Conclusions The novel ex selleck Ruxolitinib vivo model allowed for the first time to analyze hypoxia regulated gene expression in preserved human lung cancer tissue. The study shows that gene expression profiles in human hypoxic lung cancer tissue overlap with hypoxia signatures from cancer cell lines, however, MME was identified as a novel hypoxia induced gene in lung cancer. Despite the advantages of ex vivo tissue culture, cell monolayers still appear to be the method of choice to study mechanisms of adaptation of individual cell types to hypoxia, since the oxygen concen tration can be controlled only on the surface of such three dimensional structures. Thus we analyzed expression of the hypoxia regulated genes identified in the NSCLC frag ments in different NSCLC cell lines and primary CAFs iso lated from NSCLC tissue.

We show that MME expression is up regulated Inhibitors,Modulators,Libraries by hypoxia in CAFs, not in NSCLC cells. High global levels of MME mRNA in NSCLC tissue were shown in our study to predict poor survival. A direct effect of hypoxia on stromal fibroblast MME expression might thus contribute to enhanced aggressiveness of hyp oxic Inhibitors,Modulators,Libraries cancers. Background Survival following diagnosis of non small cell lung can cer is poor despite therapy. Hypoxia is typ ically present in solid tumors like lung cancer and is known to enhance tumor progression and therapy resist ance. The effects of hypoxia are largely mediated by the hypoxia inducible Inhibitors,Modulators,Libraries factors HIF 1 and HIF 2. HIFs induce the expression of many differ ent proteins that are involved in key functions of cancer cells, including cell survival, metabolic reprogramming, angiogenesis, invasion, and metastasis.

Under normoxic Inhibitors,Modulators,Libraries conditions, HIFs are rapidly degraded, while Inhibitors,Modulators,Libraries under hypoxia they are stabilized. In addition to oxygen dependent regulation, HIFs can be up regulated by other mecha nisms, e. g. growth factor induced pathways. The biological response of tumors to hypoxia is influenced by the interplay of neoplastic cancer cells and the sur rounding stroma cells, e. g. cancer associated fibroblasts. Ex vivo human cancer models based on the short term culture of small tumor fragments or slices are suitable to study tumor responses within the nat ural in situ microenvironment, comprising a close con tact between tumor cells and the accompanying stroma cells. Such models have been used e. g. for the study of drug effects in lung cancer and other cancers.

Here we used a human ex vivo lung cancer model involv ing culture of fresh tumor fragments in a hypoxic selleck chemical at mosphere to mimic in vivo tumor hypoxia and performed a comparative expression profiling study. We found that hypoxia led to overexpression of a stem cell marker with elastase activity, membrane metallo endopeptidase, in tumor fragments, which was attributable to carcinoma associated fibroblasts, not the neoplastic can cer cells.