Departments of Developmental Biology and Dermatology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
Cancer Res. 2011 Jul 1;71(13):4686-95. doi: 10.1158/0008-5472.CAN-10-4577. Epub 2011 May 6.
Stem cells are under strict regulation by both intrinsic factors and the microenvironment. There is increasing evidence that many cancers initiate through acquisition of genetic mutations (loss of intrinsic control) in stem cells or their progenitors, followed by alterations of the surrounding microenvironment (loss of extrinsic control). In neurofibromatosis type 1 (NF1), deregulation of Ras signaling results in development of multiple neurofibromas, complex tumors of the peripheral nerves. Neurofibromas arise from the Schwann cell lineage following loss of function at the NF1 locus, which initiates a cascade of interactions with other cell types in the microenvironment and additional cell autonomous modifications. In this study, we sought to identify whether a temporal "window of opportunity" exists during which cells of the Schwann cell lineage can give rise to neurofibromas following loss of NF1. We showed that acute loss of NF1 in both embryonic and adult Schwann cells can lead to neurofibroma formation. However, the embryonic period when Schwann cell precursors and immature Schwann cells are most abundant coincides with enhanced susceptibility to plexiform neurofibroma tumorigenesis. This model has important implications for understanding early cellular events that dictate neurofibroma development, as well as for the development of novel therapies targeting these tumors.
干细胞受到内在因素和微环境的严格调节。越来越多的证据表明，许多癌症是通过干细胞或其祖细胞获得遗传突变（内在控制丧失）而起始的，随后周围微环境发生改变（外在控制丧失）。在 1 型神经纤维瘤病（NF1）中，Ras 信号通路的失调导致多发性神经纤维瘤的发生，这是一种周围神经的复杂肿瘤。神经纤维瘤起源于施万细胞谱系，其 NF1 基因座功能丧失，引发了与微环境中其他细胞类型的级联相互作用以及其他细胞自主修饰。在这项研究中，我们试图确定在 NF1 丧失后，施万细胞谱系中的细胞是否存在一个短暂的“机会之窗”，从而导致神经纤维瘤的形成。我们发现，胚胎期和成年期施万细胞中 NF1 的急性缺失可导致神经纤维瘤的形成。然而，施万细胞前体和未成熟施万细胞最丰富的胚胎期与丛状神经纤维瘤肿瘤发生的易感性增强相一致。该模型对于理解决定神经纤维瘤发生的早期细胞事件以及针对这些肿瘤的新型治疗方法的开发具有重要意义。
