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Exosomes Mediate Acquisition of Disease Phenotypes by Normal WT Cells in Tuberous Sclerosis

Dr. Magdalena Karbowiscek, of Texas Tech University Health Science Center, and colleagues from Brigham and Women’s Hospital and Harvard Medical School, and the Fox Chase Cancer Center, report that extracellular vesicles such as exosomes derived from tuberous sclerosis 1 (Tsc1)-null cells (i.e., cells lacking the Tsc1 gene) transform the phenotypes of neighboring wild-type cells in vivo in such a way that these cells become functionally similar to Tsc1-null cells. The researchers noted that loss of Tsc1 in the mouse neural tube increases the number of the wild-type neuronal progenitors, which is followed by the precocious and transient acceleration of neuronal differentiation of these cells. The group’s experiments indicated that the mechanisms regulating these changes involve the exosomal delivery of exosomal shuttle Notch1 and Rheb esRNA and component of γ-secretase complex presenilin 1 from Tsc1-null cells to wild-type cells leading to the activation of Notch and Rheb signaling in the recipient cells. The scientists expressed their belief that these exosome-mediated mechanisms may also operate in the cells of angiomyolipoma (AML), which develops as a result of mutations in TSC1/TSC2 genes in TSC patients. They reached this conclusion because they observed the reactivation of mammalian target of rapamycin and Notch pathways, driven by the delivery of Rheb and Notch1 esRNA, in AML cells depleted of Rheb that were treated with the exosomes purified from AML cells with the constitutively high Rheb levels. The scientist pointed out that functions of extracellular vesicles including exosomes in the pathogenesis of tuberous sclerosis complex (TSC) had not previously been studied. This new report was published online on October 5, 2015 in the journal Oncogene. The title of the article is “Exosomes Mediate the Acquisition of the Disease Phenotypes by Cells with Normal Genome in Tuberous Sclerosis Complex.”

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare multi-system genetic diseasethat causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.

The name, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to thepathological finding of thick, firm, and pale gyri, called "tubers," in the brains of patients post-mortem. These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponym Bourneville's disease.

The image shows MRI image of tuberous sclerosis in the brain.

[Oncology abstract] [Wikipedia on tuberous sclerosis]