Coalescing lessons from oxygen sensing, tumor metabolism, and epigenetics to target VHL loss in kidney cancer.

Inactivation of the von Hippel Lindau tumor suppressor protein (pVHL) is a hallmark of clear cell Renal Cell Carcinoma (ccRCC), which is the most common form of kidney cancer in adults. In complex with Elongin B/C, pVHL functions as the substrate recognition subunit of a ubiquitin ligase, perhaps best known to target the hypoxia inducible factor (HIF) transcription factor for ubiquitin-dependent proteolysis. Beyond kidney cancer, the pseudo-hypoxic state caused due to chronic HIF activation in pVHL-deficient cells has become a biological model to study hypoxia's profound effects on tumor angiogenesis, metabolism, and epigenetics. However, a number of HIF-independent substrates of pVHL, which function in a broad range of biological pathways, have also been discovered. Independently, the development of high-throughput chemical and genetic screening strategies have enabled the identification of novel, HIF-independent, targetable dependencies in ccRCC. In this review we summarize the history of pVHL and HIF mediated oxygen sensing, discuss the current status of this field, and identify critical challenges that need to be overcome. The confluence of historical discovery, development of unbiased screening strategies, and the evolution of medicinal chemistry has allowed us to begin therapeutically targeting vulnerabilities that emerge due to pVHL loss in ccRCC. Ongoing mechanistic studies on the biological consequences of pVHL loss, therefore, are likely to become the cornerstones of modern therapeutics in renal cancer.

VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects.

PURPOSE: To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. METHODS: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. RESULTS: von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. CONCLUSION: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

[Surgical treatment of pheochromocytoma].

This review article contains a summary of modern aspects of preoperative preparation, surgical treatment, and follow-up of patients with adrenal pheochromocytomas. The main component of preoperative preparation is the use of alpha-blockers. The need to prescribe them to all patients is increasingly disputed, especially for patients without severe hypertension. An increasing number of publications demonstrate positive results of treatment without the use of alpha-blockers, advocating an individual approach and the use of the drug according to certain indications. Minimally invasive endoscopic techniques of adrenalectomy have become widespread in surgical treatment. They are represented by laparoscopic and retroperitonescopic technic, including using their single-port modifications. The earliest possible intersection of the central vein in the past was considered the most important aspect of adrenalectomy for pheochromocytoma, currently, due to the development of surgical techniques and anesthesiological manuals, this has ceased to be a mandatory rule of successful surgery. Despite the significant influence of the intersection of this vessel on intraoperative hemodynamics, surgical tactics with its later intersection have their own justifications and do not lead to a deterioration in treatment results. The standard volume of surgical intervention for pheochromocytomas is total adrenalectomy, however, in the presence of hereditary syndromes, such as multiple endocrine neoplasia type 2 syndrome, neurofibomatosis type 1, von Hippel-Lindau syndrome, it is possible to perform cortical-sparing adrenalectomy.

Von Hippel-Lindau disease in pregnancy: a brief review.

The hormonal and hemodynamic effects of pregnancy accelerate the growth of hemangioblastomas in Von Hippel-Lindau syndrome (VHL), leading to increased symptoms and risk to both the mother and fetus. A review of the literature on the treatment of VHL in pregnancy would suggest surgical intervention should be considered with worsening clinical status. Introducing this review is a description of our patient with VHL, who uniquely presented in pregnancy with a cervical hemangioblastoma.

Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein.

The von Hippel-Lindau tumor suppressor protein (pVHL) negatively regulates hypoxia-inducible mRNAs such as the mRNA encoding vascular endothelial growth factor (VEGF). This activity has been linked to its ability to form multimeric complexes that contain elongin C, elongin B, and Cul2. To understand this process in greater detail, we performed a series of in vitro binding assays using pVHL, elongin B, and elongin C variants as well as synthetic peptide competitors derived from pVHL or elongin C. A subdomain of elongin C (residues 17-50) was necessary and sufficient for detectable binding to elongin B. In contrast, elongin B residues required for binding to elongin C were not confined to a discrete colinear domain. We found that the pVHL (residues 157-171) is necessary and sufficient for binding to elongin C in vitro and is frequently mutated in families with VHL disease. These mutations preferentially involve residues that directly bind to elongin C and/or alter the conformation of pVHL such that binding to elongin C is at least partially diminished. These results are consistent with the view that diminished binding of pVHL to the elongins plays a causal role in VHL disease.

