Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion.
Cell
; 153(1): 86-100, 2013 Mar 28.
Article
em En
| MEDLINE
| ID: mdl-23540692
ABSTRACT
Glutamate and its receptor N-methyl-D-aspartate receptor (NMDAR) have been associated with cancer, although their functions are not fully understood. Herein, we implicate glutamate-driven NMDAR signaling in a mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in selected human cancers. NMDAR was upregulated at the periphery of PNET tumors, particularly invasive fronts. Moreover, elevated coexpression of NMDAR and glutamate exporters correlated with poor prognosis in cancer patients. Treatment of a tumor-derived cell line with NMDAR antagonists impaired cancer cell proliferation and invasion. Flow conditions mimicking interstitial fluid pressure induced autologous glutamate secretion, activating NMDAR and its downstream MEK-MAPK and CaMK effectors, thereby promoting invasiveness. Congruently, pharmacological inhibition of NMDAR in mice with PNET reduced tumor growth and invasiveness. Therefore, beyond its traditional role in neurons, NMDAR may be activated in human tumors by fluid flow consequent to higher interstitial pressure, inducing an autocrine glutamate signaling circuit with resultant stimulation of malignancy.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Transdução de Sinais
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Transformação Celular Neoplásica
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Receptores de N-Metil-D-Aspartato
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Tumores Neuroendócrinos
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Proliferação de Células
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Cell
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Suíça