Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The bone marrow microenvironment in patients with neuroblastoma: presence of IFN signature and significant down-regulation of CXCL12 expression

ABSTRACT: Neuroblastoma (NB) is the most common extra cranial solid tumor in infants. Although several risk factors including patient age, disease stage and genetic abnormalities, such as MYCN amplification and 11q deletion, have been shown to predict outcome, the mechanisms responsible for the heterogeneous clinical behavior of this tumor, ranging from spontaneous regression to rapid progression of disease and patient’s death, remain largely unknown. Patients with disseminated disease mainly show metastasis at bone marrow (BM) and bone. The presence of metastasis is an independent unfavorable prognostic factor for NB patients over 18 months of age at diagnosis, whose event-free and overall survivals are grim despite intensive multimodal therapies. We decided to investigate the transcriptome of both NB metastatic cells and resident hematopoietic BM cells to get insight on potential targets for diagnostic, prognostic and therapeutic purposes. Hereby, we report on the results obtained by comparing BM resident hematopoietic cells in the presence and absence of infiltrating NB hematopoietic cells with BM cells from young healthy donors. We analyzed gene expression profiles of 40 bone marrow samples: 8 from healthy young donor; 23 from NB patients with stage 1, 2, 3; 9 from NB patients with stage 4.

ORGANISM(S): Homo sapiens

SUBMITTER: PAOLA SCARUFFI

PROVIDER: E-GEOD-25624 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Neuroblastoma (NB) is a pediatric tumor with a heterogeneous presentation at diagnosis. Fifty per cent of patients present with localized disease (stage L1/L2) whereas the other half have metastatic disease (stage M), mainly involving the bone marrow (BM). In these latter patients the physical occupancy of the BM space by metastatic NB cells has been thought to be responsible for impairment of BM function. Here, based on gene expression profiles of BM resident cells obtained in a large number of stage L and stage M NB patients, as compared to gene expression profiles of BM resident cells from healthy subjects, we investigated whether the tumor growth, either at distance or locally, affected hematopoietic lineages' maturation and release of mature hematopoietic cells in the periphery (PB). Our investigation clearly demonstrated that in children with NB, regardless of the presence of metastatic cells in the BM, there was a selective impairment of erythrocyte maturation at the ortho-chromic stage. In the BM, all the other cell lineages were un-affected. The altered erythrocyte maturation resulted in a reduced amount, and increased RWD, of PB erythrocytes. In PB samples from patients with stage L disease a significant increase in the number of mature neutrophils was observed, suggesting that in these NB patients innate immunity was activated. No increase occurred in PB of stage M NB patients. Although the cause of the selective impairment of erythrocyte maturation, as well as that of the activation of innate immunity in stage L NB patients remained elusive, our observations allowed to fully refusing the tenet that BM-infiltrating NB cells affected physiological BM functions due to physical occupancy of the BM space. In addition, these findings open the way to a new area of research not only in NB and other clinically similar pediatric cancers, such as rhabdos and sarcomas, but also in adult cancers metastasizing in the BM. Looking more carefully to the BM microenvironment could help discovering novel targets for innovative therapeutic approaches.

Project description:Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor. The aim of our study was to understand which mechanisms are involved in aberrant activation of Wnt pathway and its association with MB tumor development. We studied the expression profiles of 19 MBs tumors using a genome-wide approach, furthermore we have included the data obtained from four independent public Datasets of gene expression (see README file below) to increase the statistical power of the study. The expression profiles identified the Wnt inhibitor gene, DKK3, significant down-regulated. DKK3 down-regulation was confirmed by qPCR in 80% of samples (27/33 MB tumors and in 3/5 MB human cell lines). Since DKK3 was found methylated in several cancers we also investigated the status of methylated CpG sites within the three promoters by a combination of two approaches: the MSP and pyrosequencing. MSP showed no methylation in all promoters while the pyrosequencing, a quantitative technique, indicated a very low level of methylation. To verify the epigenetic involvement on DKK3 silencing, we also studied the effect of Trichostatin A (TSA) in 4 MB cell lines (DAOY; D283; D425; D458). After TSA treatment we observed a significant DKK3 mRNA expression increase in 3/4 cell lines compared to the no treated cells. DAOY cells, that have a normal DKK3 expression value, did not change significantly the DKK3 expression after TSA treatment. To further validate the role of histone tail modifications as an epigenetic silencing mechanism for DKK3 in MB, we performed Chromatin Immunoprecipitation (ChIP) experiment using antibodies against acetylated histones. According to our earlier results, TSA treatment increased the signal of the histone modification meH3K4 which is related to a transcriptionally active gene respect to the untreated controls. Finally, we evaluated the DKK3 protein in three MB cell lines (DAOY; D283; D425) after 24h of TSA treatment, by immunofluorescence. We analysed 19 Medulloblastoma tumor from pediatric patients, a commercial pool (Clontech) of 24 normal cerebellum from female and male Caucasians (ages: 16-70 years; cause of death: sudden death) and a pool of 10 normal cerebellum from children (6 Caucasians and 4 African Americans; ages: 0-16 years; cause of death: sudden death) using 44K whole genome oligonucleotids microarray

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The bone marrow microenvironment in patients with neuroblastoma: presence of IFN signature and significant down-regulation of CXCL12 expression

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