Astrocytes Reverted to a Neural Progenitor-like State with Transforming Growth Factor Alpha Are Sensitized to Cancerous Transformation

被引：28

作者：

Dufour, Christelle ^{[1
,2
]}

Cadusseau, Josette ^{[3
]}

Varlet, Pascale ^{[1
,4
]}

Surena, Anne-Laure ^{[1
]}

de Faria, Giselle P. ^{[1
,5
]}

Dias-Morais, Amelie ^{[1
]}

Auger, Nathalie ^{[6
]}

Leonard, Nadine ^{[1
,4
]}

Daudigeos, Estelle ^{[2
]}

Dantas-Barbosa, Carmela ^{[2
]}

Grill, Jacques ^{[2
]}

Lazar, Vladimir ^{[7
]}

Dessen, Philippe ^{[7
,8
]}

Vassal, Gilles ^{[2
]}

Prevot, Vincent

Sharif, Ariane ^{[9
]}

Chneiweiss, Herve ^{[1
]}

Junier, Marie-Pierre ^{[1
,4
]}

机构：

[1] Univ Paris, INSERM, Team Glial Plast, UMR894, Descartes, France

[2] Inst Gustave Roussy, UPRES, EA3535, Villejuif, France

[3] Univ Paris, INSERM, Team 10, U955, Creteil, France

[4] Hosp St Anne, Dept Neuropathol, Paris, France

[5] Univ Fed Rio de Janeiro, Dept Anat, Rio De Janeiro, Brazil

[6] Inst Gustave Roussy, Dept Mol Pathol, Villejurif, France

[7] Inst Gustave Roussy, CNRS, FRE 2939, Villenuif, France

[8] Univ Paris 11, Orsay, France

[9] Univ Lille, INSERM, Jean Pierre Aubert Res Ctr, U837, Lille, France

来源：

STEM CELLS | 2009年 / 27卷 / 10期

关键词：

Epidermal growth factor; Transdifferentiation; Metaplasia; Radial glia; erbB; FACTOR RECEPTOR; TGF-ALPHA; STEM-CELLS; TRANSGENIC MICE; RADIATION; EXPRESSION; CARCINOMA; ACTIVATION; MECHANISMS; ORIGIN;

D O I：

10.1002/stem.155

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Gliomas, the most frequent primitive central nervous system tumors, have been suggested to originate from astrocytes or from neural progenitors/stem cells. However, the precise identity of the cells at the origin of gliomas remains a matter of debate because no pre-neoplastic state has been yet identified. Transforming growth factor (TGF)-alpha, an epidermal growth factor family member, is frequently overexpressed in the early stages of glioma progression. We previously demonstrated that prolonged exposure of astrocytes to TGF-alpha is sufficient to trigger their reversion to a neural progenitor-like state. To determine whether TGF-alpha dedifferentiating effects are associated with cancerous transforming effects, we grafted intracerebrally dedifferentiated astrocytes. We show that these cells had the same cytogenomic pro. le as astrocytes, survived in vivo, and did not give birth to tumors. When astrocytes dedifferentiated with TGF-alpha were submitted to oncogenic stress using gamma irradiation, they acquired cancerous properties: they were immortalized, showed cytogenomic abnormalities, and formed high-grade glioma-like tumors after brain grafting. In contrast, irradiation did not modify the lifespan of astrocytes cultivated in serum-free medium. Addition of TGF-alpha after irradiation did not promote their transformation but decreased their lifespan. These results demonstrate that reversion of mature astrocytes to an embryonic state without genomic manipulation is sufficient to sensitize them to oncogenic stress. STEM CELLS 2009;27:2373-2382

引用

页码：2373 / 2382

页数：10