Cancer is among the deadliest and most frequent causes of deaths in humans. Currently, established cancer treatments include radiation, surgery, chemo- and immunotherapy as well as hormonal therapy up to stem cell transplantation. In this article, we take a look at one additional and so far underestimated factor involved in the development of cancer.
The human biological clock, according to a new discovery, should be carefully considered for future cancer remedies. In a study where the circadian mechanism was disrupted in host-tissue and in cancer cells, functional oscillations revealed a link with cancer diagnosis and survival. We attempt to summarize recent advances in the field of chronobiology to help you understand the role of the host’s circadian clock in fighting cancer.
The Clock That Controls Cancer Pathways
A primary clock in the hypothalamus and minor clocks in almost all tissues and organs altogether sets a rhythm for the body’s processes on the time of day. However, the same clock in cancer cells does not function as it should or does not work at all.
Author of Enhancing Circadian Clock Function In Cancer Cells Inhibits Tumor Growth, Nicolas Cermakian says that “There were indications suggesting that the malfunctioning clock contributed to rapid tumor growth, but this had never been demonstrated.”
“Thanks to the use of a chemical or a thermic treatment, we succeeded in ‘repairing’ these cells’ clock and restoring it to its normal functioning. In these conditions, tumor growth drops nearly in half,” he adds.
The molecular bases of circadian clocks are cellular processes generated by a number of rhythmic interconnected clock genes. Analysis on murine tissues revealed that in any given organ or cell-type, hundreds and even thousands of genes move with a circadian pattern, leading to the estimation that nearly 50 percent of all genes fluctuate in at least one organ.
As a result of this, most physiological and cellular tasks show 24-hour oscillations. This is the case of many aspects of the immune system, including its cells and their responses relevant to cancer. Consistently, the proliferation and growth of the cell-cycle show circadian regulation.
Cancer And The Circadian Disruption
A mismatch between the external time and the body’s internal clock messes the circadian network, as shown for example in shift workers. This phenomenon is also linked with a wide variety of pathologies and diseases, including cancer.
Human-based epidemiological discoveries suggest an effect of clock disruption during shift work on cancer risk. For instance, the chance to develop breast cancer becomes significantly higher in nurses exposed to long-term rotating night shift work. Similar outcomes arise for prostate cancer risk in night shift employees.
In 2007, the World Health Organization released a statement classifying night shift work as ‘probably carcinogenic’ to humans. Since then, many health organizations have shown a growing interest in learning how circadian disruption may play a role in cancer development. Experiments and multiple setups were later held and revealed that a disrupted body clock coincides with faster tumor growth.
Mechanism Underlying The Clock’s Power
Since now we understand the relevance of circadian regulation with cancer, it is equally important to know the underlying mechanism behind this. In contrast to healthy cells with a rate of about 24 h, cancer cells are marked by uncontrolled fast cell division. In many cases, the gene cycle is completely altered in cancer cells. This allows them to proliferate and manipulate the circadian control of the body.
Using The Internal Rhythm In Treatments
All the evidence we have today point that using the circadian clock could be a powerful tool in targeting cancerous tumors. Time and again, literature reports say that this flow is related to many cancer-related processes, such as cell growth, cell cycle, apoptosis, and DNA damage.
At the same time, half of the drugs currently on the market are encoded by genes showing circadian regulation. It’s an interesting point to consider and something that adds to the ability of the body’s internal clock in fighting illnesses. What’s more, the body’s natural rhythm in detoxification and metabolism play a huge role in the dynamics of anticancer drugs, and thus, the result of anticancer treatments.
Thus, chronotherapy, the principle of judiciously timed administration of therapies has been recognized as a crucial aspect of fighting cancer. The strategy aims to increase treatment efficacy while minimizing side effects. For example, timed delivery of medication for colon cancer patients showed a better reaction and prolonged their survival.
Targeting The Clock In Tumors
Knowing that the body’s natural clock is extremely relevant to cancer, would it be possible to use it as a way for a cure? Indeed, cancer patients and mouse cancer models have shown disrupted circadian tempo.
In one case, the liver of mice with lung cancer expressed great shifts in its circadian rhythm. Some of its genes were seen to shift earlier or later. In humans, clock-controlled gene expression was documented in the healthy gut tissues surrounding the tumor.
A recent notable study indicates a considerable decrease in circadian activity restricted to murine colon tumor tissue, meanwhile, schedules remain unchanged in healthy colon tissue surrounding the tumor. In fact, the disruption correlates with the patient’s risk and survival. Furthermore, a tumor’s own clock mechanisms may be contributing more to cancer’s growth than the patient’s natural body clock.
In a different research, Papagiannakopoulos and colleagues used two opposite approaches to test the causative link between tumor clock and its growth. They addressed the question by editing the genes and switching off the clock specific in cancer cells. Deleting Per2 or Bmal1 in genetically-engineered mouse models of lung cancer resulted in the increased development in vitro and tumor formation in vivo. This further proves what previous reports showed about the faster spread in cultured cancer cells.
Future Perspective
Editing the tumor clock may grant more time for established anticancer therapies, such as surgical tumor resection and chemotherapy. This innovative idea might help scientists and health care providers improve the outcome of treatments and potentially the patient’s survival. The development of long-term plans to strengthen circadian rhythms in populations at risk, such as shift workers, may meaningfully decrease the risk of cancer.
Sources:
Partch CL, Green CB, Takahashi JS. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 24(2), 90–99 (2014).Crossref, Medline, CAS, Google Scholar
Papagiannakopoulos T, Bauer MR, Davidson SM et al. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 24(2), 324–331 (2016). •• One of the few studies directly addressing the causal effects between tumor circadian clock disruption and tumorigenesis, both in vitro and in tumors in mice.Crossref, Medline, CAS, Google Scholar
Zeng ZL, Wu MW, Sun J et al. Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity. J. Biochem. 148(3), 319–326 (2010).Crossref, Medline, CAS, Google Scholar
Filipski E, King VM, Li X et al. Host circadian clock as a control point in tumor progression. J. Natl Cancer Inst. 94(9), 690–697 (2002).Crossref, Medline, Google Scholar
