All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-b1 in experiments using lung fibroblasts.We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGFb1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-b mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA.ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-b1, TGF-b1 receptors and PDGFR-b, and 2) TGF-b1-dependent proliferation and PDGF-BB-dependent migration of MPM cells.These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

The calpain inhibitor calpeptin prevents bleomycin-induced pulmonary fibrosis in mice

“…Fibroblast migration plays an important role in pulmonary fibrosis, and a recent report showed that Ang-1 induced endothelial cell migration [31]. On the other hand, we found that Ang-1 induced malignant pleural mesothelioma cell migration, which has a mesenchymal origin similar to lung fibroblasts [21]. Therefore, we examined whether Calpeptin had an effect on Ang-1/Tie2 expression and Ang-1-dependent migration of lung fibroblasts and showed that Calpeptin decreased both the Ang-1 and Tie-2 mRNA expression of cultured lung fibroblasts as well as the Ang-1-induced migration of these cells.…”

“…Quantitative real-time RT-PCR was performed using TaqMan Gene expression products as described previously [17][18][19]21]. The levels of mRNA are represented as the ratio to 18SrRNA (Applied Biosystems), an endogenous control.…”

“…In vitro migration assays were performed as described previously [21]. Briefly, WI38 VA13 cells were precultured overnight with or without Calpeptin (100 nM), and then suspended at a density of 1 ¥ 10 6 cells/ml in DMEM and placed in the upper half of a Boyden chamber.…”

A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma

“…Quantitative, real-time RT-PCR was performed as previously described [10][11][12] using TaqMan Gene expression products for human Tie-2, Ang-1 and Ang-2. 18S ribosomal RNA served as an endogenous control (Applied Biosystems).…”

“…The cell proliferation assay was performed as previously described [9,10,12]. The MPM cell lines and MeT-5A cells were cultured in 96-well flat-bottomed culture plates for 2 days with or without recombinant human Ang-1 (1-100 ng?mL -1 ).…”