Johnston Angela L M, Lun Xueqing, Rahn Jennifer J, Liacini Abdelhamid, Wang Limei, Hamilton Mark G, Parney Ian F, Hempstead Barbara L, Robbins Stephen M, Forsyth Peter A, Senger Donna L
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
PLoS Biol. 2007 Aug;5(8):e212. doi: 10.1371/journal.pbio.0050212.
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 (p75(NTR)) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75(NTR) dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75(NTR)-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 p75(NTR) as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target.
一般而言，癌症具有侵袭性，恶性胶质瘤尤为如此，这是一个重大的临床问题，使得肿瘤无法通过传统疗法治愈。我们利用通过连续体内筛选建立的新型侵袭性胶质瘤小鼠模型，确定p75神经营养因子受体（p75(NTR)）是胶质瘤侵袭的关键调节因子。通过一系列功能、生化和临床研究，我们发现p75(NTR)显著增强了基因不同的胶质瘤的迁移和侵袭能力，并且在高侵袭性胶质母细胞瘤患者标本中经常表现出强烈表达。此外，我们发现p75(NTR)介导的侵袭依赖于神经营养因子，导致下游通路激活，并使侵袭细胞的细胞骨架发生显著变化。这些结果首次证明p75(NTR)是恶性胶质瘤高度侵袭性的主要促成因素，并确定了一个新的治疗靶点。
