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

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.

LIN28: A Stem Cell Factor with a Key Role in Pediatric Tumor Formation.

Differentiation and development are normally unidirectional processes in which progenitor/stem cells differentiate into more mature cells. Transformation of adult cells into cancer cells is accompanied in many cases by dedifferentiation of the adult cell, while differentiation failure of progenitor cells can result in the formation of unique type of cancers called pediatric cancer. LIN28A and its paralog LIN28B are pluripotent genes that are expressed mainly in stem/progenitor cells. Since the first identification of LIN28 in mammals, numerous studies demonstrated the general oncogenic features of these genes. In this review, we emphasize the unique role of LIN28 in pediatric tumor formation. We show, based on comprehensive literature screen and analysis of published microarray data, that LIN28 expression in pediatric tumors is even more common than in adult tumors, and discuss the possibility that in the case of pediatric cancers, LIN28 acts by preventing normal development/differentiation rather than by transformation of mature cells into cancer cells. Overall, this review highlights the role of LIN28 as a bridge point between embryonic development, stem cell biology, and cancer.