Neuroblastoma Cells Isolated from Bone Marrow Metastases Contain a Naturally Enriched Tumor-Initiating Cell

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 tumorinitiating 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.

Expression of neural stem cell markers in malignant rhabdoid tumor cell lines

“…The function of CD133 has not been established, but it may participate in the regulation of membrane topology (48). Recent data revealed that CD133 is highly expressed in CSC populations (24,25,(34)(35)(36)(37)(38) and high CD133 expression in STM91-01 was confirmed in our study. By the differentiation induction with 4-HPR, CD133 mRNA expression was gradually decreased.…”

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

“…CD133, βIII tubulin, c-kit and nestin are expressed by NB progenitor cells [15,[46][47][48]. CD24 identifies a tumor-initiating cell population in BM metastatic NB, and NB84 has been detected in neurospheres thereof [65]. Besides being neuroblastic markers, CD56 [66] is expressed by immature and TECs, and GD2 by mesenchymal stem cells [67].…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…Recently, David Kaplan's laboratory isolated neuroblastoma cells from patient bone marrows and showed that these cells grow and form neurospheres in neural stem cell promoting medium (Hansford et al 2007). These cells are highly tumorigenic in an orthotopic xenograft mouse model (Hansford et al 2007) and are, by this functional definition, tumor-initiating cells (TICs).…”

“…These cells are highly tumorigenic in an orthotopic xenograft mouse model (Hansford et al 2007) and are, by this functional definition, tumor-initiating cells (TICs). The neuroblastoma TICs virtually lack expression of SNS markers but express neural crest markers including NOTCH1, HES1, ID2 and VIM ).…”