Tuberous sclerosis-associated lesions of the kidney, brain, and skin are angiogenic neoplasms

Arbiser, Jack L.; Brat, Daniel J.; Hunter, Steve; DʼArmiento, Jeanine; Henske, Elizabeth P.; Arbiser, Zoya K.; Bai, Xianhe; Goldberg, Gerald N.; Cohen, Cynthia; Weiss, Sharon W.

doi:10.1067/mjd.2002.120530

Cited by 74 publications

(62 citation statements)

References 27 publications

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“…22 High levels of VEGF mRNA expression have been reported in angiomyolipomas and in serum from human TSC patients. 23,32 VEGF expression was enhanced after Tsc1 knockout in vivo in mice, and we observed enhanced VEGF expression in human tubers and SEGAs, as well as in perituberal cortex.…”

Section: Discussionmentioning

confidence: 53%

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Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

Parker

Orlova

Heuer

et al. 2011

The American Journal of Pathology

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Epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) regulate angiogenesis and cell growth in the developing brain. EGF, HGF, and VEGF modulate the activity of the mammalian target of rapamycin (mTOR) cascade, a pathway regulating cell growth that is aberrantly activated in tuberous sclerosis complex (TSC). We hypothesized that expression of EGF, HGF, VEGF, and their receptors EGFR, c-Met, and Flt-1, respectively, would be altered in TSC. We show by cDNA array and immunohistochemical analysis that EGF, EGFR, HGF, c-Met, and VEGF, but not Flt-1, mRNA, and protein expression was up-regulated in Tsc1 conditional knockout (Tsc1 GFAP CKO) mouse cortex. Importantly, these alterations closely predicted enhanced expression of these proteins in tuber and subependymal giant cell astrocytoma (SEGA) specimens in TSC. Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1␣, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n ‫؍‬ 6) and tubers (n ‫؍‬ 10) from 15 TSC patients. Enhanced expression of these growth factors and growth factor receptors in human SEGAs and tubers and in the Tsc1 GFAP CKO mouse may account for enhanced cellular growth and proliferation in tubers and SEGAs and provides potential target molecules for therapeutic development in TSC. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes, which encode TSC1 and TSC2 proteins, respectively. 1,2 Many individuals with TSC exhibit cognitive disability and autism, 3 and more than 75% of TSC patients develop seizures. 4 -6 Examination of the brain demonstrates cortical tubers and subependymal nodules (SENs) in more than 70% of TSC patients. Tubers are developmental malformations of the cerebral cortex highly associated with epilepsy and neurocognitive abnormalities. SENs are nodular lesions (typically smaller than 1 cm) located on the surfaces of the lateral and third ventricles. In approximately 10% to 20% of TSC patients, subependymal giant cell astrocytomas (SEGAs) arise within the lateral ventricles, often near the foramen of Monro. SEGAs are World Health Organization grade I tumors with low mitotic index as evidenced by Ki-67 immunoreactivity suggestive of slow cellular proliferation. 7,8 It is widely believed that SENs grow to form SEGAs, although the molecular mechanisms governing transformation from SEN to SEGA are unknown. 9 Both SENs and SEGAs consist of dysmorphic glial cells, enlarged giant cells (GCs), and spindle-shaped cells of unknown phenotype. 10,11 Cellular immunoreactivity for glial fibrillary acidic protein (GFAP), neurofilament, S-100, neuron-specific enoSupported by NS045877, NS045021, and Department of Defense CDMRP-TSC Program grants (P.B.C.); the National Epilepsy Fund -"Power of the Small," Hersenstichting Nederland (NEF 02-10 and NEF 05-11) and Stichting Michelle (M06.011) (E.A.); and AOA and AANS medical s...

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Section: Discussionmentioning

confidence: 53%

“…19,21,22 Brain and kidney lesions in TSC exhibit abnormally enhanced expression of the vascular endothelium protein marker CD31. 23 Altered VEGF isoform D levels were observed in serum from TSC patients with lymphangioleiomyomatosis. 24 Of note, enhanced VEGF expression in TSC may occur via both mTOR-dependent and mTOR-independent mechanisms.…”

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confidence: 95%

Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

Parker

Orlova

Heuer

et al. 2011

The American Journal of Pathology

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“…A recent case of a 19-year-old with TSC and a renal AML treated with sirolimus for 6 months was also reported [20]. As with other tumorous masses, AMLs show increased vascularity; there is evidence that it is the angiogenic component of AMLs that result in their bleeding potential [22], and thus it would seem a valid strategy to use anti-angiogenic agents such as vascular endothelial growth factor inhibitors to treat this disease [23]. Such trials are ongoing, and again there are few clinical data results available on the outcomes of this novel management strategy.…”

