The p75 neurotrophin receptor is a central regulator of glioma invasion.
The p75 neurotrophin receptor is a central regulator of glioma invasion.
复制标题
DOI：
10.1371/journal.pbio.0050212
复制
发表时间：
2007-08
期刊：
影响因子：
9.8
通讯作者：
Senger DL
中科院分区：
文献类型：
--
作者：
Johnston AL;Lun X;Rahn JJ;Liacini A;Wang L;Hamilton MG;Parney IF;Hempstead BL;Robbins SM;Forsyth PA;Senger DL
癌症的侵袭性，特别是恶性胶质瘤，是一个主要的临床问题，使得肿瘤无法通过常规治疗。通过一系列体内选择建立的新型侵袭性胶质瘤小鼠模型，我们发现p75神经营养因子受体（p75NTR）是胶质瘤侵袭的关键调节因子。通过一系列的功能、生化和临床研究，我们发现p75NTR显著增强了遗传上不同的胶质瘤的迁移和侵袭，并且在高侵袭性胶质母细胞瘤患者标本中经常表现出强劲的表达。此外，我们发现p75ntr介导的侵袭依赖于神经营养因子，导致下游通路的激活，并使入侵细胞产生显著的细胞骨架变化。这些结果首次证明p75NTR是恶性胶质瘤高度侵袭性的主要因素，并确定了一种新的治疗靶点。胶质瘤是高度恶性和侵袭性的肿瘤，其卷须延伸到远离原发肿瘤部位，使得传统治疗无效，导致预后总是很差。为了了解这种侵袭性行为背后的分子机制，我们给免疫功能低下的小鼠注射了人胶质瘤，并比较了离开原发肿瘤部位的侵袭性细胞和留在注射部位的非侵袭性细胞。我们发现神经营养因子受体p75ntr -在发育过程中通常起诱导神经突生长和促进神经元细胞死亡的作用-是胶质瘤侵袭的重要调节因子。我们提出的第一个证据表明，这种神经营养因子受体也可以是神经胶质瘤侵袭的有效介质，我们表明，这种受体的表达足以对遗传上不同的肿瘤施加戏剧性的侵袭行为。这些数据强调了这种受体以前未知的功能，并表明它可能是治疗这种毁灭性癌症的新治疗靶点。通过在人胶质瘤的体内选择，作者发现p75NTR神经营养因子受体是调节侵袭性增加的关键分子。
The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75NTR) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75NTR dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75NTR-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75NTR as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target. Gliomas are highly malignant and invasive tumors with tendrils that extend far from the primary tumor site, rendering conventional therapies ineffective and leading to an invariably poor prognosis. To understand the molecular mechanisms underlying this invasive behavior, we injected immunocompromised mice with human gliomas and compared invasive cells, which left the primary tumor site, to noninvasive cells, which remained at the site of injection. We identified the neurotrophin receptor p75NTR—which normally functions during development to induce neurite outgrowth and promote neuronal cell death—as an important regulator of glioma invasion. We present the first evidence that this neurotrophin receptor can also be a potent mediator of glioma invasion, and we show that the expression of this receptor is sufficient to impart a dramatic invasive behavior on genetically distinct tumors. These data highlight a previously unknown function of this receptor and suggest it may be a novel therapeutic target in the treatment of this devastating cancer. By in vivo selection of a human glioma, the authors identify the p75NTR neuotrophin receptor as a critical molecule regulating increased invasiveness.
登录
查看更多内容
影响因子：
3.2
作者：
Giuliani, A;D'Intino, G;Calzà, L
通讯作者：
Calzà, L
影响因子：
45.3
作者：
Eggert, A;Grotzer, MA;Evans, AE
通讯作者：
Evans, AE
影响因子：
64.8
作者：
Clark, EA;Golub, TR;Hynes, RO
通讯作者：
Hynes, RO
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A
DOI：
10.1073/pnas.91.7.2795
发表时间：
1994-03-29
影响因子：
11.1
作者：
ANTON, ES;WESKAMP, G;MATTHEW, WD
通讯作者：
MATTHEW, WD