancer. Human ovarian tumor cells (PA-1) were cocultured for 24-48 hr with various levels of recombinant human cytokines (IL-1 beta, IL-4, IFN-gamma) and the supernatants were assayed by ELISA for the soluble forms of each receptor. PA-1 cells spontaneously release the 55-kDa TNF-R and low levels of the 75-kDa TNF-R. The release of both 55- and 75-kDa TNF-R was stimulated when PA-1 cells were cultured with IL-1 beta and IFN-gamma but unaffected by IL-4. The level of 55-kDa TNF-R was elevated slightly over spontaneous release but the level of 75-kDa TNF-R increased dramatically. IFN-gamma was the most potent stimulator of receptor release particularly of the 75-kDa TNF-R. IFN-gamma also induced increased expression of cell membrane TNF-R measured by binding of 125I-labeled TNF. Membrane TNF-Rs which were induced by IFN-gamma were the 75-kDa type, because TNF binding was blocked by anti-75-kDa TNF-R antibody. These data suggest that IFN-gamma selectively induced release and expression of 75-kDa TNF-Rs.
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PMID:Release of soluble TNF/LT receptors from a human ovarian tumor cell line (PA-1) by stimulation with cytokines in vitro. 821 97

We defined a cytokine mRNA profile of 12 ovarian cancer biopsies, 10 normal/benign biopsies, six ovarian cancer cell lines and three ovarian cancer xenografts, using RT-PCR. The profile, based on screening for 25 cytokines and 12 receptor mRNAs, was rich in growth factors, pro-inflammatory cytokines and chemokines, but weak in lymphocyte-associated cytokines. The pattern was unique to ovarian tissue, but similar in normal, benign and malignant biopsies, with > 80% samples expressing 16 cytokines in common. Fourteen of these were also expressed by > 65% cell lines, but fewer were detected in xenografts. Potential autocrine loops existed for IL-1, IGF-1, M-CSF, GM-CSF and TNF-alpha. IL-4 and IFN-gamma receptors were expressed in absence of ligand. Chemokines RANTES, MIP-1 alpha and MIP-1 beta were expressed in biopsies, but were rarely detected in cell lines and absent from xenografts. IGF-1 and its receptor was expressed in every sample, as was IFN-gamma receptor. Another 10 cytokine mRNAs and six receptors were expressed in > 80% samples. These may contribute to key survival/growth loops. Similarities between normal and malignant biopsies suggest that analogous processes of remodelling and repair occur. RT-PCR proved a rapid, reproducible screen, but further assays are required to detect quantitative differences between normal and malignant tissues and tumour models.
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PMID:A cytokine profile of normal and malignant ovary. 889 39

We have reported that human ovarian-carcinoma cell lines express high-affinity IL-4 receptor. Since IL-4R has been hypothesized to share a chain with IL-13R, we investigated whether ovarian cancer cells express IL-13 receptor. In the present study, we report that the ovarian-carcinoma cell lines IGROV-1 and PA-1 express varying numbers of high-affinity IL-13 receptors. Furthermore, IL-13 inhibited the binding of IL-4 on both ovarian-carcinoma cell lines, while IL-4 did not inhibit IL-13 binding on IGROV-1 cell line. IL-13 and IL-4 induced the phosphorylation of JAK1, JAK2 and Tyk2 Janus kinases in PA-1 cells. In contrast, JAK3 tyrosine kinase was expressed in PA-1 cells, but IL-4 or IL-13 did not augment its phosphorylation. In IGROV-1 cells, Tyk2 was constitutively phosphorylated and this phosphorylation was augmented by IL-4 or IL-13. JAK1 and JAK2 but not JAK3 were expressed but only JAK2 was faintly phosphorylated in response to either IL-13 or IL-4 respectively. IRS (insulin-receptor substrate)-1 and IRS-2 were also phosphorylated constitutively in both ovarian cancer cell lines examined, but only the phosphorylation of IRS-1 was augmented in response to IL-4 or IL-13. STAT6 was phosphorylated and activated in response to IL-4 and IL-13 in all cell lines examined. Our results demonstrate that ovarian cancer cell lines may express 2 types of IL-13R and the IL-13- or IL-4-induced signaling patterns may be slightly different in each type of receptor.
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PMID:Human ovarian-carcinoma cell lines express IL-4 and IL-13 receptors: comparison between IL-4- and IL-13-induced signal transduction. 900 65

