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The Development of an Angiogenic Protein "Signature" in Ovarian Cancer Ascites as a Tool for Biologic and Prognostic Profiling.

ABSTRACT: Advanced ovarian cancer (AOC) is one of the leading lethal gynecological cancers in developed countries. Based on the important role of angiogenesis in ovarian cancer oncogenesis and expansion, we hypothesized that the development of an "angiogenic signature" might be helpful in prediction of prognosis and efficacy of anti-angiogenic therapies in this disease. Sixty-nine samples of ascitic fluid- 35 from platinum sensitive and 34 from platinum resistant patients managed with cytoreductive surgery and 1st-line carboplatin-based chemotherapy- were analyzed using the Proteome ProfilerTM Human Angiogenesis Array Kit, screening for the presence of 55 soluble angiogenesis-related factors. A protein profile based on the expression of a subset of 25 factors could accurately separate resistant from sensitive patients with a success rate of approximately 90%. The protein profile corresponding to the "sensitive" subset was associated with significantly longer PFS (8 [95% Confidence Interval {CI}: 8-9] vs. 20 months [95% CI: 15-28]; Hazard ratio {HR}: 8.3, p<0.001) and OS (20.5 months [95% CI: 13.5-30] vs. 74 months [95% CI: 36-not reached]; HR: 5.6 [95% CI: 2.8-11.2]; p<0.001). This prognostic performance was superior to that of stage, histology and residual disease after cytoreductive surgery and the levels of vascular endothelial growth factor (VEGF) in ascites. In conclusion, we developed an "angiogenic signature" for patients with AOC, which can be used, after appropriate validation, as a prognostic marker and a tool for selection for anti-angiogenic therapies.

SUBMITTER: Trachana SP

PROVIDER: S-EPMC4892506 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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The Development of an Angiogenic Protein "Signature" in Ovarian Cancer Ascites as a Tool for Biologic and Prognostic Profiling.

Trachana Sofia-Paraskevi SP Pilalis Eleftherios E Gavalas Nikos G NG Tzannis Kimon K Papadodima Olga O Liontos Michalis M Rodolakis Alexandros A Vlachos Georgios G Thomakos Nikolaos N Haidopoulos Dimitrios D Lykka Maria M Koutsoukos Konstantinos K Kostouros Efthimios E Terpos Evagelos E Chatziioannou Aristotelis A Dimopoulos Meletios-Athanasios MA Bamias Aristotelis A

PloS one 20160603 6

Advanced ovarian cancer (AOC) is one of the leading lethal gynecological cancers in developed countries. Based on the important role of angiogenesis in ovarian cancer oncogenesis and expansion, we hypothesized that the development of an "angiogenic signature" might be helpful in prediction of prognosis and efficacy of anti-angiogenic therapies in this disease. Sixty-nine samples of ascitic fluid- 35 from platinum sensitive and 34 from platinum resistant patients managed with cytoreductive surger ...[more]

PMID: 27258020

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Project description:BackgroundThe behavior of tumor cells is influenced by the composition of the surrounding tumor environment. The importance of ascites in ovarian cancer (OC) progression is being increasingly recognized. The characterization of soluble factors in ascites is essential to understand how this environment affects OC progression. The development of cytokine arrays now allows simultaneous measurement of multiple cytokines per ascites using a single array.MethodsWe applied a multiplex cytokine array technology that simultaneously measures the level of 120 cytokines in ascites from 10 OC patients. The ascites concentration of a subset (n = 5) of cytokines that was elevated based on the multiplex array was validated by commercially available ELISA. The ascites level of these 5 cytokines was further evaluated by ELISA in a cohort of 38 patients. Kaplan-Meier analysis was used to assess the association of cytokine expression with progression-free survival (PFS) in this cohort.ResultsWe observed a wide variability of expression between different cytokines and levels of specific cytokines also varied in the 10 malignant ascites tested. Fifty-three (44%) cytokines were not detected in any of the 10 ascites. The level of several factors including, among others, angiogenin, angiopoietin-2, GRO, ICAM-1, IL-6, IL-6R, IL-8, IL-10, leptin, MCP-1, MIF NAP-2, osteprotegerin (OPG), RANTES, TIMP-2 and UPAR were elevated in most malignant ascites. Higher levels of OPG, IL-10 and leptin in OC ascites were associated with shorter PFS. IL-10 was shown to promote the anti-apoptotic activity of malignant ascites whereas OPG did not.ConclusionOur data demonstrated that there is a complex network of cytokine expression in OC ascites. Characterization of cytokine profiles in malignant ascites may provide information from which to prioritize key functional cytokines and understand the mechanism by which they alter tumor cells behavior. A better understanding of the cytokine network is essential to determine the role of ascites in OC progression.

Project description:Purpose: Considerable evidence suggests that autophagy plays a crucial role in the biological processes of ovarian cancer. The aim of this study was to develop a novel autophagy-related prognostic signature for serous ovarian cancer. Methods: A univariate Cox proportional regression model was used to analyze mRNA microarray and clinical data in The Cancer Genome Atlas (TCGA) for the purpose of selecting autophagy-related prognostic genes. A multivariate Cox proportional regression model and the survival analysis were used to develop an eight-gene prognostic signature. The multivariate Cox and stratification analysis suggested that this signature was an independent prognostic factor for serous ovarian cancer patients. Bioinformatics functions were investigated by a principal components analysis and gene set enrichment analysis (GSEA). Finally, the correlation between the prognostic signature and gene mutation status was further analyzed in serous ovarian cancer, and especially with regard to the mutation status of BRCA1 and BRCA2 (BRCA1/2) genes. Results: Distinctly different autophagy-related gene expression profiles were identified in normal ovarian tissues and serous ovarian cancer tissues. We profiled an autophagy-related gene set and identified eight genes with significant prognostic values for serous ovarian cancer. Subsequently, an autophagy-related ovarian cancer risk signature was constructed, and patients at a high-risk or low-risk for poor prognosis were identified based on their signature. High-risk patients had significantly shorter overall survival (OS) and disease-free survival (DFS) times than low-risk patients. GSEA results suggested an enhanced intensity of autophagy regulation in high-risk patients when compared with low-risk patients. When studied as an independent prognostic factor for serous ovarian cancer, the significant prognostic value of this signature could be seen in the stratified cohorts. For clinical use, we developed a nomogram that included the prognostic classifier and seven clinical risk factors. Additionally, we identified the 10 most frequently mutated genes found in serous ovarian cancer patients, and analyzed them for their differences in high-risk and low-risk patients. Among 293 patients, 62 had BRCA1/2 gene mutations, and this result was significantly correlated with the autophagy-related prognostic signature. Conclusions: Our findings suggest that the eight-gene autophagy-related signature could serve as an independent prognostic indicator for cases of serous ovarian cancer.

Dataset Information

The Development of an Angiogenic Protein "Signature" in Ovarian Cancer Ascites as a Tool for Biologic and Prognostic Profiling.

Publications

The Development of an Angiogenic Protein "Signature" in Ovarian Cancer Ascites as a Tool for Biologic and Prognostic Profiling.

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