Renal Angiomyolipomas from Patients with Sporadic Lymphangiomyomatosis Contain Both Neoplastic and Non-Neoplastic Vascular Structures

Karbowniczek, Magdalena; Yu, Jane; Henske, Elizabeth P.

doi:10.1016/s0002-9440(10)63843-6

Cited by 108 publications

(102 citation statements)

References 28 publications

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“…Fat-poor TSC-associated angiomyolipomas can consist of predominantly spindle cells, epithelioid cells [25,26] or vascular elements [27][28][29] . The contribution of each of the different cell components can vary from lesion to lesion, and some lesions can exhibit a dominant cell type [30,31] .…”

Section: Fat-poor Angiomyolipomamentioning

confidence: 99%

Tuberous sclerosis complex renal disease

Dixon¹,

Kingswood²,

Bissler³

2015

Oxford Medicine Online

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and intractable epilepsy), less than 40% of affected patients have all three features [3] . TSC most often presents with neurologic symptoms, and approximately 90% of affected individuals experience seizures and about half of patients experience cognitive impairment, autism, or other behavioral disorders. Renal manifestations are the second most common findings associated with TSC, with angiomyolipomas occurring in 80% and renal cystic disease in ϳ 50% of patients. Pulmonary involvement, specifically lymphangioleiomyomatosis (LAM), is the third most common cause of TSC-associated morbidity, occurring in approximately 35% of female TSC patients. The gender predilection in LAM is not understood.TSC is caused by mutations in either the TSC1 gene, located on chromosome 9, or the TSC2 gene, located on chromosome 16. Typically children with TSC are born with normal kidneys but develop cystic disease and angiomyolipomas as they age. Both renal cystic disease and angiomyolipomas cause chronic kidney disease (CKD), affecting approximately one million patients with TSC worldwide. Renal disease poses a significant burden on patients with TSC because of the relentless progression, morbidity, and mortality of CKD. In fact, using death certificate data Shepherd et al. [4] identified renal failure as the leading cause of death in their adult patients at the Mayo Clinic. Key WordsTuberous sclerosis complex ؒ Angiomyolipoma ؒ Renal cyst ؒ Oncocytoma ؒ Mammalian target of rapamycin complex 1 ؒ Rapamycin ؒ Sirolimus AbstractAlthough not as common as other genetic renal diseases such as autosomal dominant polycystic kidney disease, patients with tuberous sclerosis complex frequently have significant renal involvement. Recent revelations in the cell biology of these renal disease manifestations as well as effective therapies for tuberous sclerosis complex-related renal issues have heralded hope of improved renal survival and improved quality of life for the TSC patient. This review specifically addresses some of the major renal manifestations of this disease.

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Section: Fat-poor Angiomyolipomamentioning

confidence: 99%

Tuberous sclerosis complex renal disease

Dixon¹,

Kingswood²,

Bissler³

2015

Oxford Medicine Online

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“…Renal AML contain abnormal blood vessels and adipose cells in addition to the smooth muscle-like LAM cells. All three types of AML cells appear to be neoplastic, based on LOH as the second genetic hit (10). LOH at the TSC2 locus was also detected in lymph nodes from a LAM transplant patient (7).…”

mentioning

confidence: 94%

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

Crooks

Pacheco–Rodriguez²,

DeCastro³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

176

122

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“…In particular, the kidney tumors include angiomyolipomas and renal cell carcinomas. Angiomyolipomas consist of smooth muscle cells, adipose tissue, and disorganized thick-walled vascular channels (3). Their abnormal vasculature may lead to spontaneous life-threatening bleeding (4).…”

Section: Introductionmentioning

confidence: 99%

Survivin Expression in Tuberous Sclerosis Complex Cells

Carelli

Lesma

Paratore

et al. 2007

Mol Med

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Tuberous Sclerosis Complex (TSC) is a tumor suppressor gene disorder with mutations of TSC1/TSC2 genes. This leads to the development of hamartomas that most frequently affect central nervous system, kidney, and skin. Angiomyolipomas are abdominal masses made up of muscle vessels and adipose tissues that grow mostly in proximity to kidneys and liver. Bleeding and kidney failure are the major justification for surgery. This study shows that angiomyolipoma-derived human smooth muscle TSC2 -/-cells express the apoptosis inhibitor protein survivin when exposed to IGF-1. Survivin expression is also triggered whenever culture conditions perturb normal TSC2-/-cell function, such as the omission of EGF from the growth medium, the supplementation of anti-EGFR, blockade of PI3K and ERK, or inhibition of mTOR. Interestingly, single or simultaneous inhibition of PI3K by LY294002 and ERK by PD98059 does not prevent IGF-1-mediated survivin expression. Apoptogenic Smac/DIABLO, which is constitutively expressed by TSC2 -/-A + cells, is down-regulated by IGF-1 even in the presence of LY294002 and PD98059. These cells release IGF-1 by means of a negative feedback-regulated mechanism that is overrun when they are exposed to antibodies to IGF-1R, which increases the released amount by more than 400%. The autocrine release of IGF-1 may therefore be a powerful mechanism of survival of the tightly packed cells in the thick-walled vessels of TSC angiomyolipoma and in lymphangioleiomyomatosis (LAM) nodules. Future experimental therapies for TSC and LAM may result from the targeted inhibition of survivin, which may enhance sensitivity to TSC2 therapy.

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Renal Angiomyolipomas from Patients with Sporadic Lymphangiomyomatosis Contain Both Neoplastic and Non-Neoplastic Vascular Structures

Cited by 108 publications

References 28 publications

Tuberous sclerosis complex renal disease

Tuberous sclerosis complex renal disease

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

Survivin Expression in Tuberous Sclerosis Complex Cells

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