Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model

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Title:	Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model
Authors:	徐沺;Bader, Hannah L.;Hsu, Tien
Contributors:	生醫理工學院生醫科學與工程學系
Keywords:	Angiogenesis;Animals;Biomarkers;Biomedical and Life Sciences;Biomedicine;Blood;Bone marrow;Cancer;Cancer Research;Care and treatment;Complications and side effects;Cytokines;Diagnosis;Disease Models, Animal;Epigenetics;Erythropoietin - blood;Erythropoietin - metabolism;Flow Cytometry;Gene Silencing;Genes;Granulocytes;Granulocytes - metabolism;Growth factors;Health Promotion and Disease Prevention;Hemangioma;Hemangioma - genetics;Hemangioma - metabolism;Hemangioma - pathology;Hematopoiesis, Extramedullary - genetics;Hematopoietic stem cells;Hematopoietic Stem Cells - cytology;Hematopoietic Stem Cells - metabolism;Homeodomain Proteins - genetics;Hypoxia;Laboratory animals;Leukocytes - metabolism;Leukocytes - pathology;Liver;Liver - metabolism;Liver - pathology;Liver Neoplasms - genetics;Liver Neoplasms - metabolism;Liver Neoplasms - pathology;Medicine/Public Health;Mice;Mice, Knockout;Mortality;Mutation;Neovascularization;Oncology;Phenotype;Research Article;Surgical Oncology;Transcription factors;Translational Oncology;Tumorigenesis;Tumors;Von Hippel-Lindau disease;Von Hippel-Lindau Tumor Suppressor Protein - genetics
Date:	2016-10-12
Issue Date:	2026-04-23 11:16:25 (UTC+8)
Publisher:	BioMed Central Ltd.;London: BioMed Central
Abstract:	摘要： Background 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. Methods 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. Results 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. Conclusion 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. 其他題名： BMC Cancer 出版者： London: BioMed Central 出版日期： 2016-10-12 出處： BMC cancer, 2016-10, Vol.16 (1), p.797, Article 797 資源來源： Springer Nature Open Access Journals (NTUSG) 版權： The Author(s). 2016 版權： COPYRIGHT 2016 BioMed Central Ltd. 版權： Copyright BioMed Central 2016 識別號： ISSN: 1471-2407 識別號： EISSN: 1471-2407 識別號： DOI: 10.1186/s12885-016-2802-3 識別號： PMID: 27733136
Appears in Collections:	[Department of Biomedical Sciences and Engineering ] journal & Dissertation

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