RESUMO
Although significant advances have been made in treating malignant pediatric central nervous system tumors such as medulloblastoma, no effective therapy exists for diffuse pontine glioma or intramedullary spinal astrocytoma. Biology of these 2 tumors is poorly understood, in part because diffuse pontine gliomas are not treated surgically, and tumor specimens from intramedullary spinal astrocytomas are rare and minuscule. At the 2007 Neurobiology of Disease in Children Symposium, we presented evidence that malignant glioma behaviors, including antiapoptosis, invasiveness, and treatment resistance, are enhanced by hyaluronan, an extracellular glycosaminoglycan. We review the clinical course of pediatric intramedullary spinal astrocytoma and diffuse pontine glioma, and show expression of membrane proteins that interact with hyaluronan: CD44, extracellular matrix metalloproteinase inducer, and breast cancer resistance protein (BCRP/ABCG2). Furthermore, we describe novel animal models of these tumors for preclinical studies. These findings suggest that hyaluronan antagonism has potential therapeutic value in malignant central nervous system tumors.
Assuntos
Astrocitoma/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Glioma/metabolismo , Ácido Hialurônico/metabolismo , Neoplasias da Medula Espinal/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Astrocitoma/tratamento farmacológico , Astrocitoma/fisiopatologia , Basigina/genética , Basigina/metabolismo , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/fisiopatologia , Criança , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Glioma/tratamento farmacológico , Glioma/fisiopatologia , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ratos , Neoplasias da Medula Espinal/tratamento farmacológico , Neoplasias da Medula Espinal/fisiopatologiaRESUMO
Ceruloplasmin (glycosylphosphatidylinositol-linked ferroxidase associated with normal astrocytes) can also be secreted by glioma cells, where its function is unknown. Ceruloplasmin is not only present in glioma cells and in human glioma specimens but also is enriched in highly malignant glioma stem-like cells. Hyaluronan is a large extracellular glycosaminoglycan that enhances malignant glioma behaviors by interacting with CD44 receptors and by downstream activation of signaling proteins and transporters associated with malignancy. We examined the relationship between hyaluronan and ceruloplasmin expression in glioma stem-like cells. Antagonism of hyaluronan interactions with short-fragment hyaluronan oligomers decreased ceruloplasmin expression in parental and stem-like glioma cells in vivo and in cell culture, implying that hyaluronan regulates ceruloplasmin expression. Further gain and loss-of-function studies are needed to fully define the relationship between hyaluronan and ceruloplasmin, and ceruloplasmin's effect on malignant behaviors.
Assuntos
Neoplasias Encefálicas/metabolismo , Ceruloplasmina/metabolismo , Glioma/metabolismo , Ácido Hialurônico/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ceruloplasmina/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Resistencia a Medicamentos Antineoplásicos/genética , Matriz Extracelular/metabolismo , Feminino , Glioma/genética , Glioma/fisiopatologia , Humanos , Receptores de Hialuronatos/efeitos dos fármacos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Invasividade Neoplásica/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neoplasias da Medula Espinal/tratamento farmacológico , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/metabolismo , Células-Tronco/efeitos dos fármacosRESUMO
PURPOSE: To determine if hyaluronan oligomers (o-HA) antagonize the malignant properties of glioma cells and treatment-resistant glioma side population (SP) cells in vitro and in vivo. EXPERIMENTAL DESIGN: A single intratumoral injection of o-HA was given to rats bearing spinal cord gliomas 7 days after engraftment of C6 glioma cells. At 14 days, spinal cords were evaluated for tumor size, invasive patterns, proliferation, apoptosis, activation of Akt, and BCRP expression. C6SP were isolated by fluorescence-activated cell sorting and tested for the effects of o-HA on BCRP expression, activation of Akt and epidermal growth factor receptor, drug resistance, and glioma growth in vivo. RESULTS: o-HA treatment decreased tumor cell proliferation, increased apoptosis, and down-regulated activation of Akt and the expression of BCRP. o-HA treatment of C6SP inhibited activation of epidermal growth factor receptor and Akt, decreased BCRP expression, and increased methotrexate cytotoxicity. In vivo, o-HA also suppressed the growth of gliomas that formed after engraftment of C6 or BCRP+ C6SP cells, although most C6SP cells lost their expression of BCRP when grown in vivo. Interestingly, the spinal cord gliomas contained many BCRP+ cells that were not C6 or C6SP cells but that expressed nestin and/or CD45; o-HA treatment significantly decreased the recruitment of these BCRP+ progenitor cells into the engrafted gliomas. CONCLUSIONS: o-HA suppress glioma growth in vivo by enhancing apoptosis, down-regulating key cell survival mechanisms, and possibly by decreasing recruitment of host-derived BCRP+ progenitor cells. Thus, o-HA hold promise as a new biological therapy to inhibit HA-mediated malignant mechanisms in glioma cells and treatment-resistant glioma stem cells.
