Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO 64108-2718, USA.
Biochem Biophys Res Commun. 2013 Aug 16;438(1):71-7. doi: 10.1016/j.bbrc.2013.07.028. Epub 2013 Jul 18.
Hemangioblastomas of the retina, central nervous system, and kidney are observed in patients with mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. Mutations in the VHL lead to constitutive activation of hypoxia-inducible-factor (HIF) pathway. HIF-mediated expression of pro-angiogenic genes causes extensive pathological neovascularization in hemangioblastomas. A number of studies have shown coexistence of pro-angiogenic and stem cell markers in 'tumorlet-like stromal cells' in the retinal and optic nerve hemangioblastomas, leading to suggestions that hemangioblastomas originate from developmentally arrested stem cells or embryonic progenitors. Since recent studies have shown that the HIF pathway also plays a role in the maintenance/de-differentiation of normal and cancerous stem cells, we evaluated the role of the HIF pathway in the expression of stem cell markers in VHL-/- renal cell carcinoma cells under normoxia or VHL+/+ retinal pigment epithelial cells under hypoxia. Here we show that the expression of stem cell markers in hemangioblastomas is due to activation of the HIF pathway. Further, we show that honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources, blocks the expression of stem cell markers. Our results show the mechanism for the cytological origin of neoplastic stromal cells in hemangioblastomas, and suggest that inhibition of the HIF pathway is an attractive strategy for the treatment of hemangioblastomas.
视网膜、中枢神经系统和肾脏的血管母细胞瘤可见于 von Hippel-Lindau（VHL）肿瘤抑制基因发生突变的患者。VHL 突变导致缺氧诱导因子（HIF）通路的组成性激活。HIF 介导的促血管生成基因的表达导致血管母细胞瘤中广泛的病理性新生血管形成。许多研究表明，视网膜和视神经血管母细胞瘤中的“肿瘤样基质细胞”中存在促血管生成和干细胞标志物共存，这导致血管母细胞瘤起源于发育停滞的干细胞或胚胎祖细胞的假说。由于最近的研究表明 HIF 通路在正常和癌性干细胞的维持/去分化中也发挥作用，我们评估了 HIF 通路在常氧下 VHL-/-肾癌细胞或低氧下 VHL+/+视网膜色素上皮细胞中干细胞标志物表达中的作用。在这里，我们表明血管母细胞瘤中干细胞标志物的表达归因于 HIF 通路的激活。此外，我们表明，来自天然来源的三种最近鉴定的 HIF 抑制剂 honokiol、地高辛和阿霉素可阻断干细胞标志物的表达。我们的结果表明了血管母细胞瘤中肿瘤性基质细胞的细胞学起源的机制，并表明抑制 HIF 通路是治疗血管母细胞瘤的一种有吸引力的策略。
