Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of RCC disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. Von Hippel-Lindau (VHL) gene inactivation is observed in most clear cell renal carcinoma, resulting in vascular endothelial growth factor (VEGF) over-expression and driving the malignant phenotype. This review discusses the efficacy of novel therapies targeting the VEGF receptor (VEGFR) (e.g. anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors, mTOR inhibitors), some of which were recently approved by the Food and Drug Administration/European Medicines Evaluation Agency (FDA/EMEA) and represent the new treatment standards in RCC patients.
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PMID:Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma. 1734 Jan 58

Tumors with identical phenotype can have markedly different biologic behavior. The differentiation between hemangioblastoma, a benign vascular brain tumor, and renal cell carcinoma (RCC), a malignant tumor that can metastasize to the brain, is a well-known pathological quandary. We report a 59-year-old female with von Hippel-Lindau disease and known RCC. She presented with a cystic cerebellar tumor that had typical MRI appearance of a hemangioblastoma. Progressive symptoms led to surgical intervention. The histology included features consistent with either hemangioblastoma with epitheloid phenotype or atypical RCC metastasis mimicking hemangioblastoma. The discrepancy between the benign clinical course and the histologic phenotype could not be clearly resolved using conventional clinical techniques. We used proteomic profiling to clarify this diagnostic dilemma. We compared the proteomic expression pattern of the unknown lesion with the patterns of three typical hemangioblastomas and three typical RCCs by using selective tissue microdissection combined with two-dimensional proteomic profiling and protein sequencing. The results clearly indicated a protein profile consistent with RCC. Proteomics may complement pathological evaluation and characterization of tumors in the future. Furthermore, these results show that metastasis of malignant RCC is not necessarily equivalent to aggressive growth patterns.
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PMID:Proteomic profiling: a novel method for differential diagnosis? 1747 Oct 20

Pheochromocytomas are catecholamine-producing tumors presenting with various clinical symptoms, but mostly with headache, sweating, palpitations and hypertension. If not properly diagnosed, secretion of catecholamines may lead to fatal cardiovascular consequences. Biochemical testing for pheochromocytoma should be performed not only in symptomatic subjects or in subjects with adrenal incidentaloma but also in subjects with a genetic predisposition for pheochromocytoma (multiple endocrine neoplasia type 2, Von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF 1)and mutations of succinate dehydrogenase (SDH) genes). Once a pheochromocytoma is proven, computed tomography (CT), magnetic resonance imaging (MRI) and functional imaging with [(123)I]-MIBG may be used for tumor localization. Adequate medical pre-treatment is essential for successful operation which is performed in most cases by laparoscopy. After tumor removal, further follow-up is necessary due to possible recurrence. Although prognosis after tumor resection is excellent, a significant proportion of pheochromocytomas recur, some as metastases. Thus, appropriate follow-up is mandatory.
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PMID:Pheochromocytoma as a catecholamine producing tumor: implications for clinical practice. 1751 88

Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than the normal tissues. Hypoxia offers resistance to radiotherapy and anticancer chemotherapy, as well as predispose to increased tumor metastases. Furthermore, hypoxia induces hypoxia-inducible factor-1 (HIF-1), which in turn increases tumor angiogenesis. Thus, eradication of HIF-1-active/hypoxic tumor cells is very important for cancer therapy. We have previously reported that procaspase-3 fused with a von Hippel-Lindau (VHL)-mediated protein destruction motif of alpha subunit of HIF-1 (HIF-1alpha) containing Pro564, named TAT-ODD-procaspase-3 (TOP3), specifically induced cell death to hypoxic cells in vivo as well as in vitro. We now report that TOP3 also eradicates the radiation-induced HIF-1-active tumor cells. HIF-1 activity in the xenografts of human tumor cells, which express luciferase under the transcriptional control of HIF-1, were monitored and quantified daily with an in vivo bioluminescence photon-counting device. HIF-1 activity in tumors was more rapidly increased by ionizing radiation (IR) compared to untreated tumors. TOP3 efficiently decreased the HIF-1-activity in irradiated tumors as well as unirradiated ones, indicating TOP3 eradicated tumor cells with HIF-1-activity induced by IR as well as hypoxia. Eradication of HIF-1-active/hypoxic cells in the xenografts during irradiation exhibited significant suppression in angiogenesis and strong enhancement in a long-term growth suppression of tumor xenografts. These results further strengthen the argument that HIF-1-active/hypoxic cells play crucial roles in angiogenesis and radioresistance.
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PMID:Significance of HIF-1-active cells in angiogenesis and radioresistance. 1756 52

