summary: Glioblastoma, an aggressive brain tumor, synchronizes its body clock to the host’s circadian rhythm and uses daily hormonal cycles for growth. Blocking these signals slowed tumor progression in mice, revealing that the timing of treatments such as dexamethasone (DEX) has a critical impact on outcome.
Administration of DEX in the morning promoted tumor growth, whereas administration in the evening inhibited tumor growth. These findings highlight the potential of chronotherapy (adjusting the timing of treatment to match the body’s biological clock) as a personalized approach to managing glioblastoma.
important facts
- Circadian synchronization: Glioblastomas grow in accordance with the host’s daily hormonal rhythms.
- Timing is important: Morning DEX administration promotes tumor growth. Evening administration suppresses it.
- Possibilities of chronotherapy: Aligning the timing of treatment with circadian rhythms may improve outcomes in glioblastoma.
sauce: wasl
Almost every cell in the human body has a biological clock. These clocks get their signals from the brain’s central clock. In a normal biological process called entrainment, a central clock coordinates daily rhythms throughout the body so that all cells and tissues perceive the same external time.
Knowing local time helps our bodies regulate important processes such as when to sleep and wake up, when to eat, and what temperature to maintain, among many other important functions. Masu.
But the dreaded intruder is also biding his time.
Glioblastoma is an aggressive, incurable brain tumor and the most common malignant brain tumor in adults. A new study from Washington University in St. Louis shows that glioblastomas have internal body clocks that synchronize and take advantage of their daily rhythms with those of their hosts. In this way, brain tumors grow in response to steroid hormones, such as cortisol, released daily by the host.
WashU scientists have discovered that blocking circadian signals dramatically slows glioblastoma growth and disease progression. The process worked both in cells in petri dishes and in animals with tumors, according to a study published Dec. 12 in the journal Cancer Cell.
“Glioblastomas take their cues from hormones released from the same central clock in the host that establishes the body’s regular daily rhythms,” said Victor Hamburger Distinguished Professor of Biology and Professor of Biology in the College of Arts and Sciences. said lead author Dr. Eric D. Herzog. of research.
“Blocking the daily surge of glucocorticoid signaling desynchronizes glioblastoma circadian rhythms from the host and dramatically slows disease progression in tumor-bearing mice.”
“Our previous research has helped us understand patterns,” said Dr. Maria F. Gonzalez-Aponte, lead author of the study.
“Whether we look at clinical data or when we look at cells from patients with model glioblastoma tumors and mice, chemotherapy treatments have always been most effective during normal waking hours. This is why these tumors That’s why we thought it knew the time outside.”
“This study provides another example of how contextualized research in real-world biology is important for improving cancer treatment. Synchronizing therapy to circadian time extends survival. “We didn’t need new drugs,” said Joshua, a professor of pediatrics and neuroscience at WashU Medicine, a longtime collaborator in Herzog’s lab and a co-author on the paper. – said B. Rubin, MD.
The finding is important because it affects the response of glioblastoma tumors to a drug called dexamethasone (DEX), a synthetic steroid commonly given to glioblastoma patients to reduce brain edema after radiation or surgery. It is to give. The study found that giving DEX in the morning promoted tumor growth in mice, while giving it in the evening suppressed growth.
“The use of DEX in glioblastoma has remained controversial for many years, with studies showing either growth-promoting or growth-inhibiting effects,” said Professor González-Aponte.
“Knowing that glioblastoma has a diurnal cycle, we immediately asked whether the time of day of DEX administration could explain these different findings. is.”
“The interaction between brain tumors and the circadian system is now a targetable mechanism to optimize therapy,” Herzog said.
reset the clock
Every day, just before a person or animal wakes up, in response to light and other environmental signals, the brain sends a signal to the adrenal glands to produce a surge of steroid hormones called glucocorticoids.
These hormones are involved in the well-known fight or flight response. But they also regulate a variety of more important biological processes, such as metabolism and immunity.
“Under normal conditions, glucocorticoid levels increase dramatically every day before you wake up,” Gonzalez-Aponte said. She and Herzog hypothesized that glioblastomas might respond to this reliable daily burst of glucocorticoids by synchronizing their clocks with their hosts.
To test this idea, Gonzalez-Aponte first decided to see if resetting the host’s daily rhythms could disrupt a tumor’s sense of timing.