Cytotoxic T-cell (CTL) cultures were generated from five ovarian cancer patients (OvCTL) and from three breast cancer patients (BrCTL). All CTL lines were T-cell receptor (TcR) alphabeta+ and predominantly CD8+ (73 +/- 13%). These CTL lines preferentially recognized autologous tumor cells in an HLA class I-restricted, and in part HLA-A2-restricted, manner. In addition, the CTL lines recognized allogeneic HLA-A2+ ovarian and breast tumor cells. Specific recognition was determined by T-cell-mediated cytotoxicity as well as cytokine release. Coculture of irradiated autologous tumor cells with OvCTL induced secretion of IFN-gamma, GM-CSF and TNF-alpha, but not IL-4, indicating a T helper-1-type response. Similar results were obtained when OvCTL and BrCTL were stimulated with histologically matched HLA-A2+ tumor cells. Also, BrCTL stimulated with HLA-A2+ but not HLA-A2- ovarian tumor cells produced significant levels of GM-CSF and TNF-alpha. Finally, the Her2/neu peptide p654-662, earlier identified as a tumor antigen in both ovarian and breast cancer, induced cytotoxicity as well as the specific release of IFN-gamma and TNF-alpha but not IL-4 by OvCTL and BrCTL. Thus, tumor-specific recognition by CTL was verified by cytotoxicity and cytokine release. The secretion of Th1-like cytokines as opposed to Th2-like cytokines suggest that therapeutically OvCTL and BrCTL could potentially enhance the endogenous immune response to tumor.
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PMID:Simultaneous production of T helper-1-like cytokines and cytolytic activity by tumor-specific T cells in ovarian and breast cancer. 902 20

The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients with ovarian cancer using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Total RNA from 20 malignant and 10 benign specimens were used to assay for expression of 12 cytokines. Additionally, monoclonal antibodies (MAbs) were used to detect T cells, CD4+ helper and CD8+ cytotoxic/suppressor T-cell subtypes, B cells, and macrophages. Our results showed the expression of transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 19, 17, and 10 malignant specimens, P < .001, .001, and .05, respectively. Other cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta/LT, IL-2, and IL-6 were expressed in a few cases, and IL-1alpha and IL-4 expression were not detected. The benign samples did not express IL-10, but GM-CSF, TGF-beta1, and IL-8 were expressed in one, one, and four specimens, respectively. Interestingly, in four cases in which samples from the primary and relapse tumors were available for analysis, the tumors in relapse showed a significant increase for TGF-beta1 (P < .05) and a decreased trend in IL-10 mRNA levels. The source of these factors was tumor cells as detected immunohistochemically. This combined alteration of TGF-beta1 and IL-10 was associated with a significant reduction in number of TIL in general, and CD8+ and macrophages in particular (P = .036 and .049, respectively). Our findings suggest the important role of certain soluble factors in the complex process of tumor progression. Furthermore, understanding the tumor-host relationship and the factors influencing the interaction may be helpful in developing effective and innovative treatment methods.
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PMID:Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas. 904 97

Immunotherapy of gynaecological cancer with tumour-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) has become a valid treatment modality with varying degrees of success in obtaining an antitumour response. TIL consist of lymphocytes, mainly T cells and minor populations of natural killer cells or B cells. Conventional cytogenetic studies of tumour cells from patients with breast and ovarian cancer have shown multiple chromosomal abnormalities including chromosomes 7 and 12. This study was designed to analyse the surface further, as well as investigate the intracellular, characteristics of TIL by multicolour flow cytometry and the cytogenetic features by fluorescence in situ hybridization. Tumour cell, peripheral blood and TIL samples from 25 patients (15 ovarian tumours, 8 breast cancers, 1 uterine sarcoma, 1 cervical carcinoma) were analysed for their phenotype, the expression of major cytokines [interleukin-2 (IL-2), IL-4 and interferon gamma (IFN gamma)], their proliferation rate, their cytotoxic ability and for the presence of numerical aberrations of chromosomes 7 and 12. All the tumour cells showed a high frequency of numerical aberration in chromosomes 7 and 12, especially trisomies or tetrasomies and combined aberrations. Trisomies of both chromosomes also occured at a low percentage in TIL and PBL. The phenotyping of TIL and PBL revealed rather similar subsets of lymphocytes. In both, T cells were the major population, with TIL containing a slightly increased CD4/CD8 ratio. The cytokine pattern showed a predominance of IL-4 production in TIL and of IFN gamma in PBL, indicating that, in TIL, cellular immunity is downregulated, whereas in PBL the cytotoxic immune response predominates. This is in accordance with the cytotoxic ability of TIL, which is weakened in comparison to PBL. Cellular characteristics revealed some disadvantages in the use of TIL for cancer treatment, explaining ineffective clinical results. The search for specific antitumour lymphocytes requires carefully designed experiments in order to define effective anticancer cells and thereby improve immunologically mediated tumour therapy.
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PMID:Cellular characteristics of peripheral blood lymphocytes and tumour-infiltrating lymphocytes in patients with gynaecological tumours. 917 70

