interleukin-8 and Carcinoma--Ovarian-Epithelial

To characterize the safety, immunogenicity, and outcomes of patients with high-grade serous ovarian cancer (HGSOC) in second or greater remission treated with a polyvalent antigen-KLH plus OPT-821 vaccine construct and bevacizumab.. Patients with recurrent HGSOC were treated with the vaccine plus bevacizumab at our institution from 01/05/2011 to 03/20/2012. Follow-up continued until 03/2021. Blood/urine samples were collected. "Responders" had an immunogenic response to ≥ 3 antigens; "non-responders" to ≤ 2 antigens.. Twenty-one patients were treated on study. One developed a dose-limiting toxicity (grade 4 fever). Two (10%) experienced bevacizumab-related grade 3 hypertension. Thirteen (68%) and 16 (84%) of 19 responded to ≥ 3 and ≥ 2 antigens, respectively (Globo-H, GM2, TF cluster Tn, MUC-1). Four of 21 patients were alive > 5 years post-treatment. Responders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI: 0.7-cannot estimate), respectively; median OS was 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively. On two-timepoint analysis (baseline, week 17), increased IL-8 exhibited improved PFS (HR as 10-unit increase, 0.43; p = 0.04); increased PDGF exhibited worse OS (HR as 10-unit increase, 1.01; p = 0.02).. This is the longest follow-up of vaccine administration with bevacizumab in patients with ovarian cancer. The vaccine was well tolerated with bevacizumab. Response was not associated with improved survival. On two-timepoint analysis, increased IL-8 was associated with significant improvement in PFS; increased PDGF with significantly worse OS. For all timepoint measurements, cytokine levels were not significantly associated with survival.. NCT01223235.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Ovarian Epithelial; Female; Humans; Interleukin-8; Neoplasm Recurrence, Local; Ovarian Neoplasms; Vaccines, Combined

Epithelial Ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. Because the disease is asymptomatic in early-stage, the majority of patients are not diagnosed until late stages, highlighting the need for the development of novel diagnostic biomarkers. Mediators of tumoral microenvironment may affect EOC progression and resistance to treatment.. Analysis of serum proteins to identify a panel of theranostic biomarkers for EOC.. Serum levels of 65 analytes were determined in EOC patients, and healthy controls with the ProcartaPlex Human Immune Monitoring 65-Plex Panel.. Twenty-one analytes: 7 cytokines (IFN-γ, IL-12p70, IL-13, IL-18 and TSLP), 7 chemokines (Eotaxin, eotaxin-2, IP-10, BLC, I-TAC, SDF-1α, and fractalkine), 2 growth factors (MMP-1, VEGF-α), and 5 soluble receptors (APRIL, CD40L, TWEAK, CD30 and TNFRII; were significantly differentially expressed between the two groups. ROC curves showed that only seven of them (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine, and Tweak) had AUC values greater than 0.70 and thus had potential clinical utility. Moreover, five cytokines: IFN-γ, IL-1 β, IL-8, MIP-1β, and TNF-α are positively associated with patients who developed resistance to taxol-platinum-based chemotherapy (CT).. This study has revealed a first panel of 7 analytes (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine and Tweak) that can be used for early detection of EOC and a second panel of five cytokines (IFN-γ, IL-1β, IL-8, MIP-1β, TNF-α) that can help clinicians to identify EOC patients who are at higher risk to develop resistance to CT of EOC.

Topics: Biomarkers; Carcinoma, Ovarian Epithelial; Chemokine CCL4; Chemokine CX3CL1; Chemokine CXCL10; Cytokines; Female; Humans; Interleukin-8; Interleukin-9; Ovarian Neoplasms; Precision Medicine; Tumor Microenvironment; Tumor Necrosis Factor-alpha

Tumour associated neutrophils (TANs) play a controversial role in regulating immune surveillance and immune evasion in various malignancies. Here, we investigated the relevance of TANs with the prognosis and immune microenvironment of epithelial ovarian cancer (EOC).. We characterised TANs using flow cytometric analysis and immunofluorescence analysis. The prognostic merit of TANs in EOC was evaluated using cox regression analysis. Furthermore, we explored the therapeutic merit of targeting Notch signalling in EOC and determined its involvement in the immune microenvironment.. High level of TANs is associated with a dismal prognosis and immune tolerance in EOC. TANs impaired cytotoxic effects of CD8. JAG2