Hypoxia-inducible factors and cancer.

Decreased oxygen availability is a common feature during embryonic development as well of malignant tumours. Hypoxia regulates many transcription factors, and one of the most studied is the hypoxia-inducible factor (HIF). As a consequence of HIF stabilisation, the cell constitutively upregulates the hypoxic programme resulting in the expression of genes responsible for global changes in cell proliferation, angiogenesis, metastasis, invasion, de-differentiation and energy metabolism. Of the three known alpha subunits of HIF transcription factors, HIF-1alpha and HIF-2alpha have been the most studied. Their differential expression and function have been widely discussed, however no clear picture has been drawn on how these two transcription factors differently regulate common and unique target genes. Their role as oncogenes has also been suggested in several studies. In this review we provide an overview of the current knowledge on some of the most important aspects of HIFalpha regulation, its role in tumour angiogenesis and energetic metabolism. We also give an overview of how the modulation of HIF regulating pathways is a potential therapeutic target that may have benefits in the treatment of cancer.

[Diagnostic and therapeutic procedures in pheochromocytoma: current trends]. / Diagnostické a terapeutické postupy u feochromocytomu: soucasné trendy.

Pheochromacytoma is a relatively rare cause of arterial hypertension. Untreated pheochromacytoma may however lead to a fatal hypertensive crisis during anaesthesia or another form of stress. It is therefore important to correctly diagnose this disease. 24-hour monitoring of blood pressure (BP) can already contribute to the diagnosis of pheochromacytoma based on the frequent occurrence of BP variability and the absence of a night-time fall in BP. 5 gene mutations have so far been identified that may be responsible for the familial form of pheochromacytoma: mutation of the von Hippel-Lindau (VHL) gene, leading to the onset of VHL syndrome, mutation of the RET-proto-oncogene in multiple endocrine adenomatosis type 2, mutation of the type 1 gene for neurofibromatosis, which is associated with von Recklinghausen's disease and finally mutation of the genes encoding the B and D subunits of succinated hydrogenase (SDHB, SDHD), which are associated with familial paragangliomas and pheochromacytoma. Genetic analysis should therefore be carried out for all confirmed cases of pheochromacytoma, especially for young people under 50 years of age. Biochemical diagnostics relies mainly on measurements of free metanephrines in plasma or urine, which usually has greater diagnostic weight than plasma, or catecholamines in urine. The diagnosis of extraadrenal or multiple forms can use not only CT/MR but also imaging using the radiopharmaceutical 123I-Metaiodobenzylguanidine (MIBG) or 18F-fluorodopamine PET (only available in the USA). Pharmacological treatment using alpha or beta receptor blockers with subsequent laparoscopic excision of the tumor is usually successful in benign forms of pheochromocytoma. Unfortunately, there are still no convincingly effective therapeutic procedures available for malign forms.

[Intramedullary hemangioblastomas]. / Les hémangioblastomes intramédullaires.

AIM AND BACKGROUND: Intramedullary hemangioblastomas are rare lesions representing 1 to 5% of spinal tumors. The aim of this study was to review our experience with the surgical management of intramedullary hemangioblastomas. MATERIALS AND METHODS: We performed a retrospective analysis of all the patients with intramedullary hemangioblastomas operated on between 1993 and 2011 in our department. All the patients were screened for Von Hippel Lindau disease. The minimum follow-up was 3 years. The clinical presentation, radiological findings, surgical procedure and outcomes were recorded and analyzed. RESULTS: Our consecutive series included 59 patients with a total of 65 tumors. The mean age at diagnosis was 38 years. Forty-two patients (72.5%) had Von Hippel Lindau disease. The main symptom was pain (58% of cases). The most common location was cervical spinal cord. The average size was 15mm. The resection was complete in 95% cases resulting in clinical improvement in 12% cases, stability in more than 86% of cases and deterioration in less than 2% cases. CONCLUSION: All patients with intramedullary hemangioblastoma should have a screening for the Von Hippel Lindau disease and if the diagnosis is correct, close monitoring should be initiated. Surgical removal is strongly advised in cases of neurological deficits or radiological progression of the tumour.

