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Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis.

Mobley BC, Kwon M, Kraemer BR, Hickman FE, Qiao J, Chung DH, Carter BD - PLoS ONE (2015)

Bottom Line: MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies.MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis.We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology, and Immunology, Division of Neuropathology, Vanderbilt University Medical Center, Nashville, Tennessee, the United States of America.

ABSTRACT
Neuroblastoma is a pediatric malignancy of the sympathetic ganglia and adrenal glands, hypothesized to originate from progenitors of the developing sympathetic nervous system. Amplification of the MYCN oncogene is a genetic marker of risk in this disease. Understanding the impact of oncogene expression on sympathoadrenal progenitor development may improve our knowledge of neuroblastoma initiation and progression. We isolated sympathoadrenal progenitor cells from the postnatal murine adrenal gland by sphere culture and found them to be multipotent, generating differentiated colonies of neurons, Schwann cells, and myofibroblasts. MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies. MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis. The proliferation, apoptosis, and neural lineage commitment induced by MYCN are tumor-like characteristics and thereby support the hypothesis that multipotent adrenal medullary progenitor cells are cells of origin for neuroblastoma. We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

MYCN Induces SAP Apoptosis.Mycn induces apoptosis of sphere cells as evidenced by greater numbers of TUNEL-positive cells. Primary adrenal sphere cells were dissociated 4 days after infection with either empty or Mycn lentivirus. Secondary spheres were grown for 4 days and then dissociated, plated on coated dishes in self-renewal medium, and fixed and TUNEL stained following attachment (n = 3, p < .05, Student’s t-test).
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pone.0133897.g004: MYCN Induces SAP Apoptosis.Mycn induces apoptosis of sphere cells as evidenced by greater numbers of TUNEL-positive cells. Primary adrenal sphere cells were dissociated 4 days after infection with either empty or Mycn lentivirus. Secondary spheres were grown for 4 days and then dissociated, plated on coated dishes in self-renewal medium, and fixed and TUNEL stained following attachment (n = 3, p < .05, Student’s t-test).

Mentions: Neuroblastoma tumors include a subset of dying cells, and measures of karyorrhexis correlate directly with tumor aggressiveness [39]. The recent finding that MYCN overexpression induces caspase-3 in zebrafish neuroblasts [17] raises the possibility that oncogene activity may be an important cause of cell death in SAPs and in tumor cells. To determine whether MYCN induces cell death in mammalian SAPs, we performed TUNEL labeling of cells from spheres infected with control or MYCN expressing lentivirus. MYCN overexpressing sphere cells showed more cell death, with approximately twice the rate of apoptosis (Fig 4).


Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis.

Mobley BC, Kwon M, Kraemer BR, Hickman FE, Qiao J, Chung DH, Carter BD - PLoS ONE (2015)

MYCN Induces SAP Apoptosis.Mycn induces apoptosis of sphere cells as evidenced by greater numbers of TUNEL-positive cells. Primary adrenal sphere cells were dissociated 4 days after infection with either empty or Mycn lentivirus. Secondary spheres were grown for 4 days and then dissociated, plated on coated dishes in self-renewal medium, and fixed and TUNEL stained following attachment (n = 3, p < .05, Student’s t-test).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4519318&req=5

pone.0133897.g004: MYCN Induces SAP Apoptosis.Mycn induces apoptosis of sphere cells as evidenced by greater numbers of TUNEL-positive cells. Primary adrenal sphere cells were dissociated 4 days after infection with either empty or Mycn lentivirus. Secondary spheres were grown for 4 days and then dissociated, plated on coated dishes in self-renewal medium, and fixed and TUNEL stained following attachment (n = 3, p < .05, Student’s t-test).
Mentions: Neuroblastoma tumors include a subset of dying cells, and measures of karyorrhexis correlate directly with tumor aggressiveness [39]. The recent finding that MYCN overexpression induces caspase-3 in zebrafish neuroblasts [17] raises the possibility that oncogene activity may be an important cause of cell death in SAPs and in tumor cells. To determine whether MYCN induces cell death in mammalian SAPs, we performed TUNEL labeling of cells from spheres infected with control or MYCN expressing lentivirus. MYCN overexpressing sphere cells showed more cell death, with approximately twice the rate of apoptosis (Fig 4).

Bottom Line: MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies.MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis.We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology, and Immunology, Division of Neuropathology, Vanderbilt University Medical Center, Nashville, Tennessee, the United States of America.

ABSTRACT
Neuroblastoma is a pediatric malignancy of the sympathetic ganglia and adrenal glands, hypothesized to originate from progenitors of the developing sympathetic nervous system. Amplification of the MYCN oncogene is a genetic marker of risk in this disease. Understanding the impact of oncogene expression on sympathoadrenal progenitor development may improve our knowledge of neuroblastoma initiation and progression. We isolated sympathoadrenal progenitor cells from the postnatal murine adrenal gland by sphere culture and found them to be multipotent, generating differentiated colonies of neurons, Schwann cells, and myofibroblasts. MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies. MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis. The proliferation, apoptosis, and neural lineage commitment induced by MYCN are tumor-like characteristics and thereby support the hypothesis that multipotent adrenal medullary progenitor cells are cells of origin for neuroblastoma. We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.

No MeSH data available.


Related in: MedlinePlus