The findings show that glioblastoma (GBM) is deeply integrated into the body’s circadian circuitry, modulating its growth based on biological clock-regulated signals such as glucocorticoids. This understanding opens up new therapeutic possibilities, including circadian-based strategies to optimize chemotherapy use and potentially block the negative effects of glucocorticoids on the tumor.
Glioblastoma (GBM) is the most common and lethal malignant brain tumor in adults. Despite aggressive treatment approaches that include maximal surgical resection, radiation, and chemotherapy with temozolomide (TMZ) combined with the use of tumor-treating fields, the prognosis remains dismal.
The median survival time after diagnosis is only 15 months, and the five-year survival rate is less than 5%. These devastating results highlight the urgent need to explore new therapeutic targets and approaches that can significantly improve outcomes for patients with GBM.
Recent research suggests that the biology of glioblastoma may be influenced by circadian rhythms, which are the 24-hour biological cycles that regulate numerous physiological processes in the human body.
Studies have shown that administering temozolomide chemotherapy according to the time of day may maximize its efficacy. A retrospective clinical study found that patients who took temozolomide in the morning compared with those who took it in the evening had a six-month increase in median survival.
This difference is associated with circadian regulation of the expression of DNA repair enzymes, such as O6-methylguanine-DNA methyltransferase (MGMT), which influences tumor sensitivity to TMZ in cellular and animal models of glioblastoma.
In addition to chemotherapy, patients with GBM often use glucocorticoids, such as dexamethasone (DEX), to reduce tumor-associated brain edema. Although DEX is effective in controlling swelling, its effects on tumor progression are contradictory.
Some studies suggest that DEX may suppress GBM growth, while others indicate that it may stimulate tumor proliferation, promote stem cell characteristics, and reduce the efficacy of TMZ.
These conflicting results may be explained by the failure to consider a crucial factor: circadian rhythms.
Recent research has demonstrated that circadian rhythms in glucocorticoid signaling play a key role in GBM progression.
Studies have shown that administration of DEX in the morning, when tumor expression of the clock gene Bmal1 peaks, promotes tumor growth. In contrast, evening administration of DEX, which coincides with the peak of the Per2 gene, suppresses tumor growth.
These effects have been confirmed in both in vitro and animal models and are consistent with observed changes in body weight: morning administration of DEX accelerated disease progression, while evening or placebo treatment resulted in improved outcomes.
These circadian effects are closely related to the glucocorticoid receptor (GR) and clock genes such as Cry1 and Cry2, which modulate GR activity according to the time of day.
Without glucocorticoids, GR remains in the cytoplasm, bound to chaperone proteins such as HSP90. After binding to glucocorticoids, GR is translocated to the cell nucleus, where it influences gene expression through transactivation or transrepression.
At night, the Cry1 and Cry2 genes repress GR activity, which reduces the transcriptional response to glucocorticoids and modulates their impact on the tumor. Furthermore, GR gene expression in GBM has been observed to vary with circadian timing, suggesting that the tumor's internal clock directly regulates its response to these hormones.
Studies in murine models have confirmed that mice lacking the glucocorticoid receptor or daily glucocorticoid augmentation have smaller tumors, longer survival, and less weight loss.
These findings support the idea that circadian glucocorticoid signaling in GBM directly regulates tumor progression in response to endogenous or exogenously administered glucocorticoids, such as DEX.
Clinical data from human samples from The Cancer Genome Atlas (TCGA) corroborate this finding, showing that high GR expression is associated with a significantly increased risk of mortality in GBM patients.
In summary, glioblastoma appears to act as a “peripheral circadian pacemaker,” synchronizing its rhythms to the host clock to regulate tumor progression.
Glucocorticoid signaling plays a central role in this process, with significant impacts on tumor growth depending on the time of day these hormones or drugs are administered.
The discovery that daily glucocorticoid signaling promotes GBM growth opens new perspectives for the development of therapies that can block or modulate these signals, and suggests that the time of day at which treatment is administered may be as important as the treatment itself.
These findings underscore the importance of integrating knowledge about circadian rhythms into treatment planning for GBM patients to improve outcomes and prolong survival.
Disruption of circadian rhythms in the host slows GBM growth and disease progression. (A) In wild-type (WT) mice, fecal corticosterone (CORT) concentrations followed a typical circadian pattern, reflecting the natural daily cycles of this regulatory hormone. However, in mice genetically engineered to lack VIP (VIP KO), these hormonal rhythms were absent, indicating the loss of circadian synchronization in the endocrine system. (B) Tumor size was larger in WT mice bearing GL261 tumors compared with VIP KO mice, demonstrating that the absence of circadian rhythms reduces tumor growth. (C) Furthermore, VIP KO mice lost less body weight from the beginning to the end of the experiment compared with WT mice. This suggests that disruption of circadian rhythms protects against the overall health deterioration associated with GBM. (D) Analysis of tumor proliferation and tumor area revealed that WT mice exhibited higher expression of Ki67, a marker of cell proliferation, indicating more aggressive GBM growth. In contrast, VIP KO mice showed lower tumor proliferation and size. These differences were visualized in histological images, where brain sections showed cell nuclei (labeled in blue by DAPI) and proliferating cells (labeled in magenta by Ki67). Images of WT mice are highlighted with a yellow frame, while those of VIP KO mice are highlighted with a green frame. Composite images of DAPI to label cell nuclei (blue) and Ki67 immunostaining (magenta) of brain sections reveal tumor location and size.
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Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host
Maria F. Gonzalez-Aponte, Anna R. Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Myung Sik Jeon, Jingqin Luo, Joshua B. Rubin, Erik D. Herzog
Cancer Cell. 2024, ISSN 1535-6108,
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.
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