We report a 68-year-old woman who had bilateral renal cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) disease. Surgical resection of a central nervous system hemangioblastoma had been done previously. This time, synchronous bilateral RCCs were found in her kidneys, with metastases to lungs and liver. Right radical nephrectomy was performed to remove the primary tumor in the right kidney. Histopathological examination of the tumor revealed clear cell RCC with a sarcomatoid component. After surgery, transcatheter arterial embolization was performed for the tumor in the left kidney and interferon therapy was commenced. The left renal tumor decreased in size and interferon therapy was effective against the metastatic lung tumors. However, 4 years after resection of the right RCC, the tumor in the left kidney increased progressively in size and partial left nephrectomy was performed. Histopathological examination of the resected tumor also showed clear cell type RCC with a sarcomatoid component. The patient eventually died of her disease at 5 years after resection of the right RCC. RCC associated with VHL is usually of the clear cell type has a relatively good prognosis. Sarcomatoid RCC is rare in VHL patients and, to our knowledge, the present report is the first case of sarcomatoid RCC associated with VHL in the Japanese literature.
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PMID:[Sarcomatoid renal cell carcinoma with von Hippel-Lindau disease: a case report]. 1768 53

Renal cell carcinoma (RCC) accounts for approximately 2.6% of all cancers in the United States. While early stage disease is curable by surgery, the median survival of metastatic disease is only 13 months. In the last decade, there has been considerable progress in understanding the genetics of RCC. The VHL tumor suppressor gene is inactivated in the majority of RCC cases. The VHL protein (pVHL) acts as an E3 ligase that targets HIF-1, the hypoxia inducible transcription factor, for degradation by the ubiquitin proteasome system (UPS). In RCC cases with mutant pVHL, HIF-1 is stabilized and aberrantly expressed in normoxia, leading to the activation of pro-survival genes such as vascular endothelial growth factor (VEGF). This review will focus on the defect in the UPS that underlies RCC and describe the development of novel therapies that target the UPS. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
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PMID:Role of the ubiquitin proteasome system in renal cell carcinoma. 1804 41

We attempted to investigate the clinicopathological correlation of renal oncocytoma (RO) with renal vein extension. We identified seven ROs with extension into the branches of renal vein. The age of seven patients ranged from 61 to 82 years. Five cases were identified incidentally; two patients had gross hematuria. After surgery, all patients were alive and free of tumors with follow-up of 1 to 5 years (mean = 3.6). Oncocytomas measured from 2.2 to 7.5 cm. Renal vein extension was grossly suspected in five of seven cases and histologically confirmed in all seven cases. Tumor cells were positive for cytokeratins, mitochondrial-antigen (MIA), epithelial membrane antigen (EMA), and parvalbumin; five of seven tumors were focally positive for CD117. Ultrastructurally, the cytoplasm was packed by mitochondria. Molecular genetic analysis did not detect abnormal numbers of chromosomes 1, 2, 6, 7, 10, 17, and XY by fluorescence in situ hybridization, loss of heterozygosity on 3p and mutation of von Hippel-Lindau gene in all cases. Array comparative genomic hybridization analysis of two cases did not show any major genetic changes. Our conclusions are as follows: (1) renal oncocytomas may have intravascular extension to the branches of the renal vein; (2) renal oncocytomas with intravascular extension to the branches of the renal vein have the same morphological, immunohistochemical, and cytogenetic findings as have their counterparts without evidence of intravascular invasion; (3) the absence of metastases suggests an overall benign behavior of this tumor, but this has to be substantiated by further studies with a long-term follow-up; and (4) in a renal tumor with granular cytoplasm showing renal vein extension, it is necessary to carefully exclude renal cell carcinomas such as chromophobe RCC, oncocytic variant of papillary RCC, and granular variant of clear cell RCC.
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PMID:Renal oncocytoma with and without intravascular extension into the branches of renal vein have the same morphological, immunohistochemical, and genetic features. 1806 90

