Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry. Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression in vitro and in vivo that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, modulating its growth through clock-controlled cues, like glucocorticoids.
Overview
- The study aimed to investigate the relationship between daily host signaling, tumor growth, and circadian rhythms in Glioblastoma (GBM) patients.
- The researchers used various methods, including in vitro and in vivo experiments, to assess the effect of daily glucocorticoids on GBM growth and to analyze human GBM samples from The Cancer Genome Atlas (TCGA).
- The study aimed to determine whether blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, could slow down GBM growth and disease progression.
Comparative Analysis & Findings
- The researchers found that daily glucocorticoids promoted or suppressed GBM growth depending on the time of day and the expression of clock genes Bmal1 and Cry.
- Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, significantly slowed down GBM growth and disease progression.
- High GR expression significantly increased the hazard of mortality in human GBM samples from TCGA.
Implications and Future Directions
- The study highlights the importance of understanding the relationship between daily host signaling, tumor growth, and circadian rhythms in GBM patients.
- Future research could investigate the potential therapeutic targets, such as blocking circadian signals, to slow down GBM growth and disease progression.
- It is necessary to develop effective treatments to improve the prognosis of GBM patients and to explore new approaches to entrain the circadian circuit of the brain.