She placed the tumor-bearing mice in cages that could be made brighter or darker using a timer. Gonzalez-Aponte persuaded the rats to adopt the opposite schedule by moving them when he turned on the lights. She knew it was working by observing when the mice started running on wheels each day.
“Rats use wheels to run more at night than during the day,” says Gonzalez-Aponte. “If you reverse the light-dark schedule, it’s basically like flying from St. Louis to India. You’re forcing a resynchronization.”
As the mice followed the new reversal schedule, the scientists monitored the cancer cells in the tumors in the mice’s brains for changes. They used a new method to image clock gene expression in cancer cells in freely behaving mice, collecting data every minute for several consecutive days.
Scientists have observed that there are two clock genes in cancer cells. Bmal1 and per 2they changed their schedules just as the rats changed their schedules.
“What we found was Bmal1 and per 2 It does the same thing that a mouse does with its wheel. In other words, just as mice resynchronize their motor activity, cancer cells resynchronize their rhythms,” said Gonzalez-Aponte.
Similarly, in the absence of environmental timing cues, tumors remained synchronized with the host, even under conditions in which mice wake and sleep according to their own circadian cycles.
More than just a wake-up signal
Glucocorticoids are just one of the circadian signals that have been shown to synchronize the clocks of cells around the body. However, glucocorticoids are important in the context of cancer treatment because synthetic steroid hormones are sometimes used in high doses to treat symptoms that cancer patients experience after surgery or treatment.
DEX is a synthetic glucocorticoid. It is often given in addition to chemotherapy and is sometimes given to glioblastoma patients to reduce brain edema that occurs after surgery or radiation therapy.
However, despite its widespread use, doctors and scientists continue to report mixed results regarding DEX. Some studies have shown that DEX has tumor suppressive effects, while other studies have shown that DEX promotes the proliferation of glioblastoma cells.
Gonzalez-Aponte and Herzog argue that if glioblastomas have their own reliable circadian rhythm, their response to DEX (a synthetic glucocorticoid hormone) depends on the time of day the DEX is administered. I thought that there was a possibility that this might change.
They designed an additional series of experiments to show that glucocorticoids promote or inhibit glioblastoma cell proliferation depending on the time of day. Researchers found that in mice with glioblastoma brain tumors, DEX administered in the morning significantly increased tumor size compared to evening or control administration.
Professor Gonzalez-Aponte said these findings in mice have implications for the use of glucocorticoids like DEX in the clinic. Additional studies are needed to determine whether there is time to use DEX to reduce brain edema without promoting glioblastoma growth.
“Timing is a key variable as we continue to study how this brain tumor grows, how it interacts with other cells in the brain, and how it responds to treatment.” It is important to recognize that
Using data from publicly available cancer databases, researchers found that glioblastoma patients tended to live 60% longer if their tumors expressed less glucocorticoid receptors. I discovered it. This will prompt clinical trials aimed at avoiding morning DEX treatments.
“To critically evaluate the potential of chronotherapy in various cancers, we need to consider how daily rhythms arise and are synchronized in specific tissues,” Herzog said.
“It is important to understand how circadian rhythms regulate tumor biology in cell- and tissue-specific contexts,” said Dr. Herzog.
“We believe this tractable and translatable approach will ultimately personalize patient care by determining when to administer treatments according to a cancer patient’s individual circadian rhythm. Masu.”
About this brain tumor research news
author: Thalia Oriole
sauce: wasl
contact: Talia Oriole – WUSTL
image: Image credited to Neuroscience News
Original research: Open access.
“Daily glucocorticoids promote glioblastoma growth and circadian synchronization to the host.Written by Eric D. Herzog et al. cancer cells
abstract
Daily glucocorticoids promote glioblastoma growth and circadian synchronization to the host.
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has a poor prognosis despite aggressive treatment.
Here we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM.
We found that daily glucocorticoids promote or suppress GBM proliferation via glucocorticoid receptor (GR) signaling depending on time of day and clock genes. Bmal1 and cry.
Blocking circadian signals such as vasoactive intestinal peptide and glucocorticoids dramatically slows GBM proliferation and disease progression.
Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases the risk of mortality.
Finally, mouse and human GBM models have inherent circadian rhythms in clock gene expression. in vitro and in vivo It is taken up by the host through glucocorticoid signaling, regardless of tumor type or host immune status.
We conclude that the GBM is entrained by the brain’s circadian circuits and regulates its growth through clock-controlled cues such as glucocorticoids.
