Cancer transcriptomics : from model studies to predictive factors Lectures L 20 . 1 Glioma-released factors induce non-inflammatory transcriptional activation of brain macrophages

Microglial cells are brain resident macrophages, activated in response to pathological conditions, including infections, brain injury, and tumors. While microglia activated by an infection exert a protective role, microglia activated in response to gliomas fail to exert an anti-tumor effect. We previously demonstrated that glioma cells secrete soluble factors, which convert microglial cells into amoeboid cells supporting glioma invasion, while attenuating inflammatory responses. Our studies indicate that gliomas can activate brain macrophages in an alternative way, different from the classical activation in response to proinflammatory stimuli. To gain an insight into transcriptional differences between these two ways of macrophage activation, we performed gene expression profiling of primary rat microglial cultures, stimulated either by Glioma-Conditioned Medium (GCM), or by a classical inflammation inducer — lipopolysaccharide (LPS). 174 genes significantly changed expression following the GCM treatment, 1794 — following the LPS treatment, and 63 – following both treatments (p=0.001, FDR<0.002 for the LPS dataset, and FDR<0.04 for the GCM dataset). Among the genes up-regulated by LPS we identified a large group of interferon-related genes. These genes were either not affected or down-regulated by GCM. Interestingly, Uba7-encoding an enzyme modulating the response to interferons was strongly down-regulated by GCM. Genes differentially regulated by the two treatments included also potential modulators of Stat3 and NFκb signaling. Last, but not least, GCM induced mRNA expression of transcription factors: c-Myc, Smad3 and 7, Id1 and 3. Analysis of the functional GO annotations revealed immune/defense/inflammatory response as the top terms associated with the genes induced by LPS. Primary metabolic process was the highest-ranking GO term associated with gene induction by GCM. More specific terms associated with the induction by GCM include: translation, negative regulation of transcription, TGFβ/SMAD signaling, chemokine signaling. We conclude that the transcriptional changes induced in microglial cells by GCM are different, and partially opposite, to the changes induced by LPS. Some of the identified differentially regulated genes may play a role in the alternative activation phenotype. L20.2