Extensive research from the last few decades demonstrated that prostaglandins are produced in excessive amounts in the great majority of tumors, and they may be responsible for several pathobiological events in tumor progression. Prostaglandins are products in almost every cell, although their chemical form and amount vary considerably with cell type, both in healthy and pathological situations. Concerning the mechanism by which prostacyclin reduces metastasis, the current view holds that prevention of tumor cell aggregation with platelets makes tumor cells much more vulnerable to the invading lymphocytes and macrophages. Reviewing the relevant reports and recalling our own experiences, we are attempting to imply that tumor progression is influenced by prostaglandins produced by both tumor and host cells. The prostaglandins formed have qualitatively different biological activity, hence, their function in tumor progression is manyfold.

19h and 28h.All cell cultures were negative for CD90 and a-SMA, positive for cytokeratin, whereas vimentin expression varied among cultures.In vivo tumorigenicity was evaluated for 5 primary cell cultures so far using the s.c.xenograft model.Tumor taking rates were 100% for 3 cell cultures, and 80% and 60% for 2 cell cultures.Tumor volumes reached ~1000 mm 3 after 40 days (4 cell cultures) and 90 days (1 cell culture).Mutational profiling identified PTEN, PIK3CA, KRAS, NRAS, BRAF and p53 mutations in the cell cultures.Interestingly, mutation profiles remained identical in the primary tumor, the established cell culture, and xenograft tumor. Conclusion:We here present the first evidence for the establishment of primary EC cell cultures.Moreover, mutation profiles remained identical in established cell cultures, and xenograft tumors, as compared to the primary patient tumor.Hence, we provide an alternative, primary tumor-based model for in vitro and in vivo (targeted) therapeutic drug screening in EC.

Cancer progression is mediated by overexpression of oncogenes and downregulation or loss of tumor suppressors. Proteins, which were traditionally categorized into these groups, have been recently joined by a species of RNA molecules known as microRNAs (miRNAs). miRNAs belong to a class of approximately 22-nt-long non-coding RNAs found in eukaryotes that hinder gene expression by inducing degradation or inhibiting translation of select mRNAs. A growing number of miRNAs have been implicated in promoting or suppressing tumorigenesis in a variety of tissues. The supporting evidence ranges from suggestive expression profiling data to direct functional validation using methods of forward and reverse genetics. We discuss the nature of published results, as well as the merits and pitfalls of various approaches aimed at identification of cancer-related miRNAs and their mRNA targets.

The metabolism of CCl4 initiates the peroxidation of polyunsaturated fatty acids producing α,β-unsaturated aldehydes, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). The facile reactivity of these electrophilic aldehydic products suggests they play a role in the toxicity of compounds like CCl4. To determine the rate at which CCl4-initiated lipid peroxidation results in the formation of 4-HNE and/or MDA hepatic protein adducts, rats were given an intragastric dose of CCl4 (1.0 ml/kg) and euthanized 0–72 h after administration. Rabbit polyclonal antisera directed toward 4-HNE- or MDA-protein epitopes were employed in immuno-histochemical and immuno-precipitation/Western analyses to detect 4-HNE and MDA-protein adducts in paraffin-embedded liver sections and liver homogenates. As early as 6 h post CCl4 exposure, 4-HNE and MDA adducts were detected immuno-histochemically in hepatocytes localized to zone 2 of the hepatic acinus. Liver injury was progressive to 24 h as lipid peroxidation and hepatocellular necrosis increased. The hallmark of CCl4 hepatotoxicity, zone 3 necrosis, was observed 24 h after CCl4 administration and immuno-positive hepatocytes were observed in zone 2 as well as zone 3. Immuno-positive cells were no longer visible by 36 to 72 h post CCl4 administration. From 6 to 48 h after CCl4 administration, at least four adducted proteins were immuno-precipitated from liver homogenates with the anti-MDA or anti-4HNE serum, which corresponded to molecular weights of 80, 150, 205, and greater than 205 kDa. These results demonstrate that 4-HNE and MDA alkylate specific hepatic proteins in a time-dependent manner, which appears to be associated with hepatocellular injury following CCl4 exposure.