Topics: Animals; Carcinoma, Ovarian Epithelial; Cells, Cultured; Chemotaxis, Leukocyte; Disease Progression; Female; Humans; Immune Evasion; Interleukin-8; Jagged-2 Protein; Mice; Mice, Inbred C57BL; Neutrophils; Ovarian Neoplasms; Prognosis; Retrospective Studies; Signal Transduction; Tumor Microenvironment

Primary cytoreduction, followed by chemotherapy, is a standard treatment of patients with epithelial ovarian cancer (EOC). However, the effectiveness of this treatment depend on various elements e.g. type of operation. It is accepted that optimal surgery correlates with longer survival of patients. The other element, an efficiency of immune system after surgical intervention although important is less elucidated. The aim of this study was to establish the impact of optimal and sub-optimal operation on immunological status of EOC patients regarding also their overall survival (OS). On the day of primary cytoreduction and 7days after, the selected serum immunological parameters were determined in 49 patients with confirmed EOC. We found that, the level of immunosuppressive (interleukin 10; transforming growth factor-β - TGF-β1) and pro-inflammatory (interleukin-6 and 8) cytokines was significantly higher in the group of patients with advanced stage of disease, compared to early stage. However, the number of circulating CD3

Topics: Carcinoma, Ovarian Epithelial; Cytoreduction Surgical Procedures; Epithelial Cells; Female; Humans; Immunosuppression Therapy; Interleukin-10; Interleukin-6; Interleukin-8; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Ovary; Postoperative Complications; Survival Analysis; T-Lymphocytes, Regulatory; Transforming Growth Factor beta1; Treatment Outcome; Tumor Microenvironment

We investigated the effect of nuclear factor of activated T cells c1 (NFATc1) on the growth and vascular generation of human ovarian carcinoma SKOV3 cell-transplanted tumors in nude mice and explored the possible underlying mechanism. NFATc1 siRNA was transfected into the SKOV3 cells, which were then subjected to immunofluorescence tests and real-time reverse transcription polymerase chain reaction (RT-PCR) to determine the transfection-induced inhibition rate. The tumor volumes in the nude mice in all groups were measured to determine the in vivo antitumor effect of NFATc1 siRNA. Immunohistochemical (IHC) methods were employed to detect NFATc1 expression in tumor tissue, combined with cytokeratin (CK) staining to label the epithelial origin of the tumor tissue. CD34 and podoplanin were used as markers for labeling microvessels and microlymphatic vessels, respectively. The densities of microvessels and microlymphatic vessels in each group were calculated and statistically analyzed. RT-PCR and western blotting were performed to detect the protein and mRNA expression levels of NFATc1, the ELR+ CXC chemokine interleukin (IL)-8, fibroblast growth factor-2 (FGF-2), and platelet-derived growth factor BB (PDGF BB) in xenografted tumor tissue in all groups. NFATc1 was highly expressed in tumor tissue in the control groups. The intervention group exhibited a tumor growth inhibition rate of 57.08% and presented a lower tumor weight and volume compared with the two control groups. In the control groups, the microvessel densities were 12.00 ± 1.65 and 11.47 ± 0.32, respectively, and the microlymphatic vessel densities were 10.03 ± 0.96 and 9.95 ± 1.12; these values were significantly higher than in the intervention group. RT-PCR and western blot shows that NFATc1 siRNA could markedly suppress the expression of IL-8, FGF-2 and PDGF BB at the mRNA and the protein level. In conclusion, it was shown that NFATc1 siRNA significantly suppresses the growth and vascular generation of SKOV3 human ovarian carcinoma cell-transplanted tumors subcutaneously xenografted into nude mice. The downregulation of the expression of IL-8, FGF-2 and PDGF BB may be one of the mechanisms underlying the above inhibitory effects.

