Unknown,Transcriptomics,Genomics,Proteomics

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Comparative genomic hybridization by array of human tumor cells with stem-like properties isolated from pediatric brain tumors

ABSTRACT: Background
Primitive brain tumors are the first cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined.
Methodology/Principal findings
Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). The vast majority (10/12) of high-grade glioma-derived oncospheres sustained long-term self-renewal numbers akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumor types. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P=0.05, chi-square test). TSCs shared a complex molecular profile combining embryonic stem cell markers with elements controlling neural stem cell properties and epithelio-mesenchymal transitions. They were radio- and chemoresistant and formed aggressive tumors after intracerebral grafting. Survival analysis of the cohort showed an association between isolation of TSCs with long-term self-renewal abilities and a patients higher mortality rate (P = 0.022, log-rank test). Patients bearing cells with limited self-renewal properties constituted an intermediate group of survival but which did not reach statistical significance.
Conclusions/Significance
In brain tumors affecting adult patients, TSC have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

ORGANISM(S): Homo sapiens

DISEASE(S): normal

SUBMITTER: Marie-Pierre Junier

PROVIDER: E-MEXP-2909 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background Primitive brain tumors are the first cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. Methodology/Principal findings Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). The vast majority (10/12) of high-grade glioma-derived oncospheres sustained long-term self-renewal numbers akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumor types. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P=0.05, chi-square test). TSCs shared a complex molecular profile combining embryonic stem cell markers with elements controlling neural stem cell properties and epithelio-mesenchymal transitions. They were radio- and chemoresistant and formed aggressive tumors after intracerebral grafting. Survival analysis of the cohort showed an association between isolation of TSCs with long-term self-renewal abilities and a patientM-^Rs higher mortality rate (P = 0.022, log-rank test). Patients bearing cells with limited self-renewal properties constituted an intermediate group of survival but which did not reach statistical significance. Conclusions/Significance In brain tumors affecting adult patients, TSC have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

Project description:BACKGROUND: While many authorities theorize that cancer vaccines are too weak to be widely effective, there are quite a few reports with clearly demonstrated, significant clinical benefit in some patients. The literature of cellular cancer immunotherapies shows that 53% (78/147) of phase II studies showed evidence of clinical activity. While not all reached their primary endpoints, 75% (12/16) of phase III studies had positive data. SV-BR-1-GM, derived from a patient with grade 2 (moderately differentiated) breast cancer, is a GM-CSF-secreting breast cancer cell line with properties of antigen-presenting cells we established. METHODS: We report detailed molecular and clinical findings from an open-label phase I, single-arm pilot study in breast (3 subjects) and ovarian (1 subject) cancer with irradiated SV-BR-1-GM cells (ClinicalTrials.gov Identifier NCT00095862). Inoculations of SV-BR-1-GM were preceded by low-dose cyclophosphamide and followed by injections of interferon-alpha2b into the SV-BR-1-GM inoculation sites. We assessed both cellular (delayed-type hypersensitivity (DTH) reactions) and humoral (anti-SV-BR-1 antibody) immune responses and conducted molecular analyses on patient blood cells and SV-BR-1-GM cells. RESULTS: Treatment was generally safe and well tolerated. Immune responses were elicited universally. Overall survival was more than 33 months for three of the four patients. As previously reported, one patient (Subject A002, with grade 2 breast cancer) had regression of metastases in lung, breast and soft tissue within 2 months of treatment initiation. At later relapse, with multiple metastases including several in the brain, rapid tumor response was again seen, including complete regression of CNS metastases. Consistent with a role of Class II HLA in contributing to SV-BR-1-GM’s mechanism of action, Subject A002 allele-matched SV-BR-1-GM at the HLA-DRB1 and HLA-DRB3 loci. Only the HLA-DRB1 alleles were clearly expressed in SV-BR-1-GM cells. However, interferon-gamma (possibly also present in situ) upregulated both HLA-DRB1 and HLA-DRB3 to substantial levels. Gene expression data supports the hypothesis that SV-BR-1-GM cells have retained some of the original breast cancer’s grade 2 character. CONCLUSIONS: We describe a whole-cell immunotherapy regimen with remarkable rapidity of response and a speedy rescue response, including complete resolution of CNS metastases after relapse. Class II HLA matches might be critical for SV-BR-1-GM’s therapeutic potential.

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Comparative genomic hybridization by array of human tumor cells with stem-like properties isolated from pediatric brain tumors

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