Staser Karl, Yang Feng-Chun, Clapp D Wade
Department of Biochemistry, and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Blood. 2010 Jul 15;116(2):157-64. doi: 10.1182/blood-2009-09-242875. Epub 2010 Mar 16.
Neurofibromatosis type 1 (NF1) is the most common genetic disorder with a predisposition to malignancy and affects 1 in 3500 persons worldwide. NF1 is caused by a mutation in the NF1 tumor suppressor gene that encodes the protein neurofibromin. Patients with NF1 have cutaneous, diffuse, and plexiform neurofibromas, tumors comprised primarily of Schwann cells, blood vessels, fibroblasts, and mast cells. Studies from human and murine models that closely recapitulate human plexiform neurofibroma formation indicate that tumorigenesis necessitates NF1 loss of heterozygosity in the Schwann cell. In addition, our most recent studies with bone marrow transplantation and pharmacologic experiments implicate haploinsufficiency of Nf1 (Nf1(+/-)) and c-kit signaling in the hematopoietic system as required and sufficient for tumor progression. Here, we review recent studies implicating the hematopoietic system in plexiform neurofibroma genesis, delineate the physiology of stem cell factor-dependent hematopoietic cells and their contribution to the neurofibroma microenvironment, and highlight the application of this research toward the first successful, targeted medical treatment of a patient with a nonresectable and debilitating neurofibroma. Finally, we emphasize the importance of the tumor microenvironment hypothesis, asserting that tumorigenic cells in the neurofibroma do not arise and grow in isolation.
1型神经纤维瘤病(NF1)是最常见的遗传性疾病,易发生恶性肿瘤,全球每3500人中就有1人受其影响。NF1由NF1肿瘤抑制基因突变引起,该基因编码神经纤维瘤蛋白。NF1患者有皮肤、弥漫性和丛状神经纤维瘤,这些肿瘤主要由施万细胞、血管、成纤维细胞和肥大细胞组成。来自人类和小鼠模型的、能密切模拟人类丛状神经纤维瘤形成的研究表明,肿瘤发生需要施万细胞中NF1杂合性缺失。此外,我们最近关于骨髓移植和药理学实验的研究表明,造血系统中Nf1(Nf1(+/-))的单倍剂量不足和c-kit信号传导是肿瘤进展所必需且充分的。在这里,我们回顾了最近关于造血系统在丛状神经纤维瘤发生中的作用的研究,阐述了干细胞因子依赖性造血细胞的生理学及其对神经纤维瘤微环境的贡献,并强调了这项研究在首例成功靶向治疗一名患有不可切除且使人衰弱的神经纤维瘤患者中的应用。最后,我们强调肿瘤微环境假说的重要性,断言神经纤维瘤中的致瘤细胞并非孤立产生和生长。