Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with À7/del7q and 11 with normal karyotype) with 23 CD34 þ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with À7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARa signaling in AML. Ski was co-immunoprecipitated and colocalized with RARa. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARa signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARa signaling.
Summary Retinoids and vitamin D are important factors that regulate cellular growth and differentiation. An additive growth-inhibitory effect of retinoids and vitamin D analogues has been demonstrated for human myeloma, leukaemic and breast cancer cells. We set out to study the effects of the vitamin D analogue EB1089 and the retinoids all-trans-and 9-cis-retinoic acid on the human pancreatic adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic carcinoma cell line Hs766T. The cell lines investigated expressed vitamin D receptor, retinoic acid receptor (RAR)-a and y as determined by polymerase chain reaction after reverse transcription. RAR-f, was expressed only in Hs766T cells. Addition of all-trans-retinoic acid increased the amount of RAR-a mRNA in the three cell lines and induced RAR-,B mRNA in Capan 1 and Capan 2 cells. All-trans-retinoic acid at a concentration of 10 nM inhibited the growth of Capan 1 and Capan 2 cells by 40% relative to controls. 9-cis-Retinoic acid was less effective. Neither all-trans-retinoic acid nor 9-cisretinoic acid affected the growth of Hs766T cells. EB1089, if added alone to the cells, did not significantly inhibit growth. However, the combination of 1 nM EB1089 with 10 nM all-trans-retinoic acid exerted a growthinhibitory effect of 90% in Capan 1 cells and of 70% in Capan 2 cells. Our data suggest that vitamin D analogues together with retinoids inhibit the growth of human pancreatic cancer cells. However, in vivo studies are necessary to examine the potential use of retinoids and vitamin D analogues on pancreatic cancer.
PTN and FGF-2 may represent promising new diagnostic markers for testicular cancer with high sensitivity even in early-stage testicular cancer. Further studies are warranted to extend our analyses.
Pleiotrophin is a heparin-binding growth factor involved in the differentiation and proliferation of neuronal tissue during embryogenesis, and also secreted by melanoma and breast carcinoma cells. Pleiotrophin exhibits mitogenic and angiogenic properties and has been shown to influence the vascular supply, expansion and metastasis of tumour cells. Our aim was to study the serum and plasma concentrations of pleiotrophin and the classical angiogenic growth factor vascular endothelial growth factor. Using a specific ELISA-test we studied patients with small cell lung cancer (n=63), and patients with non-small cell lung cancer (n=22) in comparison to healthy control subjects (n=41). In most of the lung cancer patients (81%), we found serum levels of pleiotrophin above those of control subjects (P50.001). Of the 63 small cell lung cancer patients in the study pleiotrophin serum levels were elevated in 55 cases (87%) and in 14 cases (63%) of the 22 non-small cell lung cancer patients. Pleiotrophin mean serum concentrations were 10.8-fold higher in the tumour patient group as compared to the control group (P50.001). Furthermore, pleiotrophin serum levels correlated positively with the stage of disease and inversely with the response to therapy. Plasma vascular endothelial growth factor concentrations were elevated in only in 28.6% of small cell lung cancer and 45.5% of non-small cell lung cancer patients by an average of 2.3-fold. Quite strikingly, there was no apparent correlation between the plasma vascular endothelial growth factor concentration and the stage of disease. Our study suggests that pleiotrophin may be an early indicator of lung cancer and might be of use in monitoring the efficacy of therapy, which needs to be confirmed by larger studies.
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