Neuroblastoma (NB) is a common pediatric malignancy responsible for 15% of cancer-related deaths in children. Regressing or favorable-prognosis tumors express high levels of TrkA and display phenotypes of differentiated peripheral neural cells, while malignant or unfavorable-prognosis tumors resemble proliferating sympathoadrenal precursors, typically expressing TrkB, amplified N-myc, and genes involved in neural crest development, supporting the hypothesis that NB arises from molecular alterations in developing neural crest-derived precursors that cause a block in their differentiation to postmitotic neurons. To identify a cell of origin of NB, and to begin to understand why poor-prognosis NB tumors contain differentiated cell types and why patients often relapse following chemotherapy, we isolated tumor-initiating cells (TICs, also called cancer stem cells) from 20 NB tumors of all stages using conditions to isolate Skin-derived precursor cells (SKPs) a multipotent adult human neural crest precursor cell. The NB TICs were routinely isolated as spheres from bone marrow metastases, expressed markers of neuroblastoma (NB84, TH) and neural crest (SKP) precursor cells (nestin, fibronectin, versican, vimentin), had a karyotype characteristic of NB, and differentiated into cells expressing neuronal (betaIII tubulin) and glial (S100beta, GFAP) markers. TIC from bone marrow of poor-prognosis NB was highly enriched in “cancer stem cells.” They could be passaged as clones in methylcellulose over twenty passages at a self-renewal efficiency of 15-20%, while TICs from more favorable grades of NB only self-renewed for 1-2 passages. As few as 100 dissociated TICs from poor-prognosis NB formed a tumor in an orthotopic NB mouse model. We are using these cells to identify the events that cause the progression, metastasis, and acquired drug-resistance of NB, with the hypothesis that NB originates from a SKP-like cell. We have also performed high throughput screens with drug libraries, and identified agents that selectively kill NB TICs but not non-transformed human SKPs.
TUMOUR INITIATING CELLS FROM NEUROBLASTOMA, A NEURAL CREST-DERIVED TUMOR
DATTI, Alessandro;
2006
Abstract
Neuroblastoma (NB) is a common pediatric malignancy responsible for 15% of cancer-related deaths in children. Regressing or favorable-prognosis tumors express high levels of TrkA and display phenotypes of differentiated peripheral neural cells, while malignant or unfavorable-prognosis tumors resemble proliferating sympathoadrenal precursors, typically expressing TrkB, amplified N-myc, and genes involved in neural crest development, supporting the hypothesis that NB arises from molecular alterations in developing neural crest-derived precursors that cause a block in their differentiation to postmitotic neurons. To identify a cell of origin of NB, and to begin to understand why poor-prognosis NB tumors contain differentiated cell types and why patients often relapse following chemotherapy, we isolated tumor-initiating cells (TICs, also called cancer stem cells) from 20 NB tumors of all stages using conditions to isolate Skin-derived precursor cells (SKPs) a multipotent adult human neural crest precursor cell. The NB TICs were routinely isolated as spheres from bone marrow metastases, expressed markers of neuroblastoma (NB84, TH) and neural crest (SKP) precursor cells (nestin, fibronectin, versican, vimentin), had a karyotype characteristic of NB, and differentiated into cells expressing neuronal (betaIII tubulin) and glial (S100beta, GFAP) markers. TIC from bone marrow of poor-prognosis NB was highly enriched in “cancer stem cells.” They could be passaged as clones in methylcellulose over twenty passages at a self-renewal efficiency of 15-20%, while TICs from more favorable grades of NB only self-renewed for 1-2 passages. As few as 100 dissociated TICs from poor-prognosis NB formed a tumor in an orthotopic NB mouse model. We are using these cells to identify the events that cause the progression, metastasis, and acquired drug-resistance of NB, with the hypothesis that NB originates from a SKP-like cell. We have also performed high throughput screens with drug libraries, and identified agents that selectively kill NB TICs but not non-transformed human SKPs.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