Topics: Animals; Becaplermin; Carcinoma; Carcinoma, Ovarian Epithelial; Cell Proliferation; Fibroblast Growth Factor 2; Humans; Interleukin-8; Mice; Neoplasms, Glandular and Epithelial; NFATC Transcription Factors; Ovarian Neoplasms; Proto-Oncogene Proteins c-sis; Transfection; Xenograft Model Antitumor Assays

DNA repair mechanisms, environment-mediated drug resistance and cancer initiating cells (CIC) are three major research concepts that can explain the chemoresistance of epithelial ovarian cancer (EOC). The objective was to test if changes in the expression of potential markers associated with drug resistance before and after chemotherapy would correlate with platinum resistance, defined as a recurrence within the first year after chemotherapy cessation, and with survival, in advanced EOC.. We included 32 patients with stage IIIC-IV EOC who underwent laparoscopy to evaluate the extent of carcinomatosis, neoadjuvant chemotherapy (carboplatin/taxol) and interval surgery. Biopsies taken during the initial laparoscopies and interval surgeries were evaluated using immunohistochemistry for the expression of 7 proteins: CD117, CD44 and ALDH1 to evaluate CIC; IL-6, IL-8 and BMP2 to evaluate environment-mediated drug resistance; and ERCC1 to evaluate DNA repair. Expression measurements were correlated with platin resistance and survival. The markers' relevance was confirmed in vitro using chemoresistance tests and flow cytometric measurements of the proportion of CD44+ cells.. 17 patients were chemoresistant and 15 patients were chemosensitive. We observed increases in CD44, IL-6 and ERCC1 expression and stable ALDH1, CD117, IL-8, and BMP2 expression. Reduced expression of cancer initiating cell markers and increased expression of environment-mediated drug resistance markers were associated with poor prognosis. We also demonstrated that CD44+ cells had survival advantages in vitro.. Changes in CD44 and IL-8 expression on tumor cells appeared to correlate with overall survival and should be further tested as predictors of chemoresistance using larger cohort.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carboplatin; Carcinoma, Ovarian Epithelial; Chemotherapy, Adjuvant; DNA-Binding Proteins; Drug Resistance, Neoplasm; Endonucleases; Female; Humans; Hyaluronan Receptors; Interleukin-6; Interleukin-8; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel

Epithelial ovarian cancer (EOC) typically presents with advanced disease. Even with optimal debulking and response to adjuvant chemotherapy, the majority of patients will have disease relapse. We evaluated cytokine and chemokine profiles in ascites at primary surgery as biomarkers for progression-free survival (PFS) and overall survival (OS) in patients with advanced EOC.. Retrospective analysis of patients (n =70) who underwent surgery at Roswell Park Cancer Institute between 2002 and 2012, followed by platinum-based chemotherapy.. The mean age at diagnosis was 61.8 years, 85.3% had serous EOC, and 95.7% had stage IIIB, IIIC, or IV disease. Univariate analysis showed that ascites levels of tumor necrosis factor (TNF)-α were associated with reduced PFS after primary surgery. Although the ascites concentration of interleukin (IL)-6 was not by itself predictive of PFS, we found that stratifying patients by high TNF-α and high IL-6 levels identified a sub-group of patients at high risk for rapid disease relapse. This effect was largely independent of clinical prognostic variables.. The combination of high TNF-α and high IL-6 ascites levels at primary surgery predicts worse PFS in patients with advanced EOC. These results suggest an interaction between ascites TNF-α and IL-6 in driving tumor progression and resistance to chemotherapy in advanced EOC, and raise the potential for pre-treatment ascites levels of these cytokines as prognostic biomarkers. This study involved a small sample of patients and was an exploratory analysis; therefore, findings require validation in a larger independent cohort.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Ascites; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Female; Humans; Interleukin-6; Interleukin-8; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Survival Rate; Tumor Necrosis Factor-alpha; Young Adult

Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated.. The role of NF-κB in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF-κB inhibitor DHMEQ.. In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF-κB inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor-κB inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells.. NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment.