Section: Discussionmentioning

confidence: 99%

Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated

Sooriakumaran¹,

Gibbs²,

Coughlin³

et al. 2009

BJU International

136

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Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To examine the presentation, management and outcomes of patients with renal angiomyolipoma (AML) over a period of 10 years, at St George’s Hospital, London, UK. PATIENTS AND METHODS We assessed retrospectively 102 patients (median follow‐up 4 years) at our centre; 70 had tuberous sclerosis complex (TSC; median tumour size 3.5 cm) and the other 32 were sporadic (median tumour size 1.2 cm). Data were gathered from several sources, including radiology and clinical genetics databases. The 77 patients with stable disease were followed up with surveillance imaging, and 25 received interventions, some more than one. Indications for intervention included spontaneous life‐threatening haemorrhage, large AML (10–20 cm), pain and visceral compressive symptoms. RESULTS Selective arterial embolization (SAE) was performed in 19 patients; 10 received operative management and four had a radiofrequency ablation (RFA). SAE was effective in controlling haemorrhage from AMLs in the acute setting (six) but some patients required further intervention (four) and there was a significant complication rate. The reduction in tumour volume was only modest (28%). No complications occurred after surgery (median follow‐up 5.5 years) or RFA (median follow‐up 9 months). One patient was entered into a trial and treated with sirolimus (rapamycin). CONCLUSIONS The management of AML is both complex and challenging, especially in those with TSC, where tumours are usually larger and multiple. Although SAE was effective at controlling haemorrhage in the acute setting it was deemed to be of limited value in the longer term management of these tumours. Thus novel techniques such as focused ablation and pharmacological therapies including the use of anti‐angiogenic molecules and mTOR inhibitors, which might prove to be safer and equally effective, should be further explored.

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“…A common feature of all TS associated hamartomas and benign and malignant tumors is that these tumors are highly angiogenic. Indeed, our laboratory has demonstrated that these lesions produce the angiogenic stimulator vascular endothelial growth factor (VEGF) (7). Although tuberin and hamartin deletions have been generated in mice, these models do not fully recapitulate human TS.…”

Section: Tuberous Sclerosis (Ts) Is a Common Autosomal Dominant Disormentioning

confidence: 99%

Transgenic Expression of Dominant Negative Tuberin through a Strong Constitutive Promoter Results in a Tissue-specific Tuberous Sclerosis Phenotype in the Skin and Brain

Gunasekaran

Brat

Csete

et al. 2005

Journal of Biological Chemistry

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Tuberous sclerosis (TS) is a common autosomal dominant disorder caused by loss or malfunction of hamartin (tsc1) or tuberin (tsc2). Many lesions in TS do not demonstrate loss of heterozygosity for these genes, implying that dominant negative forms of these genes may account for some hamartomas and neoplasms in TS. To test this hypothesis, we expressed a dominant negative allele of tuberin (⌬RG) behind the cytomegalovirus promoter in NIH3T3 cells and transgenic mice. This allele binds hamartin but has a deletion in the C terminus of tuberin, leading to constitutive activation of rap1 and rab5/rabaptin. Expression of ⌬RG in NIH3T3 cells led to a strong induction of reactive oxygen species, induction of vascular endothelial growth factor, and malignant transformation in vivo. Expression of ⌬RG driven by the constitutive cytomegalovirus promoter led to high level expression in all murine tissues examined, including skin, kidney, liver, and brain. Surprisingly, mice expressing the ⌬RG transgene developed a fibrovascular collagenoma in the dermis, which closely resembles the Shagreen patch observed in human patients with TS. In addition, numerous small subpial collections of external granule cells in the cerebellum were observed, which may be the murine equivalent of subependymal giant cell astrocytomas or tubers commonly seen in TS patients. Thus, expression of a dominant negative tuberin in multiple tissues can lead to a tissue-specific phenotype resembling some of the findings in human TS. Our data are the first to demonstrate that specific signaling abnormalities underlie specific hamartomas in a model of a human genetic disorder.

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Tuberous sclerosis-associated lesions of the kidney, brain, and skin are angiogenic neoplasms

Cited by 74 publications

References 27 publications

Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated

Transgenic Expression of Dominant Negative Tuberin through a Strong Constitutive Promoter Results in a Tissue-specific Tuberous Sclerosis Phenotype in the Skin and Brain

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