Trk receptor expression and inhibition in neuroblastomas.
Trk receptor expression and inhibition in neuroblastomas.
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DOI：
10.1158/1078-0432.ccr-08-1815
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发表时间：
2009-05-15
期刊：
影响因子：
--
通讯作者：
Evans AE
中科院分区：
文献类型：
--
作者：
Brodeur GM;Minturn JE;Ho R;Simpson AM;Iyer R;Varela CR;Light JE;Kolla V;Evans AE
神经母细胞瘤是儿童中最常见且致命的实体瘤，其临床行为具有异质性，从自发消退到持续进展不等。目前的证据表明，神经营养因子受体的TRK家族在这些不同行为中起着关键作用。表达TrkA的神经母细胞瘤在生物学上是有利的，并且根据微环境中其配体（神经生长因子，NGF）的有无，容易自发消退或分化。相比之下，表达TrkB的肿瘤经常伴有MYCN基因扩增，是极具侵袭性且往往致命的肿瘤。这些肿瘤还表达TrkB配体（脑源性神经营养因子，BDNF），从而形成一种自分泌或旁分泌的生存通路。接触BDNF会促进表达TrkB的肿瘤的存活、耐药性和血管生成。在此，我们综述了Trk在正常发育中的作用、Trk异构体的不同功能以及主要的Trk信号通路。我们还综述了这些受体在神经母细胞瘤异质性生物学和临床行为中的作用，以及Trk受体在其他癌症中的激活情况。最后，我们阐述了在开发针对Trk的选择性抑制剂用于治疗神经母细胞瘤和其他Trk表达激活的肿瘤的靶向治疗方面所取得的进展。
Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.