Unknown,Transcriptomics,Genomics,Proteomics

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Inflammatory gene profiling of Ewing sarcoma family of tumors (set B)

ABSTRACT: Purpose: Unlike in most adult-onset cancers, an association between typical paediatric neoplasms and inflammatory triggers is rare. We studied whether immune system related genes are activated and have prognostic significance in Ewing sarcoma family of tumours (ESFT). Experimental design: Data-analysis was performed on gene expression profiles of 44 ESFT patient, 11 ESFT cell line, and 18 normal muscle tissue samples. 238 inflammation related genes were selected based on literature and a macrophage gene expression signature was derived from SymAtlas. Differential expression of the genes was analysed by t-test and survival analysis was performed according to gene expression. Results: Inflammatory genes are activated in ESFT patient samples, as 38 of 238 (16%) inflammatory genes were significantly upregulated (p<0.001) when compared to ESFT cell lines. This inflammatory gene activation was characterized by significant enrichment of macrophage related gene expression with 58 of 299 (19%) of these genes being upregulated (p<0.001). By combining expression data from ESFT patients, cell lines and muscle tissue samples we were able to identify a total of 32 presumptive inflammatory genes that characterize and distinguish tumour site in vivo from surrounding normal tissues. High expression of C5 correlated with better event free (p=0.01) and overall survival (p=0.004) in dose dependent manner. C5 and its receptor C5aR1 expression was verified at protein level by immunohistochemistry on tumor tissue microarray. Also, high expression of JAK1 correlated with favourable overall survival (p=0.04) and high expression of IL8, derived presumably from infiltrating immune cells, resulted in poor overall survival in Ewing sarcoma (p=0.04). Conclusions: Immune system related gene activation is observed in ESFT patient samples and several prognostically significant inflammatory genes (C5, JAK1 and IL8) for ESFT were identified. 44 Ewing sarcoma family of tumor patient and 18 normal muscle samples obtained from GSE6798 and GSE3526.

ORGANISM(S): Homo sapiens

SUBMITTER: Suvi Savola

PROVIDER: E-GEOD-17674 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Purpose: Unlike in most adult-onset cancers, an association between typical paediatric neoplasms and inflammatory triggers is rare. We studied whether immune system related genes are activated and have prognostic significance in Ewing sarcoma family of tumours (ESFT). Experimental design: Data-analysis was performed on gene expression profiles of 44 ESFT patient, 11 ESFT cell line, and 18 normal muscle tissue samples. 238 inflammation related genes were selected based on literature and a macrophage gene expression signature was derived from SymAtlas. Differential expression of the genes was analysed by t-test and survival analysis was performed according to gene expression. Results: Inflammatory genes are activated in ESFT patient samples, as 38 of 238 (16%) inflammatory genes were significantly upregulated (p<0.001) when compared to ESFT cell lines. This inflammatory gene activation was characterized by significant enrichment of macrophage related gene expression with 58 of 299 (19%) of these genes being upregulated (p<0.001). By combining expression data from ESFT patients, cell lines and muscle tissue samples we were able to identify a total of 32 presumptive inflammatory genes that characterize and distinguish tumour site in vivo from surrounding normal tissues. High expression of C5 correlated with better event free (p=0.01) and overall survival (p=0.004) in dose dependent manner. C5 and its receptor C5aR1 expression was verified at protein level by immunohistochemistry on tumor tissue microarray. Also, high expression of JAK1 correlated with favourable overall survival (p=0.04) and high expression of IL8, derived presumably from infiltrating immune cells, resulted in poor overall survival in Ewing sarcoma (p=0.04). Conclusions: Immune system related gene activation is observed in ESFT patient samples and several prognostically significant inflammatory genes (C5, JAK1 and IL8) for ESFT were identified. 44 Ewing sarcoma family of tumor patient and 11 cell line samples were analysed for their gene expression.

Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

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Inflammatory gene profiling of Ewing sarcoma family of tumors (set B)

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