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[S39]: EGFR signalling identifies an embryonic peripheral nerve progenitor cell amplified by mutation in the Nf1 gene
Author(s) -
Ratner N.,
Williams J.P.,
Wu J.,
Kordich J.J.,
Miller S.C.,
Colbert M.C.,
Cancelas J.A.
Publication year - 2006
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2006.09.046
Subject(s) - miller , university hospital , medicine , gerontology , family medicine , biology , ecology
tumor suppressor protein encoded by NF1 has rasGap activity thus, implicating constitutive activation of the ras pathway as a major consequence of NF1 loss of function. Patients with NF1 also have increased incidence of glioblastoma formation. We have sought to model these tumors for which no effective therapies have been developed. The prognosis remains unchanged over the past three decades. According to the WHO classification, four grades of astrocytoma exist. Grade 1 is benign and also referred to as pilocytic astrocytoma. Grade II or low grade astrocytoma is characterized by infiltrative cells that home on neuronal bodies (perineural satellosis). Grade III or anaplastic astrocytoma is cell dense and highly proliferative. Grade IV or glioblastoma multiforme is characterized by pseudopalisading, necrotic foci, and intense microvascularization. All forms of astrocytoma express primitive cell markers such as nestin. In addition, all forms of astrocytoma appear throughout the brain but do not leave the CNS. These observations have led to the suggestion that the CNS provides a niche that is required for tumor growth and that spontaneous tumorigenesis occurs throughout. Historically, the prevalent model for astrocytoma formation invoked mechanisms of dedifferentiation of glial cells, followed by genetic and epigenetic signals that drive neoplastic transformation. The more recent appreciation of the existence of stem cells in the lateral ventricles and dentate gyrus has raised the question of a potential role for stem cells in tumor formation. We have undertaken to model NF1 in mice through conventional knock out and conditional knock out technologies and have developed tumor suppressor based mouse models of glioblastoma. The resultant tumors histologically and molecularly resemble human glioblastoma, including progression from Grades II through IV. Through analysis of a variety of criteria, our data have provided evidence that stem cells could account for the origin of glioblastoma. Through the use of virally transduced cre delivery to stem cell compartments as well as use of tamoxifen inducible stem cell specific cre transgenes, we have developed direct evidence for precursor cells as the origin of tumor cell.