The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation
The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation
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DOI：
10.1038/sj.onc.1206980
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发表时间：
2004-01-08
期刊：
影响因子：
8
通讯作者：
Bogenmann, E
中科院分区：
文献类型：
--
作者：
Peterson, S;Bogenmann, E
神经母细胞瘤（NB）是一种发生在肾上腺的儿童癌症，通常显示分化的神经元和神经胶质成分。RET受体信号通路在大多数NB中是功能性的，而神经生长因子（NGF）受体（trkA）基因表达的丧失与侵袭性表型相关。因此，我们假设RET和TRKA信号通路合作指导NB分化，使人联想到正常的神经元成熟。在这里，我们证明了RET受体的胶质细胞源性神经营养因子（GDNF）的激活增加了RET受体复合物的表达在一个小组的恶性人类NB细胞系，表示一个正反馈机制。GDNF还诱导生长停止，伴随着细胞停滞在细胞周期的G（0）/G（1）期。此外，GDNF与睫状神经营养因子（CNTF）协同作用以增强TRKA受体表达，从而加强NGF介导的分化信号。分化的NB细胞下调扩增的N-myc基因的表达，同时细胞增殖停滞，同时表达神经元特异性标志物（即，SCG10）。有趣的是，分化的NB细胞在培养物中的维持不依赖于GDNF的营养活性，而是依赖于TRKA信号传导，从而重新产生正常交感肾上腺（SA）祖细胞的分化。
Neuroblastoma (NB) is a childhood cancer that arises in the adrenal gland and often shows differentiated neuronal and glial elements. The RET receptor signal pathway is functional in most NB, while loss of nerve growth factor (NGF) receptor (trkA) gene expression correlates with an aggressive phenotype. Thus, we hypothesized that the RET and TRKA signal pathways collaborate to instruct NB differentiation, reminiscent of normal neuronal maturation. Here, we demonstrate that activation of the RET receptor by glial cell line-derived neurotrophic factor (GDNF) increases expression of the RET receptor complex in a panel of malignant human NB cell lines, indicative of a positive feedback mechanism. GDNF also induces growth cessation concomitant with an arrest of cells in the G(0)/G(1) phase of the cell cycle. Furthermore, GDNF synergizes with ciliary neurotrophic factor (CNTF) to enhance TRKA receptor expression, thereby strengthening the NGF-mediated differentiation signal. Differentiated NB cells downregulate expression of the amplified N-myc gene, concurrent with the arrest of cell proliferation, while expressing neuron-specific markers (i.e., SCG10). Interestingly, maintenance of differentiated NB cells in culture is independent of the trophic activity of GDNF, but depends on TRKA signaling, thereby re-enacting the differentiation of normal sympathoadrenal (SA) progenitor cells.