Abstract
Epithelioid sarcoma is a highly malignant soft tissue tumour that is refractory to conventional chemotherapy and irradiation. Since permanent cell lines of this tumour are extremely rare, in vitro data on compounds with significant antiproliferative effects are still lacking. Therefore, we investigated the effects of retinoic acid (RA) and tumour necrosis factor alpha (TNF-alpha) on tumour cell proliferation of three different clonal subpopulations (GRU-1A, GRU-1B, GRU-1C) derived from the same human epithelioid sarcoma cell line, GRU-1. In GRU-1A both RA (P=0.01) and TNF-alpha (P=0.002) exhibited highly significant and dose-dependent growth inhibitory effects, which could further be increased by a combined application of both compounds (P<0.006). GRU-1B proved to be sensitive to RA (P=0.006), whereas no response to TNF-alpha was observed. GRU-1C was resistant to both RA and TNF-alpha. The antiproliferative effect of TNF-alpha was mediated by TNF receptor 1(TNF-R1) and correlated positively with both the number of TNF-R1 per cell and receptor affinity. No correlation was detected between RA-induced growth inhibition and the expression pattern of the RA receptors (RARs) RAR-alpha, RAR-beta, and RAR-gamma. Plating efficiency, however, could exclusively be reduced by RA in GRU-1B, the only cell line expressing RAR-alpha. Taken together, these data are the first showing significant antiproliferative effects in human epithelioid sarcoma by RA and TNF-alpha. Whereas the TNF-alpha response seems to depend on the expression of TNF-R1, no simple correlation could be found between RA sensitivity and the expression pattern of RARs.
Highlights
We investigated the effects of retinoic acid (RA) and tumour necrosis factor alpha (TNF-a) on tumour cell proliferation of three different clonal subpopulations (GRU-1A, GRU-1B, GRU-1C) derived from the same human epithelioid sarcoma cell line, GRU-1
The antiproliferative effect of TNF-a was mediated by TNF receptor I(TNF-RI) and correlated positively with both the number of TNF-RI per cell and receptor affinity
Whereas the TNF-a response seems to depend on the expression of TNF-RI, no simple correlation could be found between RA sensitivity and the expression pattern of RA receptors (RARs)
Summary
The clonal cell lines GRU-1A, GRU-1B and GRU-1C used in this study were isolated from the epithelioid sarcoma cell line GRU-1 as described previously (Engers et al, 1994). L929s, L929sAneg, L929sATmTNFWTC3 and L929M 1.1 high prod cell lines, known to produce different amounts of TNF-c, were kindly provided by Dr B Vanhaesebroeck, University of Gent (Vanhaesebroeck et al, 1991, 1992). All cell lines were maintained in Dulbecco's modified Eagle medium (DMEM; Gibco, Germany) supplemented with 10%. The same batch of FCS was used to eliminate any possible changes in quality. All-trans-retinoic acid (RA), 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyl tetrazolium bromide (MTT) and dimethyl sulphoxide (DMSO) were purchased from Sigma (Germany). Human recombinant TNF-c and ['25I]TNF-a were kindly provided by Knoll (Germany). All experiments for RA effects were performed under light protection in order to avoid inactivation and production of unknown metabolites by light
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