Professional article

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

Published inCancer Research, vol. 78, no. 22, p. 6447-6461
Publication date2018

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.Significance: These findings uncover a novel mechanism by which the thiazolidinedione compound rosiglitazone contributes to tumorigenesis, thus highlighting a potential risk associated with its use in patients with established tumors. Cancer Res; 78(22); 6447-61. ©2018 AACR.

  • Angiogenesis Inducing Agents/metabolism
  • Animals
  • Carcinogenesis
  • Cell Line
  • Tumor
  • Fibroblasts/metabolism
  • Human Umbilical Vein Endothelial Cells/drug effects
  • Humans
  • Inflammation
  • Leukocytes
  • Mononuclear/cytology
  • Macrophages/drug effects
  • Melanoma/metabolism/pathology
  • Mice
  • Mice
  • Inbred NOD
  • Mice
  • SCID
  • Monocytes/metabolism
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • PPAR gamma/agonists/metabolism
  • Paracrine Communication
  • Rosiglitazone/pharmacology
  • Skin Neoplasms/metabolism/pathology
  • Stromal Cells/metabolism
  • T-Lymphocytes/cytology
Affiliation Not a UNIGE publication
Citation (ISO format)
PICH, Christine et al. Induction of paracrine signaling in metastatic melanoma cells by PPARγ agonist rosiglitazone activates stromal cells and enhances tumor growth. In: Cancer Research, 2018, vol. 78, n° 22, p. 6447–6461. doi: 10.1158/0008-5472.CAN-18-0912
Main files (1)
Article (Published version)
ISSN of the journal0008-5472

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