Topics: Adoptive Transfer; Animals; Arginase; Benzamides; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Culture Media, Conditioned; Cyclohexanones; Dendritic Cells; Female; Humans; Immune Tolerance; Interleukin-6; Interleukin-8; Macrophages; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Signal Transduction; Transcription Factor RelA; Transplantation, Heterologous

Pro-inflammatory mechanisms may explain the increased ovarian cancer risk linked to more lifetime ovulations, endometriosis, and exposure to talc and asbestos, as well as decreased risk with non-steroidal anti-inflammatory drugs. Limited data are available to estimate ovarian cancer risk associated with levels of circulating inflammatory markers.. We conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Pre-diagnostic serum levels of 46 inflammation-related biomarkers (11 with a priori hypotheses; 35 agnostic) were measured in 149 incident ovarian cancer cases and 149 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression and adjusted for identified covariates.. Increased ovarian cancer risk was associated with elevated levels of C-reactive protein (CRP) [tertile (T)3 vs. T1: OR (95% CI) 2.04 (1.06-3.93), p-trend=0.03], interleukin (IL)-1α [detectable vs. undetectable: 2.23 (1.14-4.34)] and tumor necrosis factor alpha (TNF-α) [T3 vs. T1: 2.21 (1.06-4.63), p-trend=0.04]. Elevated IL-8 was non-significantly associated with risk [T3 vs. T1: 1.86 (0.96-3.61), p-trend=0.05]. In analyses restricted to serous ovarian cancer (n=83), the associations with CRP and IL-8 remained or strengthened [CRP T3 vs. T1: 3.96 (1.14-11.14), p-trend=0.008; IL-8 T3 vs. T1: 3.05 (1.09-8.51), p-trend=0.03]. Elevated levels of CRP and TNF-α remained positively associated with ovarian cancer risk in analysis restricted to specimens collected at least 5years before diagnosis (n=56).. These results suggest that CRP, IL-1α, IL-8, and TNF-α are associated with increased risk of subsequently developing ovarian cancer.

Topics: Aged; Biomarkers, Tumor; C-Reactive Protein; Carcinoma, Ovarian Epithelial; Case-Control Studies; Early Detection of Cancer; Female; Humans; Inflammation; Interleukin-1alpha; Interleukin-8; Logistic Models; Middle Aged; Neoplasms, Glandular and Epithelial; Odds Ratio; Ovarian Neoplasms; Risk; Tumor Necrosis Factor-alpha

A high expression of O-glycosylated proteins is one of the prominent characteristics of ovarian carcinoma cells associated with cell migration, which would be attributed to the upregulated expression of glycosyltransferases. Therefore, elucidating glycosyltransferases and their substrates may improve our understanding of their roles in tumor metastasis. In the present study, we reported that knockdown of polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14) by small interfering RNA significantly suppressed the cell migration and altered cellular morphology. Immunoprecipitation and western blot analyses indicated that GALNT14 contributed to the glycosylation of transmembrane mucin 13 (MUC13), which was significantly higher in ovarian cancer cells compared with the normal/benign ovary tissues. Furthermore, interleukin-8 (IL-8), which could regulate the migration ability of epithelial ovarian cancer (EOC) cells, had no remarkable effect on the expression of GALNT14 and the tumor-associated carbohydrate epitope Tn antigen. In addition, extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor modulated the expression levels of GALNT14. Our findings provide evidence that GALNT14 may contribute to ovarian carcinogenesis through aberrant glycosylation of MUC13, but not through the IL-8 pathway. These data provide novel insights into understanding the function of MUC13 on neoplasm metastasis and may aid in the development of new anticancer drugs for EOC.

