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Andrea Lius
For several decades, scientists have observed that disruptions to the body’s internal clock, also known as the circadian rhythm, can promote cancer development and progression.1 They also found that many fast-growing cancers have circadian rhythms that are desynchronized from healthy cells. However, glioblastoma (GBM), a deadly and aggressive type of brain tumor, seems to keep a stable circadian rhythm that is in sync with healthy cells in the body.2
In a recent study published in Cancer Cell, researchers at the Washington University found that signaling by glucocorticoids, a key player in circadian rhythm regulation, synchronized GBM’s circadian rhythm with the rest of the body.3 This synchronization, in turn, promoted GBM cell proliferation, tumor growth and disease progression both in vitro and in vivo.
GBM disease progression depends on the circadian rhythm
The circadian rhythm is regulated by a part of the brain called the suprachiasmatic nucleus (SCN), also commonly referred to as the “central clock”. The SCN mostly infers the time of day based on daylight, and this signal is transmitted by neuropeptides, or short amino acid chains that are synthesized and released by neurons and act as chemical messengers. One of these neuropeptides is the vasoactive intestinal peptide (VIP). Researchers in this study found that when GBM is implanted into mice that lack VIP, tumor sizes did not increase and the mice maintained their body weight, which indicated that disease progression was stalled.
To demonstrate that GBM can indeed synchronize its circadian rhythm to host cells, the researchers injected GBM cells into mice, then altered their daily light/dark cycle and observed how the tumor cells adjusted to this change. Since mice are mostly active at night, the researchers used the animals’ physical activity as a metric for the host cells’ circadian rhythm. On the other hand, they monitored the tumor’s circadian rhythm via the expression of “clock genes”, such as basic helix-loop-helix ARNT-like protein 1 (BMAL1) and period circadian regulator 2 (PER2), whose expression levels depend on the circadian rhythm and oscillate throughout the day. BMAL1 expression typically peaks at the end of the mice’s period of activity, around morning time, while PER2’s expression usually peaks at night, following the peak in the mice’s physical activity closely.
The researchers generated genetic constructs which consist of luciferase, an enzyme that catalyzes a light-producing reaction, driven by BMAL1 and PER2 gene promoters. They introduced these constructs separately to GBM cells in a dish or tumors that were later injected into mice. When BMAL1 or PER2 is expressed, the tumor cells glow. This allowed the scientists to observe BMAL1 and PER2 expression patterns throughout the day using live imaging experiments.
In a six-week experiment, the scientists implanted mice with GBM cells, let them live in a normal light/dark cycle for two weeks, flipped their light/dark cycle for the next two weeks, then placed them in complete darkness for the final two weeks. Despite these dramatic changes, the researchers found that GBM’s circadian rhythm, represented by the expression patterns of BMAL1 and PER2, adjusted to follow the host’s circadian rhythm, represented by the mice’s pattern in physical activity. However, when the GBM cells were injected into mice that lack VIP, whose circadian rhythm was completely disrupted and lacked daily movement, PER2 expression levels peaked at random times during the day.
…and glucocorticoid signaling
The SCN regulates the circadian rhythm throughout the body by releasing different signals into the bloodstream—one of these signals is the glucocorticoid hormone. Glucocorticoids synchronize the circadian rhythms of multiple organs in the body, such as the brain, liver, kidney and heart.4 Their level typically peaks in the morning.
The researchers analyzed publicly available data on The Cancer Genome Atlas (TCGA), an online site that contains genomic, epigenomic, transcriptomic, and proteomic data of over 20,000 cancer tissue samples across 33 cancer types and their matched, normal counterparts. By doing this, the researchers found that glucocorticoid receptor (GR) expression is significantly higher in GBM tissue samples compared to healthy controls. In their experiments, the scientists also showed that genetic knockdown of GR stopped tumor growth, prolonged survival and slowed disease progression in mice. Both of these observations indicated the importance of glucocorticoid signaling in GBM.
Moreover, the researchers showed that GBM needs glucocorticoid signaling to synchronize its internal clock to the rest of the body. In a 36-hour live imaging experiment, the scientists found that in normal GBM tumors, PER2 expression peaks with mice’s peak physical activity. However, in tumors that lack GR, PER2 expression peaks at different times throughout the day, mimicking the effect of eliminating VIP.
Synthetic glucocorticoids, such as dexamethasone (DEX), are commonly used to help mitigate brain swelling in patients with GBM. However, there are conflicting reports on whether DEX promotes or halts GBM disease progression. Considering the role of glucocorticoids in modulating the circadian rhythm, researchers in the study hypothesized that the variable effects of DEX on GBM tumor growth could be influenced by the time of day when the drug is administered.
The researchers tested their hypothesis by administering DEX to GBM cells in a dish or tumors in mice at different times of the day. There was an increase in GBM tumor growth and progression when researchers administered DEX in the morning, when glucocorticoid levels are high and PER2 levels are low, compared to when they administered it at night. This time-dependent effect was significantly reduced when the researchers reduced the expression of GR by genetic knockdown, further solidifying the link between glucocorticoid signaling, the circadian rhythm and GBM progression.
The idea that administering treatment at different times may produce different outcomes is not new. In an approach called chronotherapy, cancer treatments are scheduled to maximize effectiveness and minimize toxicities. Chronotherapy arose from the mounting evidence that links the circadian rhythm to cancer. It has been described as far back as 1995.4 Scientists don’t currently know whether the circadian rhythm of glucocorticoid signaling can also drive tumor growth and progression in other cancer types. However, this study demonstrated that it may be an important new factor to consider in chronotherapy and general cancer therapeutics, especially in GBM.
Header Image Source: https://unsplash.com/photos/sunset-over-the-horizon-xP_AGmeEa6s
Edited by Shan Grewal
References
1. Fu L, Lee CC. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer. 2003;3(5):350-361. doi:10.1038/nrc1072
2. Dong Z, Zhang G, Qu M, et al. Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock. Cancer Discov. 2019;9(11):1556-1573. doi:10.1158/2159-8290.CD-19-0215
3. Gonzalez-Aponte MF, Damato AR, Simon T, et al. Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host. Cancer Cell. 2025;43(1):144-160.e7. doi:10.1016/j.ccell.2024.11.012
4. Focan C. Circadian rhythms and cancer chemotherapy. Pharmacol Ther. 1995;67(1):1-52. doi:10.1016/0163-7258(95)00009-6
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