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

Autor: Nira Varda-Bloom, Dorit Omer, Naomi Pode-Shakked, Orit Harari-Steinberg, Leah Armon, Hadas Alfandary, Rachel Shtainfeld, Klaudyna Dziedzic, Oren Pleniceanu, Michal Mark-Daniei, Yehudit Gnatek, Sara Pri-Chen, Arnon Nagler, Tomer Kalisky, Naomi Bollag, Einav Vax, Itamar Kanter, Dekel D. Bar-Lev, Benjamin Dekel, Achia Urbach, Racheli Shukrun, Jack L. Arbiser
Rok vydání: 2017
Předmět:
cancer stem cells
0301 basic medicine
Angiomyolipoma
Urogenital System
Peroxisome proliferator-activated receptor
Therapeutics
tuberous sclerosis complex
mTORC1
Mice
03 medical and health sciences
Transforming Growth Factor beta
Cancer stem cell
Cell Line
Tumor
hemic and lymphatic diseases
Mole
medicine
Animals
Humans
neoplasms
Research Articles
Cancer
chemistry.chemical_classification
mesenchymal stem cells
PDGFB
biology
Microarray analysis techniques
Gene Expression Profiling
Stem Cells
Mesenchymal stem cell
Connective Tissue Growth Factor
Proto-Oncogene Proteins c-sis
Transforming growth factor beta
medicine.disease
angiomyolipoma
3. Good health
PPAR gamma
CTGF
030104 developmental biology
chemistry
Immunology
PPARG
biology.protein
Cancer research
Molecular Medicine
Corrigendum
Research Article
Zdroj: EMBO Molecular Medicine
ISSN: 1757-4684
1757-4676
Popis: 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 PPARγ‐pathway activation. Similarly, immunostaining revealed strong PPARγ expression in human AML specimens. Accordingly, we demonstrate that while PPARγ agonism accelerates AML growth, PPARγ 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 PPARγ‐activated renal MSC lineage that is skewed toward adipocytes and smooth muscle and away from osteoblasts, and uncover PPARγ as a regulator of AML growth, which could serve as an attractive therapeutic target.‡
Databáze: OpenAIRE
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