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Induction of paracrine signaling in metastatic melanoma cells by PPARγ agonist rosiglitazone activates stromal cells and enhances tumor growth


Pich, Christine; Meylan, Patrick; Mastelic-Gavillet, Beatris; Nguyen, Nhan Thanh; Loyon, Romain; Trang, Bao Khanh; Moser, Hélène; Moret, Catherine; Goepfert, Christine; Hafner, Jürg; Levesque, Mitchell P; Romero, Pedro; Jandus, Camilla; Michalik, Liliane (2018). Induction of paracrine signaling in metastatic melanoma cells by PPARγ agonist rosiglitazone activates stromal cells and enhances tumor growth. Cancer Research, 78(22):6447-6461.

Abstract

In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best-characterized target PPARγ have been proposed as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated nonmalignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. Although studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious.

Abstract

In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best-characterized target PPARγ have been proposed as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated nonmalignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. Although studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Cancer Research, Oncology
Language:English
Date:5 September 2018
Deposited On:29 Nov 2018 12:45
Last Modified:30 Nov 2018 08:36
Publisher:American Association for Cancer Research
ISSN:0008-5472
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/0008-5472.can-18-0912
PubMed ID:30185551
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_156469
  • : Project TitleOptimizing immune cell signaling during cancer immunotherapy

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