Our in silico analyses of GEO datasets now reveal significant selleck chem inhibitor correlations between MIF expression and patient outcome. While MIF levels in primary tumours had no bearing on patient outcomes there was a clear indication that high MIF expression levels in metastatic lesions were significantly associated with shorter survival times. Indeed, in the GSE19234 cohort, 70% of patients whose tumours has lower MIF expression remained alive approaching 40 months of clinical follow up. One caveat to consider when linking our in vitro find ings to the clinical setting is the inherent complexity of tumour tissues in vivo. It seems probable that MIF ex pression in melanoma cells has an impact upon their proliferative capacity in vivo but whether the MIF gene expression detected in clinical samples is wholly tumour derived is not entirely clear.

Tumour tissue comprises a non homogenous mixture of tumour and stromal cells including variable amounts of infiltrating immune cells. In breast cancer, MIF is expressed in both tumour cells and stromal cells, including tumour associated macrophages. Indeed, MIF is a key cytokine in both innate and adap tive immune cells and thus infiltrating immune cells must also be considered as an intra tumoural source of MIF. Some breast cancer cells respond to exogenous MIF by triggering a massive burst of MIF secretion suggesting auto or paracrine regulation of MIF. Finally, it is already well established that interactions between the tumour and its microenvironment play an important role in influencing the behaviour of tumour cells.

Again in breast cancer, it was found that MIF was highly up regulated in tumours cells when they were co cultured with macrophages. In turn, increased MIF secretion by tumour cells contributed to metalloproteinase production by the macrophages and this augmented the invasive po tential of the tumour cells. Similarly it is known that tumour associated macrophages can enhance melanoma growth though secreted factors and equally there are other infiltrating cells such as lymphocytes which are also potential sources of MIF. However the rela tive importance of MIF production in melanoma tumour cells versus stromal Drug_discovery cells remains to be established. Conclusions Our results establish the concept that high MIF expression levels in metastatic melanoma is associated with faster re lapse and death. Through in vitro analyses, a mechanism in suggested where MIF expression is associated with acti vation of Akt signalling and promotion of melanoma pro liferation and survival. In the current environment where mutant BRAF status dominates the clinical approach, the effects of MIF signalling are notionally independent of BRAF mutational status.