Role of preoperative embolization of intramedullary hemangioblastoma.

OBJECT: Hemangiobastomas (HB) are rare lesions accounting for 1 to 5% of all spinal cord tumors. Due to their hypervascular nature, an angiography may be proposed preoperatively in order to identify tumoral vascular anatomy. Preoperative embolization may be indicated to reduce intraoperative bleeding, thus facilitating tumor resection and minimizing surgical risk. The aim of this paper is to report our experience of preoperative embolization in intramedullary hemangioblastomas. METHODS: We performed a retrospective analysis of all patients operated on for intramedullary hemangioblastomas between 1995 and 2014 who had undergone embolization before surgery. RESULTS: Seven patients were analyzed: there were 6 females and 1 male, mean age 43years, 6 patients had Von Hippel-Lindau disease. Four tumors were located in the cervical spine and three in the dorsal spine. The average maximum sagittal diameter was 19mm (range 8-32mm), while the average maximum axial diameter was 11.5mm (range 6-21mm). The embolic agent used was Histoacryl (NBCA). Endovascular embolization was routinely performed the day before surgery. One patient experienced a major preoperative complication with a vertebrobasilar infarctus with consequent unilateral cerebellar syndrome and gait instability. Minor extravasation of embolic agent was observed in two cases. In one of these two cases, there was also the penetration of the embolic agent in the tumor; the resection was impossible due to the hard consistency of the tumor. In the other 6 patients, the resection was total. Six patients had identical preoperative and postoperative McCormick score and one patient shifted to a better score at follow-up. CONCLUSION: Preoperative endovascular embolization is an effective adjunct treatment. It is useful in reducing the surgical bleeding and thus the operative risks. The procedure is not always safe and complications could occur. We recommend preoperative embolization in selected cases.

Perturbations in hypoxia detection: a shared link between hereditary and sporadic tumor formation?

The discovery and characterization of the von Hippel Lindau (VHL) syndrome has brought about tremendous advances in understanding the molecular mechanisms of renal cell carcinoma. VHL mutations are known to act through hypoxia inducible factor, which has a physiologic role in detecting hypoxia. Recent investigations into other hereditary forms of kidney cancer with mutations in genes involving energy metabolism and oxidative changes, such as fumarate hydratase, suggest that metabolic changes related to hypoxia detection may be a common mechanism of tumorigenesis. This implicates aberrations in the kidney's physiologic role in detection of hypoxia in tumor formation. Germline mutations of genes involved in energy metabolism and oxidative perturbations lead to tumors in other tissues that detect hypoxia, such as head and neck paragangliomas that occur in the area of the carotid body. Therefore, aberrations in physiologic detection of hypoxia that predispose to tumor formation may not be a mechanism unique to the kidney. Furthermore, inducers of hypoxic perturbations other than germline mutations in metabolic genes may predispose to cancers in organs that have a physiologic role in detecting hypoxia. Conditions that effectively lead to tissue hypoxia in hypoxia detecting tissues is one such mechanism. We propose that some of the common molecular and physiologic mechanisms in heritable forms of kidney cancer, namely detection of hypoxia, may play a role in the genesis of sporadic kidney cancer. We survey evidence suggesting that the mechanism of some recognized risk factors of kidney cancer, such as smoking and obesity, may be due in part to tissue hypoxia, reflecting physiologic detection of hypoxia gone awry.

Intracranial hemangioblastomas: an institutional experience.

