Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Cancer Discov. 2012 Oct;2(10):906-21. doi: 10.1158/2159-8290.CD-12-0085. Epub 2012 Jul 9.
We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo.
我们表明，血管内皮生长因子受体神经纤毛蛋白-2（NRP2）与高级别、PTEN 缺失的前列腺癌相关，其在肿瘤细胞中的表达是由 PTEN 缺失引起的，这是 c-Jun 激活的结果。VEGF/NRP2 信号抑制胰岛素样生长因子-1 受体（IGF-IR）的表达和信号，其机制涉及 Bmi-1 介导的 IGF-IR 的转录抑制。我们评估了这一机制的重要功能和治疗意义。在前列腺肿瘤中，IGF-IR 的表达与 PTEN 呈正相关，与 NRP2 呈负相关。NRP2 是预测 IGF-IR 治疗反应的一个强有力的生物标志物，因为表达 NRP2 的前列腺癌表现出低水平的 IGF-IR。相反，靶向 NRP2 的效果仅为适度，因为 NRP2 抑制会诱导代偿性 IGF-IR 信号。然而，抑制 NRP2 和 IGF-IR 两者可完全阻断体内肿瘤生长。
