RESUMO
Tumor-initiating cells have been suggested to be rare in many cancers. We tested this in mouse malignant peripheral nerve sheath tumors (MPNSTs) and found that 18% of primary and 49% of passaged MPNST cells from Nf1(+/-); Ink4a/Arf(-/-) mice formed tumors upon transplantation, whereas only 1.8% to 2.6% of MPNST cells from Nf1(+/-); p53(+/-) mice did. MPNST cells of both genotypes require laminin binding to ß1-integrin for clonogenic growth. Most MPNST cells from Nf1(+/-); Ink4a/Arf(-/-) mice expressed laminin, whereas most MPNST cells from Nf1(+/-); p53(+/-) mice did not. Exogenous laminin increased the percentage of MPNST cells from Nf1(+/-); p53(+/-) but not Nf1(+/-); Ink4a/Arf(-/-) mice that formed tumorigenic colonies. Tumor-forming potential is common among MPNST cells, but the assay conditions required to detect it vary with tumor genotype.
Assuntos
Transformação Celular Neoplásica , Neoplasias de Bainha Neural/patologia , Animais , Proliferação de Células , Genótipo , Integrina beta1/metabolismo , Integrina beta1/fisiologia , Laminina/metabolismo , Camundongos , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/metabolismo , Células Tumorais CultivadasRESUMO
The polycomb gene Bmi-1 is required for the self-renewal of stem cells from diverse tissues, including the central nervous system (CNS). Bmi-1 expression is elevated in most human gliomas, irrespective of grade, raising the question of whether Bmi-1 over-expression is sufficient to promote self-renewal or tumorigenesis by CNS stem/progenitor cells. To test this we generated Nestin-Bmi-1-GFP transgenic mice. Analysis of two independent lines with expression in the fetal and adult CNS demonstrated that transgenic neural stem cells formed larger colonies, more self-renewing divisions, and more neurons in culture. However, in vivo, Bmi-1 over-expression had little effect on CNS stem cell frequency, subventricular zone proliferation, olfactory bulb neurogenesis, or neurogenesis/gliogenesis during development. Bmi-1 transgenic mice were born with enlarged lateral ventricles and a minority developed idiopathic hydrocephalus as adults, but none of the transgenic mice formed detectable CNS tumors, even when aged. The more pronounced effects of Bmi-1 over-expression in culture were largely attributable to the attenuated induction of p16(Ink4a) and p19(Arf) in culture, proteins that are generally not expressed by neural stem/progenitor cells in young mice in vivo. Bmi-1 over-expression therefore has more pronounced effects in culture and does not appear to be sufficient to induce tumorigenesis in vivo.
Assuntos
Encéfalo/anormalidades , Neurogênese/fisiologia , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Células-Tronco/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Neoplasias Encefálicas/embriologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Glioma/embriologia , Glioma/metabolismo , Glioma/patologia , Humanos , Hidrocefalia/embriologia , Hidrocefalia/metabolismo , Hidrocefalia/patologia , Proteínas de Filamentos Intermediários/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Nestina , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Proteínas Nucleares/genética , Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Células-Tronco/citologiaRESUMO
Neurofibromatosis is caused by the loss of neurofibromin (Nf1), leading to peripheral nervous system (PNS) tumors, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). A long-standing question has been whether these tumors arise from neural crest stem cells (NCSCs) or differentiated glia. Germline or conditional Nf1 deficiency caused a transient increase in NCSC frequency and self-renewal in most regions of the fetal PNS. However, Nf1-deficient NCSCs did not persist postnatally in regions of the PNS that developed tumors and could not form tumors upon transplantation into adult nerves. Adult P0a-Cre+Nf1(fl/-) mice developed neurofibromas, and Nf1(+/-)Ink4a/Arf(-/-) and Nf1/p53(+/-) mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice. Tumors appeared to arise from differentiated glia, not NCSCs.