S03: PPAR-induced sarcoma: Cell proliferation and altered gene expression in tumour precursor cells

Abstract

The development of the dual PPAR α/γ agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumor data from a 2-year rat carcinogenicity study with focus on the findings of subcutaneous fibrosarcomas with a predominant spindle cell appearance that occurred at the highest dose level of 10 μmol/kg in both sexes. This dose level was at or above the maximum tolerated dose and caused considerable cardiovascular mortality. To investigate the mechanism for induction of fibrosarcomas, replicative DNA synthesis and expression of PPARγ in subcutaneous adipose tissues was assessed in rats administered 1, 3 and 10 μmol/kg tesaglitazar for 2 weeks, 3 and 6 months. Tesaglitazar stimulated DNA synthesis mainly in subcutaneous interstitial mesenchymal cells. The percentage of BrdU-labeled interstitial cells was increased dose dependently after 2 weeks. The increase in DNA synthesis was still statistically significant at later time points but only at 10 μmol/kg, the dose producing fibrosarcoma. Immunohistochemical analyses showed no detectable PPARγ protein in the majority of BrdU-labeled interstitial mesenchymal cells in white and brown fat. This indicates that stimulation of DNA synthesis is not mediated via direct activation of PPARγ in these cells. Gene expression analysis of adipose tissue revealed that by six months the cells were less responsive to PPARγ stimulation and that markers of adipose tissue differentiation were down regulated. Furthermore, increased gene expression of inflammatory cytokines was associated with increased occurrence of necrotic or fibrotic lesions in subcutaneous adipose tissues. In summary, the data suggest that high dose tesaglitazar increases cell turnover in mesenchymal interstitial cells that results in depletion of adipogenic precursor cells and preneoplastic lesions.