Hypoxia mediated expression of stem cell markers in VHL-associated hemangioblastomas

• Published in: Biochemical and biophysical research communications 2013-08, Vol.438 (1), p.71-77
• Main Authors: Ponnaluri, V.K. Chaithanya, Vavilala, Divya Teja, Prakash, Swami, Mukherji, Mridul
• Format: Article
• Language: English
• Subjects: Angiogenesis; Cancer; Cell Hypoxia; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Hemangioblastoma - metabolism; Hemangioblastoma - pathology; Hemangioblastomas; HIF signaling; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inhibitor; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.07.028

•Hemangioblastomas are observed in patients with mutations in the VHL gene.•This leads to constitutive activation of the hypoxia-inducible-factor (HIF) pathway.•Activated HIF pathway induces stem cell markers in hemangioblastomas.•Inhibitors of the HIF pathway block the expression of stem cell markers.•Specific inhibitors of the HIF pathway can be used to treat hemangioblastomas. 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.