Notch-signalling has been implicated as a pathogenetic factor and a therapeutical target in T-cell leukaemias and in some lymphomas of B-cell origin. Our aim was to investigate the role of Notch-signalling in apoptosis regulation in human non-Hodgkin B-cell lymphoma (B-NHL) cell lines and in primary chronic lymhocytic leukaemia (CLL) cells using Delta-like 4 (Dll4) ligand mediated Notch activation and gamma-secretase inhibitor (GSI) mediated Notch inhibition in vitro. The potential cross-talk of Notch with the transforming growth factor-beta (TGFb) pathway in apoptosis induction was also explored, and the effect of GSI on drug-induced apoptosis was assessed. Modulation of Notch-signalling by itself did not change the rate of apoptosis in B-NHL cell lines and in CLL cells. TGFb-induced apoptosis was decreased - but not completely abolished - by GSI in TGFb-sensitive cell lines, but resistance to the apoptotic effects of TGFb were not reversed by Notch activation or inhibition. Drug-induced apoptosis was not modified by GSI. We identified Hairy/Enhancer of Split (HES)-1 as a TGFb target gene in selected - TGFb-sensitive - B-NHL cell lines. TGFb-induced HES-1 was only partially Notch-dependent in later phases. Apoptosis regulation by TGFb and GSI was not dependent on the transcriptional regulation of c-myc. In conclusion, our data does not support a unifying role of Notch in regulating apoptosis in B-NHL, but warns that gamma-secretase inhibitors may actually counteract apoptosis in some cases.

Bevezetés: A molekulárisan célzott gyógyszeres kezelés forradalmasítja a klinikai onkológiai gyakorlatot. A növekedési faktor receptorok és jelátviteli fehérjéinek gátlószerei mellett már megjelentek a programozott sejthalál jelátvitelét közvetlenül aktiváló célzott hatóanyagok is, mint például a sejtfelszíni halálrecepetorokat aktiváló TRAIL illetve a mitokondriális apoptotikus jelutat aktiváló proteaszoma gátlók mint a bortezomib.

Cardiovascular complications are common in patients with type 2 diabetes. Adipokines have been implicated in the induction of proliferative and pro-atherogenic alterations in human vascular smooth muscle cells (hVSMC). Other reports demonstrated the importance of the miRNA cluster miR-143/145 in the regulation of VSMC homeostasis and insulin sensitivity. Here we investigated whether the detrimental effects of adipokines on hVSMC function could be ascribed to alterations in miR-143/145 expression. The exposure of hVSMC to conditioned media (CM) from primary human subcutaneous adipocytes increased the expression of smooth muscle α-actin (SMA), and the miR-143/145 cluster, but markedly impaired the insulin-mediated phosphorylation of Akt and its substrate endothelial nitric oxide synthase (eNOS). Furthermore, CM promoted the phosphorylation of SMAD2 and p38, which have both been linked to miR-143/145 induction. Accordingly, the induction of miR-143/145 as well as the inhibition of insulin-mediated Akt- and eNOS-phosphorylation was prevented when hVSMC were treated with pharmacological inhibitors for Alk-4/5/7 and p38 before the addition of CM. The transfection of hVSMC with precursor miR-143, but not with precursor miR-145, resulted in impaired insulin-mediated phosphorylation of Akt and eNOS. This inhibition of insulin signaling by CM and miR-143 is associated with a reduction in the expression of the oxysterol-binding protein-related protein 8 (ORP8). Finally, the knock-down of ORP8 resulted in impaired insulin-mediated phosphorylation of Akt in hVSMC. Thus, the detrimental effects of adipocyte-derived conditioned media on insulin action in primary hVSMC can be ascribed to the Alk- and p38-dependent induction of miR-143 and subsequent downregulation of ORP8.

Dysregulation of the Notch‐pathway has been implicated in the pathogenesis of chronic lymphocytic leukaemia (B‐CLL). We characterized the mRNA expression of Notch pathway elements in circulating normal B‐ and B‐CLL cells, and compared expression profiles with clinical and prognostic data. Similar expression profiles were found in normal B‐cells and B‐CLL cells, however, most B‐CLL samples showed lower Hairy/Enhancer of Split‐1 expression than normal B‐cells, which suggests that the pathway is not over‐activated in B‐CLL. The expression of Notch‐pathway genes did not correlate with other prognostic factors of B‐CLL. The importance of Notch‐signalling in CLL cells in lymphatic tissue microenvironments remains to be determined.