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Sofia, Bulgaria

Birner P.,Medical University of Vienna | Tchorbanov A.,Bulgarian Academy of Science | Natchev S.,St. Ivan Rilski Hospital | Tuettenberg J.,Kohler | Guentchev M.,Kohler
Journal of Clinical Pathology | Year: 2015

Aims The chemokine receptor CXCR7 is found on glioma cells and glioma-associated vessels and dependent upon its localisation on tumour or endothelial cells the CXCR7 receptor can mediate glioma cell invasion and tumour angiogenesis. Its expression predicts survival in several types of cancers. Methods We immunohistochemically studied the expression of CXCR7 and its ligand SDF1? in a cohort of 354 human patients with glioma. In an in vivo glioma model, we studied the effect of selective CXCR7 inhibition on mean vascular density. Results Here we show that expression of either mutant isocitrate dehydrogenase (IDH) 1 or podoplanin (PDPN), two proteins present in basically non-overlapping glioma populations, predicts the prognostic significance of CXCR7. Specifically, expression of CXCR7 on endothelial cells in IDH1 mutant cases predicted poor outcome. Surprisingly, in PDPN expressing gliomas, one of the marker genes for the recently identified mesenchymal subgroup, expression of CXCR7 predicts diminished prognosis on tumour cells and better prognosis on endothelial cells. Conclusions Since CXCR7 is expressed on migrating cells our data suggest that, although ubiquitously present, angiogenesis and invasion are outcome-relevant events in specific glioma subgroups, providing a potentially important tool for targeted therapy assignment.

Karakolev I.,Trakia University | Stanilov N.,St. Ivan Rilski Hospital | Miteva L.,Trakia University | Jovchev J.,University Hospital | And 2 more authors.
Biotechnology and Biotechnological Equipment | Year: 2012

The IGF-1R signalling pathway can positively regulate cell-cycle progression and thus play a critical role in cancer development. Although recent studies provide sufficient evidence supporting the functional importance of IGF-1R in cancer, the prognostic significance of IGF-1R expression levels to colorectal cancer (CRC) remains obscure. Expression of IGF-1R mRNA was examined in paired samples of CRC and adjacent normal mucosa, as well as in CRC patients’ venous blood. We also investigated the effect of two monocytes stimulus - C3bgp and LPS on induced mRNA of IGF-1R from normal and colorectal human monocytes. The role of a member of MAPK signal transduction pathways - JNK in IGF-1R expression was assessed. The expression of IGF-1R mRNA was measured by relative RT-PCR. The results demonstrated that expression of IGF-1R mRNA in venous blood from CRC was down-regulated compared to venous blood from healthy donors (1.426 vs. 0.645; p=0.024). Mean IGF-1R mRNA level was found to be approximately 5.8 fold higher in tumour tissue compared to adjacent normal mucosa (p=0.02). Strong IGF-1R mRNA expression was found for early stages of CRC. The results showed that both stimuli used, strongly up-regulated mRNA expression for IGF-1R in CRC monocytes, then in monocytes from healthy donors. The highest level of IGF-1R expression was detected after C3bgp stimulation, regardless of JNK inhibitor presence. The significance for increasing expression of IGF-1R was observed for early CRC when patients were divided according to the tumour stage. We can conclude that downregulation of mRNA expression of IGF-1R in peripheral blood cells and stimulated monocytes from patients with advanced stages of colorectal cancer are a hallmark of tumour progression and can be used as a prognostic factor. © 2012 Taylor and Francis Group, LLC.

Birner P.,University of Heidelberg | Birner P.,Medical University of Vienna | Pusch S.,University of Heidelberg | Pusch S.,German Cancer Research Center | And 9 more authors.
Cancer | Year: 2014

BACKGROUND Recently, isocitrate dehydrogenase 1 (IDH1) was identified as a major participant in glioma pathogenesis. At present, the enzymatic activity of the protein has been the main topic in investigating its physiological function, but its signaling pathway allocation was unsuccessful. Interestingly, proteins regulated by phosphoinositide 3-kinase (PI3K)/Akt signaling, are among the top downregulated genes in gliomas associated with high percentage of IDH1 and IDH2 mutations. The aim of this study was to investigate a hypothetical relation between IDH1 and PI3K signaling. METHODS The presence of mutant IDH1 and markers for active PI3K/Akt signaling, present as phosphorylated Akt and podoplanin (PDPN), were investigated in a discovery cohort of 354 patients with glioma. In vitro experiments were used to confirm functional links. RESULTS This study shows an inverse correlation between mutant IDH1 and markers for active PI3K/Akt signaling. In support of a functional link between these molecules, in vitro expression of mutant IDH1 inhibited Akt phosphorylation in a 2-hydroxyglutarate-dependent manner. CONCLUSIONS This study provides patient tumor and in vitro evidence suggesting that mutant IDH1 inhibits PI3K/Akt signaling. © 2014 American Cancer Society.

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