Abstract
Neuroblastoma is a heterogeneous pediatric tumor thought to arise from the embryonic neural crest. Identification of the cell responsible for propagating neuroblastomas is essential to understanding this often recurrent, rapidly progressing disease. We have isolated and characterized putative tumor-initiating cells from 16 tumors and bone marrow metastases from patients in all neuroblastoma risk groups. Dissociated cells from tumors or bone marrow grew as spheres in conditions used to culture neural crest stem cells, were capable of self-renewal, and exhibited chromosomal aberrations typical of neuroblastoma. Primary spheres from all tumor risk groups differentiated under neurogenic conditions to form neurons. Tumor spheres from low-risk tumors frequently formed large neuronal networks, whereas those from high-risk tumors rarely did. As few as 10 passaged tumor sphere cells from aggressive neuroblastoma injected orthotopically into severe combined immunodeficient/Beige mice formed large neuroblastoma tumors that metastasized to liver, spleen, contralateral adrenal and kidney, and lung. Furthermore, highly tumorigenic tumor spheres were isolated from the bone marrow of patients in clinical remission, suggesting that this population of cells may predict clinical behavior and serve as a biomarker for minimal residual disease in high-risk patients. Our data indicate that high-risk neuroblastoma contains a cell with cancer stem cell properties that is enriched in tumor-initiating capacity. These cells may serve as a model system to identify the molecular determinants of neuroblastoma and to develop new therapeutic strategies for this tumor.
Highlights
Neuroblastoma is an embryonal tumor of the autonomic nervous system and the most common extracranial solid tumor of childhood
We show that cells from all risk groups of neuroblastoma can be propagated as neurospheres in minimal medium with basic fibroblast growth factor 2 (bFGF) and epidermal growth factor (EGF)
Our characterization of these cells support the following conclusions: (a) sphere-forming cells from high-risk tumors expressed markers of neural crest stem cells and clinical markers of neuroblastoma; (b) cells from high-risk tumors self-renewed at a higher frequency than those from low-risk tumors; (c) cells from all tumor risk groups were capable of differentiating into neurons, but only cells from low-risk neuroblastoma tumors formed complex neural networks; (d) cells from high-risk tumors formed metastatic tumors in a murine xenograft model with as few as 10 cells and could be serially passaged in immunocompromised mice; and (e) tumor formation and growth was accelerated by enriching for cells expressing the cell surface markers CD24 and CD34
Summary
Neuroblastoma is an embryonal tumor of the autonomic nervous system and the most common extracranial solid tumor of childhood. Growing evidence exists to support the hypothesis that a reservoir of tumor cells within a tumor that share similar properties to normal stem cells drives tumorigenesis and results in aberrantly programmed and differentiated cells [2] This subpopulation of cells has been termed cancer stem cells or tumorinitiating cells (TIC) and have been described in adult leukemia [3], breast cancer [4], pediatric brain tumors [5, 6], melanoma [7], ependymomas [8], colon cancer [9, 10], and head and neck squamous cell carcinoma [11] based on their abilities to self-renew, differentiate into the cellular lineages observed in the tumors from which they were derived, and serially propagate tumors in vivo
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