BACKGROUND AND AIMS: We present our Institutional experience with intracranial hemangioblastomas. SETTINGS AND DESIGN: A retrospective study. MATERIALS AND METHODS: This study included all patients of intracranial hemangioblastomas admitted in our institution over a period of 11 years from January 1992 through June 2003. RESULTS: There were a total of 69 patients (45 males and 24 females). The average age at presentation was 34.5 years. The tumor was located in the cerebellar hemispheres, vermian and brainstem regions in 42 (60%) patients, 19 (28%) patients and 8 (12%) patients, respectively. Hydrocephalus was seen in 48 (69%) patients. Thirty-three patients underwent CSF diversion procedures prior to surgery on the tumor. All except one underwent definitive surgery. The mortality was 8 (11%). Sixty eight patients underwent surgery on the tumor. The follow-up ranged from 1 month to 11 years. Fifteen patients developed recurrent lesions. CONCLUSION: Lifelong surveillance is necessary in cases with hemangioblastomas to identify recurrences especially in those patients having VHL syndrome.

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

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.

Solitary retinal capillary hemangioma: hereditary (von Hippel-Lindau disease) or nonhereditary?

OBJECTIVE: To estimate the probability of von Hippel-Lindau (VHL) disease in patients with solitary retinal capillary hemangioma. METHODS: Risk estimation was performed mathematically on the basis of the Bayes theorem using the published data on prevalence of VHL disease, prevalence of solitary retinal capillary hemangioma, and age-dependent penetrance of VHL disease. RESULTS: The probability of VHL disease in patients with solitary retinal capillary hemangioma was estimated to be 46%. When adjusted for age at the time of diagnosis, the risk varied from 45% in the young age group (

Solitary retinal capillary hemangioma: lack of genetic evidence for von Hippel-Lindau disease.

PURPOSE: To report the results of genetic testing for von Hippel-Lindau (VHL) disease in patients presenting with solitary retinal capillary hemangioma (RCH). METHODS: Ten patients with solitary RCH, who were excluded clinically as having VHL disease, underwent genetic testing using a combination of Southern blot, conformation sensitive gel electrophoresis, and direct sequence analysis. The results of the genetic tests were used to refine the empiric risk for VHL disease using principles of probability. RESULTS: Genetic testing for VHL disease was negative for mutation in all patients. The negative results of the genetic tests diminished the empiric risk for VHL disease by 100-fold. CONCLUSIONS: Solitary RCH can occur sporadically or be associated with VHL disease. In addition to clinical evaluation, genetic testing should be considered to exclude VHL disease with a high level of certainty.

[Intracranial haemorrhage associated with phaeochromocytoma]. / Hémorragie intracrânienne et phéochromocytome.

INTRODUCTION: Pheochromocytoma is rarely disclosed by intracranial hemorrhage. We report two cases. OBSERVATION: The first 26-year-old patient developed subarachnoid hemorrhage due to a ruptured aneurysm of the middle cerebral artery. The second patient, aged 44 years, had a temporal hematoma. Diagnosis was suggested in both patients by hypertension and elevated urinary catecholamines and confirmed by imaging and MIBG scintigraphy. Adrenal gland tumors, on both glands in the first patient and on the right gland in the second were successfully removed; cranial hypertension totally regressed. Von Hippel Lindau disease was diagnosed by molecular genetics in the first patient. Paroxysmal hypertension could explain the brain hemorrhage in the first patient and may have favored aneurysmal rupture in the second. CONCLUSION: The relationships between pheochromocytoma and cerebral aneurysm are discussed.

Childhood predictive genetic testing for Li-Fraumeni syndrome.

Presymptomatic genetic testing in childhood for adult onset conditions is generally discouraged as it does not directly benefit the child and removes their autonomy. In certain cancer prone conditions such as Familial Adenomatous Polyposis and Von Hippel Lindau disease there are risks of disease in childhood and benefit to children not inheriting a mutation in being able to forego unpleasant screening tests. Li-Fraumeni syndrome caused by constitutional TP53 mutations there are also implications in childhood with a risk of around 20% of a childhood malignancy. However, as yet no evidence based surveillance programme has been identified. We describe our experience of childhood testing for four children in two Li-Fraumeni families caused by TP53 mutations.

VHL and p53: tumor suppressors team up to prevent cancer.

In a recent issue of Molecular Cell, Roe et al. (2006) report that the von Hippel-Lindau (VHL) protein is a positive regulator of p53, thus providing insight into the mechanisms by which VHL loss of function leads to cancer.