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Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells.

ABSTRACT: Neuroblastoma (NB)-associated endothelial microvessels (EMs) may be lined by tumor-derived endothelial cells (TECs), that are genetically unstable and chemoresistant. Here we have addressed the identification of TEC progenitors in NB by focusing on Octamer-binding transcription factor 4 (Oct-4) as a putative marker. Oct-4(+) cells were detected in primary NB samples (n = 23), metastatic bone marrow aspirates (n = 10), NB cell lines (n = 4), and orthotopic tumors (n = 10) formed by the HTLA-230 NB cell line in immunodeficient mice. Most Oct-4(+) cells showed a perivascular distribution, with 5% of them homing in perinecrotic areas. All Oct-4(+) cells were tumor-derived since they shared amplification of MYCN oncogene with malignant cells. Perivascular Oct-4(+) cells expressed stem cell-related, neural progenitor-related and NB-related markers, including surface Tenascin C (TNC), that was absent from perinecrotic Oct-4(+) cells and bulk tumor cells. TNC(+) but not TNC(-) HTLA-230 cells differentiated in vitro into endothelial-like cells expressing vascular-endothelial-cadherin, prostate-specific membrane antigen and CD31 upon culture in medium containing vascular endothelial growth factor (VEGF). TNC(+) but not TNC(-) HTLA-230 cells formed neurospheres when cultured in serum-free medium. Both cell fractions were tumorigenic, but only tumors formed by TNC(+) cells contained EMs lined by TECs. In conclusion, we have identified in NB tumors two putative niches containing Oct-4(+) tumor cells. Oct-4(+)/TNC(+) perivascular NB cells displayed a high degree of plasticity and served as progenitors of TECs. Therapeutic targeting of Oct4(+)/TNC(+) progenitors may counteract the contribution of NB-derived ECs to tumor relapse and chemoresistance.

SUBMITTER: Pezzolo A

PROVIDER: S-EPMC3193450 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells.

Pezzolo Annalisa A Parodi Federica F Marimpietri Danilo D Raffaghello Lizzia L Cocco Claudia C Pistorio Angela A Mosconi Manuela M Gambini Claudio C Cilli Michele M Deaglio Silvia S Malavasi Fabio F Pistoia Vito V

Cell research 20110315 10

Neuroblastoma (NB)-associated endothelial microvessels (EMs) may be lined by tumor-derived endothelial cells (TECs), that are genetically unstable and chemoresistant. Here we have addressed the identification of TEC progenitors in NB by focusing on Octamer-binding transcription factor 4 (Oct-4) as a putative marker. Oct-4(+) cells were detected in primary NB samples (n = 23), metastatic bone marrow aspirates (n = 10), NB cell lines (n = 4), and orthotopic tumors (n = 10) formed by the HTLA-230 N ...[more]

PMID: 21403679

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Project description:BackgroundIt has been proposed that mesenchymal stromal cells (MSCs) promote tumor progression by interacting with tumor cells and other stroma cells in the complex network of the tumor microenvironment. We characterized MSCs isolated and expanded from tumor tissues of pediatric patients diagnosed with neuroblastomas (NB-MSCs) to define interactions with the tumor microenvironment.MethodsSpecimens were obtained from 7 pediatric patients diagnosed with neuroblastoma (NB). Morphology, immunophenotype, differentiation capacity, proliferative growth, expression of stemness and neural differentiation markers were evaluated. Moreover, the ability of cells to modulate the immune response, i.e. inhibition of phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cytotoxic function, was examined. Gene expression profiles, known to be related to tumor cell stemness, Wnt pathway activation, epithelial-mesenchymal transition (EMT) and tumor metastasis were also evaluated. Healthy donor bone marrow-derived MSCs (BM-MSC) were employed as controls.ResultsNB-MSCs presented the typical MSC morphology and phenotype. They showed a proliferative capacity superimposable to BM-MSCs. Stemness marker expression (Sox2, Nanog, Oct3/4) was comparable to BM-MSCs. NB-MSC in vitro osteogenic and chondrogenic differentiation was similar to BM-MSCs, but NB-MSCs lacked adipogenic differentiation capacity. NB-MSCs reached senescence phases at a median passage of P7 (range, P5-P13). NB-MSCs exhibited greater immunosuppressive capacity on activated T lymphocytes at a 1:2 (MSC: PBMC) ratio compared with BM-MSCs (p?=?0.018). NK cytotoxic activity was not influenced by co-culture, either with BM-MSCs or NB-MSCs. Flow-cytometry cell cycle analysis showed that NB-MSCs had an increased number of cells in the G0-G1 phase compared to BM-MSCs. Transcriptomic profiling results indicated that NB-MSCs were enriched with EMT genes compared to BM-MSCs.ConclusionsWe characterized the biological features, the immunomodulatory capacity and the gene expression profile of NB-MSCs. The NB-MSC gene expression profile and their functional properties suggest a potential role in promoting tumor escape, invasiveness and metastatic traits of NB cancer cells. A better understanding of the complex mechanisms underlying the interactions between NB cells and NB-derived MSCs should shed new light on potential novel therapeutic approaches.

Project description:Mesenchymal stem cells (MSCs) are currently thought to transdifferentiate into neural lineages under specific microenvironments. Studies have reported that the tenascin family members, tenascin-C (TnC) and tenascin-R (TnR), regulate differentiation and migration, in addition to neurite outgrowth and survival in numerous types of neurons and mesenchymal progenitor cells. However, the mechanisms by which TnC and TnR affect neuronal differentiation are not well understood. In this study, we hypothesized that different forms of tenascin might regulate the neural transdifferentiation of human bone marrow-derived mesenchymal stem cells. Human MSCs were cultured in media incorporated with soluble tenascins, or on precoated tenascins. In a qualitative polymerase chain reaction analysis, adding a soluble TnC and TnR mixture to the medium significantly enhanced the expression of neuronal and glial markers, whereas no synaptic markers were expressed. Conversely, in groups of cells treated with coated TnC, hMSCs showed neurite outgrowth and synaptic marker expression. After being treated with coated TnR, hMSCs exhibited neuronal differentiation; however, it inhibited neurite outgrowth and synaptic marker expression. A combination of TnC and TnR significantly promoted hMSC differentiation in neurons or oligodendrocytes, induced neurite formation, and inhibited differentiation into astrocytes. Furthermore, the effect of the tenascin mixture showed dose-dependent effects, and a mixture ratio of 1:1 to 1:2 (TnC:TnR) provided the most obvious differentiation of neurons and oligodendrocytes. In a functional blocking study, integrin ?7 and ?9?1-blocking antibodies inhibited, respectively, 80% and 20% of mRNA expression by hMSCs in the coated tenascin mixture. In summary, the coated combination of TnC and TnR appeared to regulate neural differentiation signaling through integrin ?7 and ?9?1 in bone marrow-derived hMSCs. Our findings demonstrate novel mechanisms by which tenascin regulates neural differentiation, and enable the use of cell therapy to treat neurodegenerative diseases.

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Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells.

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Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells.

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