We attempted to investigate the clinicopathological correlation of renal oncocytoma (RO) with renal vein extension. We identified seven ROs with extension into the branches of renal vein. The age of seven patients ranged from 61 to 82 years. Five cases were identified; incidentally, two patients had gross hematuria. After surgery, all patients were alive and free of tumors with follow-up of 1 to 5 years (mean=3.6). Oncocytomas measured from 2.2 to 7.5 cm. Renal vein extension was grossly suspected in 5/7 cases and histologically confirmed in all seven cases. Tumor cells were positive for cytokeratins, mitochondrial antigen, epithelial membrane antigen, and parvalbumin; 5/7 tumors were focally positive for cluster of differentiation 117. Ultrastructurally, the cytoplasm was packed by mitochondria. Molecular genetic analysis did not detect abnormal numbers of chromosomes 1, 2, 6, 7, 10, 17, and XY by fluorescence in situ hybridization, loss of heterozygosity on 3p, and mutation of Von Hippel-Lindau gene in all cases. Array comparative genomic hybridization analysis of two cases did not show any major genetic changes. Conclusions are: (1) renal oncocytomas may have intravascular extension to the branches of the renal vein; (2) renal oncocytomas with intravascular extension to the branches of the renal vein have the same morphological, immunohistochemical, and cytogenetic findings as have their counterparts without evidence of intravascular invasion; (3) the absence of metastases suggests an overall benign behavior of this tumor, but this has to be substantiated by further studies with a long-term follow-up; (4) in a renal tumor with granular cytoplasm showing renal vein extension, it is necessary to carefully exclude renal cell carcinomas (RCC) such as chromophobe RCC, oncocytic variant of papillary RCC, and granular variant of clear cell RCC.
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PMID:Renal oncocytoma with and without intravascular extension into the branches of renal vein have the same morphological, immunohistochemical and genetic features. 1819 70

Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2alpha regulate the expression of an expansive array of genes associated with cellular responses to hypoxia. Although HIF-regulated genes mediate crucial beneficial short-term biological adaptations, we hypothesized that chronic activation of the HIF pathway in cardiac muscle, as occurs in advanced ischemic heart disease, is detrimental. We generated mice with cardiac myocyte-specific deletion of the von Hippel-Lindau protein (VHL), an essential component of an E3 ubiquitin ligase responsible for suppressing HIF levels during normoxia. These mice were born at expected frequency and thrived until after 3 months postbirth, when they developed severe progressive heart failure and premature death. VHL-null hearts developed lipid accumulation, myofibril rarefaction, altered nuclear morphology, myocyte loss, and fibrosis, features seen for various forms of human heart failure. Further, nearly 50% of VHL(-/-) hearts developed malignant cardiac tumors with features of rhabdomyosarcoma and the capacity to metastasize. As compelling evidence for the mechanistic contribution of HIF-1alpha, the concomitant deletion of VHL and HIF-1alpha in the heart prevented this phenotype and restored normal longevity. These findings strongly suggest that chronic activation of the HIF pathway in ischemic hearts is maladaptive and contributes to cardiac degeneration and progression to heart failure.
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PMID:Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. 1828 56

Sporadic pheochromocytoma is a rare tumor that should be taken into account in patients with hypertensive crisis, arrhythmias, and panic disorder. Familial pheochromocytoma is frequently found in subjects with von Hippel-Lindau disease, multiple endocrine neoplasia type II, neurofibromatosis, and SDHD gene mutations. The prevalence of sporadic pheochromocytoma is very low, approximately 0.05% among subjects with essential hypertension and even less in the general population. However, aggressive diagnostic intervention is recommended whenever a pheochromocytoma is suspected because the uncontrolled catecholamine release from the tumor can lead to serious and potentially lethal complications. Plasma free metanephrines have been shown to have high sensitivity and specificity in the biochemical diagnosis of sporadic and familial pheochromocytoma. Measurement of 24-hour urinary fractionated metanephrines may be an acceptable alternative in many patients. The current approach to the diagnostic localization of pheochromocytoma relies on computed tomography (CT), magnetic resonance imaging (MRI) and [123-I] and [131-I] MIBG scintigraphy. CT and MRI have very high sensitivity but low specificity, whereas MIBG scintigraphy has good specificity but its sensitivity is less than optimal, especially for the detection of metastases. In difficult cases, PET imaging appears to be promising.
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PMID:[The sympathetic system and neuroendocrine hypertension]. 1835 May


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