Bader Hannah L, Hsu Tien
Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Department of Biomedical Sciences and Engineering, National Central University, Chung-li, Taiwan.
BMC Cancer. 2016 Oct 12;16(1):797. doi: 10.1186/s12885-016-2802-3.
Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome-VHL disease-and are also frequently observed in sporadic renal cell carcinoma of the clear cell type (ccRCC). VHL disease is characterized by malignant and benign tumors in a few specific tissues, including ccRCC, hemangioblastoma and pheochromocytoma. The etiology of these tumors remains unresolved.
Conditional inactivation of the VHL gene in mouse (Vhlh) was generated to examine the pathophysiological role of the VHL gene function. Specific cell populations were isolated by fluorescence-activated cell sorting (FACS) and bone marrow transplants were performed to identify the Vhlh-inactivated cells responsible for the phenotype.
Previously we showed that inactivation of Vhlh in a subpopulation of kidney distal tubule cells resulted in hyperplastic clear-cell lesions and severe inflammation and fibrosis. Here, we show that this knockout mouse strain also develops Hif-2α-dependent vascular overgrowth (hemangioma) and extramedullary erythropoiesis in the liver. However, Vhlh inactivation was not detected in the liver parenchyma. We instead demonstrate that in these mice, Vhlh is inactivated in liver granulocytes and that hemangiomas are partially rescued in knockout mice reconstituted with wild-type hematopoietic stem cells, indicating the involvement of bone-marrow-derived leukocyte. Interestingly, bone marrow from knockout mice failed to generate the liver phenotype in wild-type recipients, suggesting that an additional cell type that is not derived from the bone marrow is involved in the development of the hemangioma phenotype.
These results support the idea that the development of a full-blown VHL disease phenotype requires inactivation of the VHL gene not only in the tumor proper, but also in the stromal compartment.
肿瘤抑制基因冯·希佩尔-林道（VHL）的突变是遗传性癌症综合征——VHL病的基础，并且在散发性透明细胞型肾细胞癌（ccRCC）中也经常被观察到。VHL病的特征是在一些特定组织中出现恶性和良性肿瘤，包括ccRCC、成血管细胞瘤和嗜铬细胞瘤。这些肿瘤的病因仍未明确。
通过条件性失活小鼠中的VHL基因（Vhlh）来研究VHL基因功能的病理生理作用。通过荧光激活细胞分选（FACS）分离特定细胞群体，并进行骨髓移植以鉴定导致该表型的Vhlh失活细胞。
此前我们发现，肾远端小管细胞亚群中Vhlh的失活导致增生性透明细胞病变以及严重的炎症和纤维化。在此，我们表明这种基因敲除小鼠品系还会出现Hif-2α依赖性的血管过度生长（血管瘤）以及肝脏中的髓外造血。然而，在肝实质中未检测到Vhlh失活。相反，我们证明在这些小鼠中，Vhlh在肝脏粒细胞中失活，并且在用野生型造血干细胞重建的基因敲除小鼠中，血管瘤部分得到挽救，这表明骨髓来源的白细胞参与其中。有趣的是，基因敲除小鼠的骨髓未能在野生型受体中产生肝脏表型，这表明血管瘤表型的发展还涉及一种并非源自骨髓的额外细胞类型。
这些结果支持这样一种观点，即完整的VHL病表型的发展不仅需要肿瘤本身的VHL基因失活，还需要基质区室中的VHL基因失活。