Topics: Antigens, Tumor-Associated, Carbohydrate; Carcinogenesis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Movement; Female; Glycosylation; Humans; Interleukin-8; MAP Kinase Signaling System; Mucins; N-Acetylgalactosaminyltransferases; Neoplasm Metastasis; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Polypeptide N-acetylgalactosaminyltransferase

Ovarian Cancer is the leading cause of death from gynecological malignancy. The poor prognosis is mainly due to presentation at a late stage and poor response to therapy. Much research is needed to identify diagnostic and prognostic biomarkers as well as therapeutic targets for ovarian cancer. Interleukin-8 is expressed by many tumour types and is known to have mitogenic, motogenic and angiogenic effects on tumour cells.. The aim of this study was to investigate the expression of IL-8 and IL-8 receptors (IL-8RA and IL-8RB) in different histological subtypes of ovarian tumours, as potential prognostic biomarkers in ovarian tumours.. Immunohitochemistry was used to study the expression of IL-8 and IL-8 receptors in 115 ovarian tumours including 21 benign tumours, 25 borderline tumours and 69 carcinomas of serous, clear cell, endometrioid and mucinous types. The correlation of expression profile, tumour type, stage, and progression free survival and overall survival was statistically analysed.. IL-8 and IL-8 receptors were expressed in all types of tumours with variable intensity and subcellular distribution. There was a statistically significant correlation between levels of expression and tumour stage and tumour type, being mostly significant in serous tumours. No correlation with patient progression free survival or overall survival was found.. This is the first study investigating the expression of IL-8 and IL-8 receptors using immunohistochemistry in different types of ovarian tumours, including benign and borderline tumours. IL-8 and IL-8RA are potential prognostic biomarkers and therapeutic targets in ovarian cancer, particularly in ovarian serous carcinoma.

Topics: Adenocarcinoma, Clear Cell; Adenocarcinoma, Mucinous; Biomarkers, Tumor; Carcinoma, Endometrioid; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous; Disease-Free Survival; Female; Humans; Interleukin-8; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Receptors, Interleukin-8; Survival

The acellular fraction of epithelial ovarian cancer (EOC) ascites promotes de novo resistance of tumor cells and thus supports the idea that tumor cells may survive in the surrounding protective microenvironment contributing to disease recurrence. Levels of the pro-inflammatory cytokines IL-6 and IL-8 are elevated in EOC ascites suggesting that they could play a role in tumor progression.. We measured IL-6 and IL-8 levels in the ascites of 39 patients with newly diagnosed EOC. Commercially available enzyme-linked immunosorbent assay (ELISA) was used to determine IL-6 and IL-8 ascites levels. Ascites cytokine levels were correlated with clinicopathological parameters and progression-free survival.. Mean ascites levels for IL-6 and IL-8 were 6419 pg/ml (SEM: 1409 pg/ml) and 1408 pg/ml (SEM: 437 pg/ml) respectively. The levels of IL-6 and IL-8 in ascites were significantly lower in patients that have received prior chemotherapy before the surgery (Mann-Whitney U test, P = 0.037 for IL-6 and P = 0.008 for IL-8). Univariate analysis revealed that high IL-6 ascites levels (P = 0.021), serum CA125 levels (P = 0.04) and stage IV (P = 0.009) were significantly correlated with shorter progression-free survival. Including these variables in a multivariate analysis revealed that elevated IL-6 levels (P = 0.033) was an independent predictor of shorter progression-free survival.. Elevated IL-6, but not IL-8, ascites level is an independent predictor of shorter progression-free survival.

Topics: Ascites; Carcinoma, Ovarian Epithelial; Female; Humans; Interleukin-6; Interleukin-8; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Survival Analysis

Epithelial ovarian cancer is the leading cause of cancer death from gynecological malignancies. Angiogenesis is considered essential for tumor growth and the development of metastases. VEGF, IL-8, beta-FGF are potent angiostimulatory molecules and their expression has been demonstrated in many solid tumors, including ovarian cancer. The aim of this study was to compare the levels of VEGF, IL-8 and beta-FGF in the serum and ascites of patients with ovarian cancer VEGF, IL-8, beta-FGF concentrations were measured by ELISA (Quantikine R&D). The median VEGF, IL-8 and beta-FGF levels were significantly higher in the ascites than sera of ovarian cancer patient. VEGF, IL-8, beta-FGF levels in ascites might be regarded as an additional tool in the diagnosis of ovarian cancer.

Topics: Ascitic Fluid; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Vascular Endothelial Growth Factor A; Women's Health