Dataset Information

Peroxisome proliferator-activated receptor gamma (PPAR?) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target

ABSTRACT: Angiomyolipoma (AML), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While mTORC1 activation is involved in its growth, mTORC1 inhibitors fail to eradicate AML, highlighting the need for new therapies. Moreover, the identity of the AML cell of origin is obscure. AML research, however, is hampered by the lack of in vivo models. Here, we establish a human AML-xenograft (Xn) model in mice, recapitulating AML at the histological and molecular levels. Microarray analysis demonstrated tumor growth in vivo to involve robust PPAR?-pathway activation. Similarly, immunostaining revealed strong PPAR? expression in human AML specimens. Accordingly, we demonstrate that while PPAR? agonism accelerates AML growth, PPAR? antagonism is inhibitory, strongly suppressing AML proliferation and tumor-initiating capacity, via a TGFB-mediated inhibition of PDGFB and CTGF. Finally, we show striking similarity between AML cell lines and mesenchymal stem cells (MSCs) in terms of antigen and gene expression and differentiation potential. Altogether, we establish the first in vivo human AML model, which provides evidence that AML may originate in a PPAR?-activated renal MSC lineage that is skewed toward adipocytes and smooth muscle and away from osteoblasts, and uncover PPAR? as a regulator of AML growth, which could serve as an attractive therapeutic target.

SUBMITTER: Pleniceanu O

PROVIDER: S-EPMC5376758 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Peroxisome proliferator-activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target

Pleniceanu Oren O Shukrun Racheli R Omer Dorit D Vax Einav E Kanter Itamar I Dziedzic Klaudyna K Pode-Shakked Naomi N Mark-Daniei Michal M Pri-Chen Sara S Gnatek Yehudit Y Alfandary Hadas H Varda-Bloom Nira N Bar-Lev Dekel D DD Bollag Naomi N Shtainfeld Rachel R Armon Leah L Urbach Achia A Kalisky Tomer T Nagler Arnon A Harari-Steinberg Orit O Arbiser Jack L JL Dekel Benjamin B

EMBO molecular medicine 20170401 4

Angiomyolipoma (AML), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While mTORC1 activation is involved in its growth, mTORC1 inhibitors fail to eradicate AML, highlighting the need for new therapies. Moreover, the identity of the AML cell of origin is obscure. AML research, however, is hampered by the lack of <i>in vivo</i> models. Here, we establish a human AML-xenograft (Xn) model in mice, recapitulating AML at the histological and molec ...[more]

PMID: 28275008

Similar Datasets

Project description:Ascites (serous fluid accumulation in the abdominal cavity) has been observed worldwide in fast growing broilers. Pulmonary vascular remodeling is an important pathological feature of broiler ascites syndrome. Peroxisome proliferators-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) are expressed in pulmonary vascular endothelial cells and vascular smooth muscle cells (VSMC) where they participate in the regulation of normal pulmonary vascular function. The objective of the present study was to investigate the effects of omega-3 fatty acids (found in fish oil) and pioglitazone (PIO) as natural and synthetic PPARγ ligands supplementation on PPARγ and PGC-1α expression in the prevention of pulmonary arterial hypertension (PAH) syndrome in broiler chickens. The experiment was conducted with 4 treatment groups: 1) negative control, normal temperature conditions with basal diet; 2) positive control, low-temperature conditions with basal diet; 3) positive control + 10 mg PIO/kg of weight/d and 4) positive control + 1% FO. Each treatment had 5 replicates. Ascites heart index (RV/TV) was significantly (P < 0.05) reduced in chickens receiving FO (0.20) and PIO (0.21) compared to the positive control group (0.26). The addition of PIO in broilers under cold-induced ascites significantly increased the expression of PPARγ (9.44) and PGC-1α (5.81) genes in lung tissue compared to the negative control group (1.03, P < 0.05). Proliferative indexes of VSMC in pulmonary arteries such as PMT, PIT, and percentage wall thickness were significantly elevated in positive control group, indicating that pulmonary vascular remodeling occurred following VSMC proliferation in ascites. The vessel internal diameter was increased in FO and PIO groups. Based on these results, activation and expression of PPARγ and PGC-1α genes as a critical regulator of pulmonary artery smooth muscle cell using ligands, especially PIO, can be effective in reducing the incidence of PAH in broiler chickens.

Dataset Information

Peroxisome proliferator-activated receptor gamma (PPAR?) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target

Publications

Peroxisome proliferator-activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets