Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis
Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis
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DOI：
10.1158/0008-5472.can-07-0121
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Peeper, Daniel S.
中科院分区：
文献类型：
--
作者：
Geiger, Thomas R.;Peeper, Daniel S.
失巢凋亡，或由细胞脱离诱导的细胞死亡，提供针对肿瘤细胞转移扩散的保护。我们以前已经表明，神经营养受体酪氨酸激酶TrkB抑制大鼠肠上皮细胞的失巢凋亡，使他们高度致瘤性和转移性。由于TrkB在几种侵袭性人类癌症中过表达，因此首次尝试在癌症治疗中靶向TrkB。然而，TrkB介导的失巢凋亡抑制、肿瘤发生和转移的机制仍然很难解释。尽管迄今为止，大多数中和肿瘤中TrkB的尝试旨在灭活其激酶活性，但尚不清楚TrkB激酶活性是否是其致癌功能所必需的。事实上，已经表明受体的其他特性也有助于与肿瘤细胞存活相关的功能。具体地，几个粘附基序位于TrkB的细胞外结构域内。与此一致，表达TrkB的上皮细胞在悬浮培养物中形成大的细胞聚集体，可能促进肿瘤细胞存活。因此，我们着手研究TrkBs激酶活性及其粘附结构域对失巢凋亡抑制和致瘤性的相对贡献。在结构-功能分析的基础上，我们报告说，TrkB激酶活性是必需的，出乎意料的是，也足以抑制失巢凋亡，肿瘤形成和实验转移。因此，TrkB可以独立于其粘附基序发挥致瘤作用。这些结果表明，靶向TrkB的酶活性可能在癌症治疗中是有益的。
Anoikis, or cell death induced by cell detachment, provides protection against the metastatic spread of tumor cells. We have previously shown that the neurotrophic receptor tyrosine kinase TrkB suppresses anoikis in rat intestinal epithelial cells and renders them highly tumorigenic and metastatic. Because TrkB is overexpressed in several aggressive human cancers, first attempts are being made to target TrkB in cancer therapy. However, the mechanisms underlying TrkB-mediated anoikis suppression, tumorigenesis, and metastasis still remain largely elusive. Although, to date, most attempts to neutralize TrkB in tumors aim to inactivate its kinase activity, it is unclear whether TrkB kinase activity is required for its oncogenic functions. Indeed, it has been suggested that also other properties of the receptor contribute to functions that are relevant to tumor cell survival. Specifically, several adhesion motifs reside within the extracellular domains of TrkB. In line with this, TrkB-expressing epithelial cells form large cellular aggregates in suspension cultures, possibly facilitating tumor cell survival. Therefore, we set out to study the relative contributions of TrkBs kinase activity and its adhesion domains to anoikis suppression and oncogenicity. On the basis of a structure-function analysis, we report that TrkB kinase activity is required and, unexpectedly, also sufficient for anoikis suppression, tumor formation, and experimental metastasis. Thus, TrkB can act tumorigenically independent of its adhesion motifs. These results suggest that targeting the enzymatic activity of TrkB might be beneficial in cancer therapy.