RESUMO
Pilocytic astrocytomas are WHO grade I gliomas that occur predominantly in childhood. They share features of both astroglial and oligodendroglial lineages. These tumours affect preferentially the cerebellum (benign clinical course) and the optic pathway, especially the hypothalamo-chiasmatic region (poor prognosis). Understanding the molecular basis responsible for the aggressive behaviour of hypothalamo-chiasmatic pilocytic astrocytomas is a prerequisite to setting up new molecular targeted therapies. We used the microarray technique to compare the transcriptional profiles of five hypothalamo-chiasmatic and six cerebellar pilocytic astrocytomas. Validation of the microarray results and comparison of the tumours with normal developing tissue was done by quantitative real-time PCR and immunohistochemistry. Results demonstrate that cerebellar and hypothalamo-chiasmatic pilocytic astrocytomas are two genetically distinct and topography-dependent entities. Numerous genes upregulated in hypothalamo-chiasmatic pilocytic astrocytomas also increased in the developing chiasm, suggesting that developmental genes mirror the cell of origin whereas migrative, adhesive and proliferative genes reflect infiltrative properties of these tumours. Of particular interest, NOTCH2, a gene expressed in radial glia and involved in gliomagenesis, was upregulated in hypothalamo-chiasmatic pilocytic astrocytomas. In order to find progenitor cells that could give rise to hypothalamo-chiasmatic pilocytic astrocytomas, we performed a morphological study of the hypothalamo-chiasmatic region and identified, in the floor of the third ventricle, a unique population of vimentin- and glial fibrillary acidic protein-positive cells highly suggestive of radial glia cells. Therefore, pilocytic astrocytomas of the hypothalamo-chiasmatic region should be considered as a distinct entity which probably originates from a unique population of cells with radial glia phenotype.
Assuntos
Astrocitoma/diagnóstico , Neoplasias do Nervo Óptico/diagnóstico , Adolescente , Adulto , Astrócitos/metabolismo , Astrocitoma/genética , Astrocitoma/patologia , Proliferação de Células , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , DNA de Neoplasias/genética , Diagnóstico Diferencial , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Hipotálamo/metabolismo , Lactente , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Neuroglia/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Quiasma Óptico/citologia , Quiasma Óptico/embriologia , Quiasma Óptico/metabolismo , Neoplasias do Nervo Óptico/genética , Neoplasias do Nervo Óptico/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Regulação para Cima , Vimentina/metabolismo , Adulto JovemRESUMO
Although the role of estradiol in maintaining bone mass is well established, the relative contributions of the estradiol receptors ERalpha and ERbeta and of the androgen receptor (AR) remain controversial. To determine the role of ERalpha-mediated, ERbeta-mediated, and non-ER-mediated mechanisms in maintaining bone mass, gonadectomy and estradiol treatment were studied in ER-knockout mice. Estradiol treatment of ovariectomized ERalphabeta(-/-) mice failed to prevent bone loss, precluding significant effects of estradiol on bone through non-ER-signaling pathways. In contrast, estradiol prevented ovariectomy-induced bone loss in ERbeta(-/-) mice, as in WT males and females, indicating that ERalpha is the major mediator of estradiol effects in bone. No response of bone to estradiol was detected in orchidectomized ERalpha(-/-) mice, suggesting estradiol cannot protect bone mass via the AR in vivo. In contrast to female ERalphabeta(-/-) and male ERalpha(-/-) mice, female ERalpha(-/-) mice were partially protected against ovariectomy-induced bone loss by estradiol, confirming that ERbeta mediates estradiol effects in bone, but only in females and with a lower efficacy than ERalpha. We conclude that ERalpha is the main effector of estradiol's protective function in bone in both male and female mice, and that, in its absence, AR is not sufficient to mediate this response.