Fig. 5: Impact of the clock on angiogenesis and tumour promoting inflammation in GBM.
From: Molecular mechanisms of tumour development in glioblastoma: an emerging role for the circadian clock
a Impact of the clock on GBM angiogenesis. CLOCK/BMAL1 activate the transcription of POSTN via the CLOCK/BMAL1-OLFML3-HIF1α axis. POSTN promotes angiogenesis induction in endothelial cells via activation of TBK1 possibly by integrins, which is proposed to activate the transcription factor IRF3 (Interferon Regulatory Factor 3) leading to the expression of pro-angiogenic factors and directed migration of endothelial cells. Stress of hypoxia or nutrient deficiency activates the UPR-protein IRE1α, which in turn reduces the expression of PER1. PER1 acts as a transcriptional repressor of the pro-angiogenic factor CXCL3. PER2 activates PTEN and therefore inhibits the AKT/SMAD5/ID3-dependent transcription of the angiogenesis-promoting cytokines IL-6, IL-8 and GRO-1. Angiogenesis-promoting factors affect endothelial cells to form new blood vessels. This process is especially important for tumour cells after reaching a certain size to ensure sufficient supply of oxygen and nutrients. b Impact of the clock on GBM tumour promoting inflammation. Tumour promoting inflammation refers to the reprogramming of immune cells to immunosuppressive and tumour-promoting phenotypes. In the context of GBM especially microglia, MDSCs and regulatory T-suppressor cells (Tregs) are regulated by the circadian clock. Microglia are brain-resident macrophages. Tumour promoting inflammation in the context of microglia is promoted by CLOCK/BMAL1, which induces the migration and immunosuppressive phenotype of microglia, as well as secretion of tumour-promoting mediators into the microenvironment. In more detail, CLOCK/BMAL1 activate the TNFα/NF-κB pathway and the LIC-loop to promote tumour promoting inflammation and immune escape. The LIC-loop is a feedforward loop in which CLOCK/BMAL activates the transcription of IL1β and LDHA leading to the production of lactate. IL1β positively influences CLOCK/BMAL1 and LDHA and lactate positively influences CLOCK/BMAL1 and IL1β. CLOCK/BMAL1 induces the reprogramming of microglia via the HIF1α/OLFML3/LGMN axis. Reprogrammed microglia suppress immune cells, promote tumorigenesis and acquire an infiltrative phenotype. Reprogrammed microglia also signal back to the tumour cell by exosomes containing miR-7239-3p to increase CLOCK and reduce BMAL1. RORα negatively affects tumour promoting inflammation in MDSCs and Tregs via inhibiting the secretion of tumour promoting cytokines into the TME, as well as inhibiting their differentiation and function as suppressor cells. It acts by activating NDRG2, which in turn reduces the JAK2/STAT3-dependent expression of IL-6. It also negatively regulates the TNFα/NF-κB-dependent expression of various cytokines associated with immune responses. RORα is negatively regulated by miR-10a and miR-18a. The figure was created with BioRender.com.
