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Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.

Similarity in structure and sequence homology has led to the identification of new members of the interleukin‐1 (IL‐1) ligand and receptor superfamilies. IL‐1F6, IL‐1F8 and IL‐1F9 have been shown to signal through IL‐1R‐related protein 2 and IL‐1 receptor accessory protein leading to activation of NFκB, while IL‐1F7 and IL‐1F10 interact with the IL‐18 receptor and the soluble IL‐1 receptor type I respectively. In contrast, identification of a biological role for IL‐1F5 has remained elusive, with conflicting data relating to its possible ability to antagonize IL‐1F9‐stimulated activation of NFκB in Jurkat cells transfected with IL‐1R‐related protein 2. In this study, we set out to investigate a possible role for IL‐1F5 in the brain and report that it antagonizes the inflammatory effects of IL‐1β and lipopolysaccharide (LPS) in vivo and in vitro including the inhibitory effect on long‐term potentiation (LTP) in rat hippocampus. We demonstrate that IL‐1F5 induces IL‐4 mRNA and protein expression in glia in vitro and enhances hippocampal expression of IL‐4 following intracerebroventricular (i.c.v.) injection. The inhibitory effect of IL‐1F5 on LPS‐induced IL‐1β is attenuated in cells from IL‐4‐defective (IL−4−/− mice). Our findings suggest that IL‐1F5 mediates anti‐inflammatory effects through its ability to induce IL‐4 production and that this is a consequence of its interaction with the orphan receptor, single Ig IL‐1R‐related molecule (SIGIRR)/TIR8, as the effects were not observed in SIGIRR−/− mice. In contrast to its effects in brain tissue, IL‐1F5 did not attenuate LPS‐induced changes, or up‐regulated IL‐4 in macrophages or dendritic cells, suggesting that the effect is confined to the brain.

BackgroundColorectal cancer (CRC) is a leading cause of cancer mortality in the Western world and commonly treated with genotoxic chemotherapy. Stress in the endoplasmic reticulum (ER) was implicated to contribute to chemotherapeutic resistance. Hence, ER stress related protein may be of prognostic or therapeutic significance.MethodsThe expression levels of ER stress proteins calnexin, calreticulin, GRP78 and GRP94 were determined in n = 23 Stage II and III colon cancer fresh frozen tumour and matched normal tissue samples. Data were validated in a cohort of n = 11 rectal cancer patients treated with radiochemotherapy in the neoadjuvant setting. The calnexin gene was silenced using siRNA in HCT116 cells.ResultsThere were no increased levels of ER stress proteins in tumour compared to matched normal tissue samples in Stage II or III CRC. However, increased calnexin protein levels were predictive of poor clinical outcome in the patient cohort. Data were validated in the rectal cancer cohort treated in the neoadjuvant setting. Calnexin gene-silencing significantly reduced cell survival and increased cancer cell susceptibility to 5FU chemotherapy.ConclusionIncreased tumour protein levels of calnexin may be of prognostic significance in CRC, and calnexin may represent a potential target for future therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0948-z) contains supplementary material, which is available to authorized users.