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

Hannah L Bader,Tien Hsu

doi:10.1186/s12885-016-2802-3

Hannah L Bader, Tien Hsu

Open Access

https://doi.org/10.1186/s12885-016-2802-3

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Journal: BMC Cancer	Publication Date: Oct 12, 2016
Citations: 32	License type: CC BY 4.0

Affiliation: Boston University, National Central University

Abstract

BackgroundMutations 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.MethodsConditional 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.ResultsPreviously 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.ConclusionThese 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.

Highlights

Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome—VHL disease—and are frequently observed in sporadic renal cell carcinoma of the clear cell type
We showed that inactivation of Vhlh in a subpopulation of kidney distal tubules, using the HOXB7-Cre driver, resulted in Hif-1α-dependent hyperplastic clear-cell lesions and severe inflammation and fibrosis [25]
Hemangioblastoma is a serious tumor associated with the VHL disease and is difficult to study because of a lack of animal models

Summary

Introduction

Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome—VHL disease—and are 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. VHL protein (pVHL) is an essential negative regulator of the hypoxia-inducible factor (HIF), a transcription factor induced by low oxygen tension [5]. The active HIF transcription factor is a dimer consisting of an α and a β subunit [1, 5]. Hydroxylation is oxygen dependent, and is inhibited under hypoxic conditions. Hypoxia leads to stabilization of the HIF-α protein, allowing formation of the dimeric HIF transcription factor and transactivation (or repression) of HIF responsive genes

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