PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

Charytonowicz, Elizabeth; Terry, Melissa; Coakley, Katherine; Telis, Leonid; Remotti, Fabrizio; Cordon‐Cardo, Carlos; Taub, Robert N.; Matushansky, Igor

doi:10.1172/jci60015

Cited by 57 publications

(52 citation statements)

References 38 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, our findings might help optimizing the design of trabectedin-based therapies. For example, the increase in TSP-1 provides a further rationale to the combination of trabectedin with PPARc agonists-suggested to be active in patients with liposarcoma, 43 as they might potentiate the differentiating activity of trabectedin 44 as well as the antiangiogenic activity of TSP-1, by increasing the expression of the TSP-1 receptor CD36 on endothelial cells. 45 …”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

Dossi

Frapolli

Giandomenico

et al. 2014

Intl Journal of Cancer

View full text Add to dashboard Cite

Trabectedin is a marine natural product, approved in Europe for the treatment of soft tissue sarcoma and relapsed ovarian cancer. Clinical and experimental evidence indicates that trabectedin is particularly effective against myxoid liposarcomas where response is associated to regression of capillary networks. Here, we investigated the mechanism of the antiangiogenic activity of trabectedin in myxoid liposarcomas. Trabectedin directly targeted endothelial cells, impairing functions relying on extracellular matrix remodeling (invasion and branching morphogenesis) through the upregulation of the inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2. Increased TIMPs synthesis by the tumor microenvironment following trabectedin treatment was confirmed in xenograft models of myxoid liposarcoma. In addition, trabectedin upregulated tumor cell expression of the endogenous inhibitor thrombospondin-1 (TSP-1, a key regulator of angiogenesis-dependent dormancy in sarcoma), in in vivo models of myxoid liposarcomas, in vitro cell lines and primary cell cultures from patients' myxoid liposarcomas. Chromatin Immunoprecipitation analysis showed that trabectedin displaced the master regulator of adipogenesis C/EBPb from the TSP-1 promoter, indicating an association between the upregulation of TSP-1 and induction of adipocytic differentiation program by trabectedin. We conclude that trabectedin inhibits angiogenesis through multiple mechanisms, including directly affecting endothelial cells in the tumor microenvironment-with a potentially widespread activity-and targeting tumor cells' angiogenic activity, linked to a tumor-specific molecular alteration.Trabectedin (Yondelis; ET-743) is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinate and now obtained by chemical synthesis.1 It has been approved in Europe for the treatment of advanced or metastatic soft tissue sarcoma and relapsed ovarian cancer, and is currently undergoing phase II trials for several other tumors.Although not yet fully elucidated, its mechanism of action appears different from other antitumor DNA-damaging agents. It binds to N2 of guanine in the minor groove of DNA and interacts with DNA-binding proteins such as DNA repair proteins and transcription factors.1 It affects transcription regulation in a gene-and promoter-dependent fashion in both cancer and normal cells (i.e., macrophages).1-4 As a result trabectedin has a dual antineoplastic effect. It directly targets tumor cells and impairs the recruitment, viability and activity of stroma cells, particularly monocytes/macrophages, 4,5 profoundly affecting the tumor microenvironment, and depriving the tumor of the inflammatory-mediated support.Although trabectedin has shown activity against several types of soft tissue sarcomas, myxoid liposarcomas are the most sensitive to the drug. 6 Myxoid liposarcomas are characterized by chromosomal translocations, most frequently the translocation t(12;16)(q13;p11) leading to the formation of a fusion oncoprotein between FUS (fu...

show abstract

Section: Discussionmentioning

confidence: 99%

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

Dossi

Frapolli

Giandomenico

et al. 2014

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Differentiation therapy in solid tumors has garnered renewed interest over the past decade (7)(8)(9)(10), yet description of these approaches in sarcomas is only now being appreciated. In two studies, peroxisome proliferator-activated receptor γ agonists were able to induce differentiation in a subset of patients with liposarcoma and myxoid liposarcoma, respectively (11,12), suggesting that differentiation therapy will be possible in sarcoma. However, a role for these drugs in specifically suppressing self-renewal and inducing differentiation within the TPC subpopulation has not been reported.…”

mentioning

confidence: 99%

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Chen

DeRan

Ignatius

et al. 2014

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

126

127

View full text Add to dashboard Cite

Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Selfrenewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress ERMS self-renewal and induce differentiation of TPCs, a large-scale chemical screen was completed. Glycogen synthase kinase 3 (GSK3) inhibitors were identified as potent suppressors of ERMS growth through inhibiting proliferation and inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT/ β-catenin pathway, recombinant WNT3A and stabilized β-catenin also enhanced terminal differentiation of human ERMS cells. Treatment of ERMS-bearing zebrafish with GSK3 inhibitors activated the WNT/ β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. Activation of the canonical WNT/β-catenin pathway also significantly reduced selfrenewal of human ERMS, indicating a conserved function for this pathway in modulating ERMS self-renewal. In total, we have identified an unconventional tumor suppressive role for the canonical WNT/ β-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.

show abstract

“…The finding that GLPG1790 treatment induces cell cycle alteration and commits ERMS cells to myogenesis suggests that this compound has a therapeutic potential as a differentiating agent in ERMS tumours. Differentiation therapy has been shown to have a significant clinical antitumour activity in acute promyelocytic leukemia, and promising preclinical activity in liposarcoma and osteosarcoma [45,46], this outlining the importance to test the antitumour effects of this EPH inhibitor in xenograft models [21]. We also found that GLPG1790 exposure was able to significantly reduce the migratory as well as the clonogenic capacity of RD and TE671 cells by altering the expression of specific proteins, including members of the integrin superfamily, this supporting the role of EPH signalling in regulating the migratory behaviour and metastatic potential of cancer cells [6][7][8].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

et al. 2017

View full text Add to dashboard Cite

show abstract

PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

Abstract: Myxoid round cell liposarcoma (MRCLS) is

Cited by 57 publications

References 38 publications

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

Contact Info

Product

Resources

About