Hemangioblastomas and Neurogenic Polyglobulia

Gläsker, Sven; Krüger, Marie T.; Klingler, Jan-Helge; Wlodarski, Marcin W.; Klompen, Julia; Schatlo, Bawarjan; Hippchen, Beate; Neumann, Hartmut P. H.; Velthoven, Vera Van

doi:10.1227/neu.0b013e31828ba793

Cited by 15 publications

(17 citation statements)

References 22 publications

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“…There is no increase in hematocrit in HOXB7-Cre driven Vhlh knockouts (data not shown). This pattern of focal erythropoiesis resembles the pattern observed in VHL patients, who develop polycythemia only rarely, despite tumor-associated extramedullary erythropoiesis [ 34 ].…”

Section: Discussionsupporting

confidence: 55%

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

Bader

Hsu

2016

BMC Cancer

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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.

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Section: Discussionsupporting

confidence: 55%

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

Bader

Hsu

2016

BMC Cancer

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“…In this study we found a significant association of polyglobulia and tumor size. Interestingly, the literature of the distant past stated incidences for polyglobulia much higher than in more recent studies [ 2 ]. In 1972, Palmer [ 11 ] published a case series of 81 patients with hemangioblastomas stating that 25 patients (49%) of the patients with available Hb levels (51 cases) suffered from polyglobulia.…”

Section: Discussionmentioning

confidence: 91%

“…Hemangioblastomas are highly vascular neoplasms, which can occur as sporadic tumors or as part of the von Hippel–Lindau (VHL) disease [ 1 ]. They comprise approximately 3% of all tumors of the central nervous system and are mainly located in the cerebellum and spinal cord [ 2 ]. The tumors are composed of a dense reactive angiogenetic capillary network with “stromal” cells in between, which are the neoplastic component.…”

Section: Introductionmentioning

confidence: 99%

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Polyglobulia in patients with hemangioblastomas is related to tumor size but not to serum erythropoietin

Krüger

Klingler

Jilg

et al. 2018

Hered Cancer Clin Pract

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BackgroundHemangioblastomas are associated with elevated hemoglobin (Hb) levels (polyglobulia), which is associated with a higher risk for cerebral stroke, cardiac infarction and pulmonary embolism. The pathomechanism of polyglobulia remains unclear and different theories have been postulated. Among those are elevated serum erythropoietin (EPO) levels caused by secretion of the tumor or associated tumor cyst.MethodsTo elucidate the pathomechanism, we systematically investigated the relation between polyglobulia, serum EPO level, size of the solid tumor and associated cyst in hemangioblastomas. We prospectively evaluated hemoglobin and EPO levels in a series of 33 consecutive patients operated on hemangioblastomas in our center. We measured the size of the solid tumor and associated cyst in magnetic resonance imaging. Statistical evaluations were performed using the Fisher’s exact test and student’s t-test.ResultsAs a result five patients had elevated hemoglobin levels. Only one of these had an elevated serum EPO level. Of 26 patients with normal hemoglobin levels, 4 patients had elevated EPO levels.Patients with low or normal hemoglobin levels (84%) had an average tumor size of 0.8 cm3, which differed significantly from patients with elevated hemoglobin levels (16%), who had an average solid tumor size of 8.0 cm3 (p < 0.05). We did not observe a significant correlation between EPO levels or polyglobulia and associated cysts.ConclusionsWe therefore conclude that in contrast to previous case reports and interpretations, our data show no correlation between polyglobulia and EPO levels or associated cysts in patients with hemangioblastomas. In fact, it is the size of the solid tumor that correlates with polyglobulia.The study was retrospectively registered in the German Clinical Trial Registry on 10 July 2014; Trial registration: DRKS00006310.

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“…HIF-2α has been demonstrated to be a transcriptional target of STAT5, and STAT5 activation can drive glucose uptake and metabolic supply in hematopoietic cells 16 . The upregulation of the STAT5 target GLUT1 also suggests STAT5-activation mediating selective HIF cascade activation.…”

Section: Resultsmentioning

confidence: 99%

Loss of Quiescence in von Hippel-Lindau Hemangioblastomas is Associated with Erythropoietin Signaling

Feldman

Sizdahkhani

Edwards

et al. 2016

Sci Rep

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von Hippel-Lindau (VHL) patients develop multiple central nervous system hemangioblastomas (HB). Some HBs become symptomatic with exponential growth or cyst formation following long periods of quiescence. Understanding the factors underlying growth in hemangioblastoma may lead to better strategies to arrest or prevent tumor growth. In 5 VHL patients, we resected quiescent hemangioblastomas (Q-HB) that were en-route during surgical access to symptomatic hemangioblastomas (S-HB), for matched tumor analysis. Quantitative reverse transcriptase analysis demonstrated a 2-fold increase in EPO expression in all S-HB, while 4/5 showed either Hypoxia Inducible Factor-1α or 2α upregulation. Additionally, all S-HB had increased phosphorylated erythropoietin (EPO) receptor and phosphorylated STAT-5 relative to matched Q-HB, with increased phosphorylated JAK-2 largely confined to the stromal cells in clusters within the tumors. These findings suggest that Q-HB to S-HB conversion may be associated with an erythropoietin-signaling loop. Furthermore, we found that EPO is detectable in cyst fluid from S-HB (n = 14), while absent in CSF (n = 1). Additionally, S-HB presentation or S-HB resection does not result in discernible change in serum EPO or hemoglobin (n = 60). These observations suggest that the altered erythropoietin signaling is focal and suggests that studying modulation of erythropoietin receptor pathway may lead to strategies in preventing HB growth.

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Hemangioblastomas and Neurogenic Polyglobulia

Cited by 15 publications

References 22 publications

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

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

Polyglobulia in patients with hemangioblastomas is related to tumor size but not to serum erythropoietin

Loss of Quiescence in von Hippel-Lindau Hemangioblastomas is Associated with Erythropoietin Signaling

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