A study of soft tissue sarcomas after childhood cancer in Britain

Among 16 541 3-year survivors of childhood cancer in Britain, 39 soft tissue sarcomas (STSs) occurred and 1.1 sarcomas were expected, yielding a standardised incidence ratio (SIR) of 16.1. When retinoblastomas were excluded from the cohort, the SIR for STSs was 15.9, and the cumulative risk of developing a soft tissue tumour after childhood cancer within 20 years of 3-year survival was 0.23%. In the case–control study, there was a significant excess of STSs in those patients exposed to both radiotherapy (RT) and chemotherapy, which was five times that observed among those not exposed (P=0.02). On the basis of individual radiation dosimetry, there was evidence of a strong dose–response effect with a significant increase in the risk of STS with increasing dose of RT (P<0.001). This effect remained significant in a multivariate model. The adjusted risk in patients exposed to RT doses of over 3000 cGy was over 50 times the risk in the unexposed. There was evidence of a dose–response effect with exposure to alkylating agents, the risk increasing substantially with increasing cumulative dose (P=0.05). This effect remained after adjusting for the effect of radiation exposure

PPARγ agonists inhibit growth and expansion of CD133+ brain tumour stem cells

Brain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARγ) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARγ agonist, 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARγ in gliosphere cells. These findings demonstrate that PPARγ agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour

PPARγ agonists inhibit growth and expansion of CD133+ brain tumour stem cells

Brain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARγ) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARγ agonist, 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARγ in gliosphere cells. These findings demonstrate that PPARγ agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour

Antineoplastic effects of rosiglitazone and PPARγ transactivation in neuroblastoma cells

Neuroblastoma (NB) is the most common extracranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. In the present study, we evaluated the role of the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (RGZ) in two NB cell lines (SK-N-AS and SH-SY5Y), which express PPARγ. Rosiglitazone decreased cell proliferation and viability to a greater extent in SK-N-AS than in SH-SY5Y. Furthermore, 20 μM RGZ significantly inhibited cell adhesion, invasiveness and apoptosis in SK-N-AS, but not in SH-SY5Y. Because of the different response of SK-N-AS and SH-SY5Y cells to RGZ, the function of PPARγ as a transcriptional activator was assessed. Noticeably, transient transcription experiments with a PPARγ responsive element showed that RGZ induced a three-fold increase of the reporter activity in SK-N-AS, whereas no effect was observed in SH-SY5Y. The different PPARγ activity may be likely due to the markedly lower amount of phopshorylated (i.e. inactive) protein observed in SK-N-AS. To our knowledge, this is the first demonstration that the differential response of NB cells to RGZ may be related to differences in PPARγ transactivation. This finding indicates that PPARγ activity may be useful to select those patients, for whom PPARγ agonists may have a beneficial therapeutic effect