Researchers report that chronic jet lag alters the microenvironment surrounding tumor cells, making it more favorable for tumor growth, and also hinders the body’s natural immune defenses. Their study “Circadian disruption promotes tumor-immune microenvironment remodeling favoring tumor cell proliferation” appears in Science Advances and highlights the rapidly growing scientific field of the effect of circadian disruption on health and wellbeing.
“Circadian disruption negatively affects physiology, posing a global health threat that manifests in proliferative, metabolic, and immune diseases, among others. Because outputs of the circadian clock regulate daily fluctuations in the immune response, we determined whether circadian disruption results in tumor-associated immune cell remodeling, facilitating tumor growth,” the investigators wrote.
“Our findings show that tumor growth rate increased and latency decreased under circadian disruption conditions compared to normal light-dark (LD) schedules in a murine melanoma model. Circadian disruption induced the loss or inversion of daily patterns of M1 (proinflammatory) and M2 (antiinflammatory) macrophages and cytokine levels in spleen and tumor tissues. Circadian disruption also induced (i) deregulation of rhythmic expression of clock genes and (ii) of cyclin genes in the liver, (iii) increased CcnA2 levels in the tumor, and (iv) dampened expression of the cell cycle inhibitor p21WAF/CIP1, all of which contribute to a proliferative phenotype.”
The research was led by corresponding authors Carla Finkielstein, PhD, an associate professor at the Fralin Biomedical Research Institute at the Virginia Tech Carilion School of Medicine (VTC), and Diego Golombek, PhD, a professor at the National University of Quilmes in Argentina.
“A key takeaway from this study is that if someone has a proliferative disorder, in this case melanoma, doing shift work or regularly changing time zones could exacerbate the problem by dampening immune system response to tumor growth,” said Finkielstein, who is also an associate professor of biology in Virginia Tech’s College of Science, and director of the Molecular Diagnostics Laboratory at the Fralin Biomedical Research Institute. “This research also helps explain why some tumors win the race when a person is exposed to the chronically stressful conditions that occur when the environment and the body’s clocks are misaligned.”
The researchers wanted to know how chronic jet lag impacts the microenvironment surrounding cancer cells and examined two groups of mice that were injected with melanoma cells. The first group was exposed to a normal circadian schedule: 12 hours of light and 12 hours of dark. The second group’s light and dark exposure was shifted by six hours every two days—the equivalent of roaming across 21 time zones per week.
A month later, the scientists observed that the tumors in the jet lagged group were roughly three times the size of the control group.
They also examined samples from the microenvironment surrounding the tumor, the spleen, which produces immune cells, and the liver. The researchers found peculiar contrasts in how the immune system responded to the tumor.
For example, the levels of different types of immune cells called macrophages were inverted to be more prone to accept tumor growth in the jet lagged group.
Similarly, the rhythms of other immune cells and molecules, including cytokines, were disrupted. Even though the tumors didn’t spread into their neighboring organ, the liver, or the spleen, the scientists observed that the circadian variations in the immune system in both of these organs were deregulated.
“We combined two different approaches of chronobiology research to study the effects of circadian desynchronization on both tumor growth and immune rhythms, and we found a link,” Golombek said. “You need optimal rhythms in immune cells and immune humoral factors to quell rapid tumor growth. When circadian rhythms are chronically disrupted, these rhythms are impaired, inverted, or disappear entirely, which could help explain why the tumors were significantly larger in the desynchronized group.”
Finkielstein and Golombek plan to continue studying how immune genes and cell cycle genes are related in the context of cancer.