Previous studies have characterized the reactivity of CD8+ CTLs with ovarian and breast cancer. There is little information about the antigens and epitopes recognized by CD4+ T cells in these patients. In this study, we analyzed the ability of T cells from peripheral blood mononuclear cells of breast cancer patients to recognize HER-2/neu (HER-2) peptides. We found that 13 of 18 patients responded by proliferation to at least one of the HER-2 peptides tested. Of these peptides, one designated G89 (HER-2: 777-789) was recognized by T cells from 10 patients. Seven of nine responding patients were HLA-DR4+, suggesting that this peptide is recognized preferentially in association with HLA-DR4. Analysis of the specificity and restriction of the cytokine responses to G89 by G89-stimulated T cells revealed that these cells secreted significantly higher levels of IFN-gamma than interleukin 4 and interleukin 10, suggesting priming for a Th0-T helper 1 response. The same pattern of cytokine responses was observed to the intracellular domain of HER-2 protein, suggesting that G89-stimulated T cells recognized epitopes of the HER-2 protein in association with HLA-DR4. Because HLA-DR4 is present in 25% of humans, characterization of MHC class II-restricted epitopes inducing Th0-T helper 1 responses may provide a basis for the development of multivalent HER-2-based vaccines against breast and ovarian cancer.
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PMID:Proliferative and cytokine responses to class II HER-2/neu-associated peptides in breast cancer patients. 971 33

To investigate and compare the phenotype and function of lymphocytes collected from patients harboring advanced ovarian cancer, leukocytes from peripheral blood (n = 18), ascitic fluid (n = 13) and tumor tissues (n = 13) were evaluated for the relative proportions of lymphocyte subsets, including CD3+, CD4+, CD8+, CD19+, CD56 and the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells. The ability to synthesize type 1 cytokines (IFN-gamma and IL-2) and a type 2 cytokine (IL-4) was assessed by flow cytometry. In all patients, T cells (CD3+) were the major leukocyte population detected in each tissue, with CD4+ T cells being dominant in peripheral blood lymphocytes (PBL) and tumor-associated lymphocytes (TAL) but not in tumor-infiltrating lymphocytes (TIL) (CD4:CD8 ratios: 3.0 vs. 2.0 vs. 1.0, respectively). CD19+ lymphocytes (B cells) and CD56+ lymphocytes (NK cells) were significantly higher in PBL compared to TAL and TIL (p < 0.05). TAL and TIL had a higher proportion of T cells expressing the late activation marker HLA-DR compared to PBL. In contrast, no significant differences were detected in PBL, TAL and TIL in the expression of the early activation marker CD25. Type 1 cytokines were the dominant type produced by in vitro stimulated T cells for each population, with a greater proportion of IFN-gamma+ T cells in TAL and TIL compared to PBL (p < 0.01), and a higher proportion of IL-2+ T cells in PBL compared with TAL and TIL (p < 0.05). Low percentages of IL-4+ T cells (i.e. Th2) were detected in each tissue. Taken together, these data demonstrate the recruitment and accumulation of high concentrations of antigen-experienced T lymphocytes in TAL and TIL compared to PBL. However, low surface expression of IL-2 receptor (i.e. CD25), as well as depressed intracellular IL-2 production in chronically stimulated TAL and TIL suggests that the impaired antitumor function commonly detected in these lymphocyte populations may be secondary to an acquired dysregulation of the IL-2 pathway.
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PMID:Phenotypic and functional analysis of tumor-infiltrating lymphocytes compared with tumor-associated lymphocytes from ascitic fluid and peripheral blood lymphocytes in patients with advanced ovarian cancer. 1140 37

Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8(+) cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8(+) T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccessful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8(+) T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8(+) T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-gamma expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8(+) T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8(+) CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy.
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PMID:Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer. 1185 27

Our clinical studies revealed significantly increased soluble HLA-G (sHLA-G) plasma levels in patients suffering from malignant melanoma, glioma, breast and ovarian cancer. Specific ELISpot assays demonstrate that sHLA-G molecules expressing intron-4 sequences are preferentially secreted by peripheral blood monocytes. In vitro, the sHLA-G secretion of monocytes and tumor cells was strongly enhanced by TH1 cytokines like IFN-alpha, -beta, -gamma whereas TH2 cytokines (e.g. IL-4, -10) had minor effects. As sHLA-G can inhibit the functions of T and NK cells high concentration of these molecules should systemically or at the tumor side reduce the immune surveillance and thus favour the progression of cancer.
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PMID:Secretion of sHLA-G molecules in malignancies. 1470 17


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