In a recent study published in Cancer Cell, scientists explore how daily glucocorticoid signaling influences glioblastoma growth and synchronizes its circadian rhythms with the host.

Researchers examine the mechanisms by which glucocorticoid receptor activity, which varies by time of day, modulates tumor progression and how targeting circadian-driven tumor behaviors could be used to treat glioblastoma.

The role of the circadian rhythm in glioblastoma treatment

Glioblastoma is the most common and aggressive malignant brain tumor in adults, with limited survival outcomes despite extensive treatments, including surgery, radiation, and chemotherapy.

Recent research indicates that circadian rhythms, the biological cycles driven by internal clocks, may influence tumor growth and therapeutic responses in glioblastoma.

Unlike many cancers with disrupted circadian rhythms, glioblastoma retains robust circadian activity. Previous studies have also demonstrated that timing chemotherapy treatments according to circadian rhythms improves their efficacy, thus emphasizing the interplay between tumor biology and time-of-day variations.

Glucocorticoids, which are often administered to reduce inflammation and cerebral edema in glioblastoma patients, are also under circadian regulation. Glucocorticoids can either suppress or promote tumor progression; however, the role of circadian rhythms in these effects remains unclear.

Understanding how circadian rhythms contribute to glioblastoma progression has the potential to clarify whether targeting these rhythms might enhance treatment effectiveness for glioblastomas.

About the study

In the present study, researchers use human and murine glioblastoma cell lines and in vivo models to study the impact of daily glucocorticoid signaling on tumor growth and circadian synchronization.

Glioblastoma cells were modified with luciferase reporters for clock genes such as Bmal1, which codes for the brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1, as well as Period2 (Per2) to monitor circadian rhythms in vitro and in vivo.

The synthetic glucocorticoid dexamethasone (DEX) was administered at different circadian phases in vitro and in vivo to assess growth effects.

Glucocorticoid receptor knockdown experiments were also performed using viral-mediated approaches to determine the role of glucocorticoid receptors in these processes.

The in vivo experiments involved orthotopic xenografts, in which human and mouse glioblastoma cells were injected directly into the brains of immunocompromised and immunocompetent mice, respectively.

Tumor bioluminescence was recorded to monitor growth and clock gene expression rhythms.

Mice were subjected to light/dark cycles, constant darkness, and glucocorticoid treatments at specific times to investigate circadian-driven growth dynamics. Control groups consisting of glucocorticoid receptor-deficient tumors were also included to evaluate their dependency on glucocorticoid receptor signaling.

Human glioblastoma patient samples from The Cancer Genome Atlas database were also analyzed to correlate glucocorticoid receptor expression levels with patient survival outcomes. Additional experiments were conducted to test synchronization mechanisms by disrupting circadian signals in mice, such as knocking out vasoactive intestinal peptide (VIP), which mediates circadian rhythmicity.

To confirm the impact of glucocorticoid signaling on tumor progression, tumor tissues were analyzed for proliferation markers like Ki67, which is a nuclear protein that is expressed during all cell-cycle phases except the resting phase, and is associated with tumor proliferation.

Study findings

Daily glucocorticoid signaling promotes glioblastoma growth that is dependent on the time of day. Administering glucocorticoids like DEX was found to enhance tumor proliferation when provided during specific circadian phases.

Glioblastoma tumors treated at the circadian trough of Per2 expression exhibited increased growth, whereas treatments at its peak suppressed growth. These effects were mediated by glucocorticoid receptor signaling and were dependent on intact circadian rhythms within glioblastoma cells.

Knocking down glucocorticoid receptors in glioblastoma cells disrupted the time-dependent effects of DEX, which subsequently reduced cancer cell growth both in vitro and in vivo. In mice, glucocorticoid receptor-deficient tumors grew significantly slower and expressed lower levels of proliferation markers than wild-type tumors.

Circadian disruptions in the host, such as VIP-knockout in mice, also reduced tumor growth and desynchronized tumor clock gene expression from the circadian signals.

The analysis of patient data revealed elevated glucocorticoid receptor expression in glioblastoma tissues as compared to non-tumor samples. Furthermore, high glucocorticoid receptor expression correlated with increased mortality risk, thus supporting the relevance of glucocorticoid receptor signaling in glioblastoma progression.

Conclusions

The current study reveals the critical role of daily glucocorticoid signaling and circadian rhythms in glioblastoma growth. By demonstrating the time-of-day dependency of glucocorticoid effects, circadian modulation emerged as a significant factor in tumor progression.

Taken together, these findings indicate that targeting glucocorticoid receptor signaling and leveraging circadian dynamics may improve therapeutic strategies. Thus, they support future studies investigating the potential importance of chronotherapy in glioblastoma management.