Clockwork in cancer: the importance of the circadian rhythm in the formation and progression of tumors

In a recent study published in the Trends in Cell Biology journal, researchers from the Swiss Federal Institute of Technology (ETH) reviewed the importance of the circadian rhythm in the formation and progression of tumors.

Study: A new time dimension in the fight against metastasis. Image Credit: kanyanatwongsa/Shutterstock.com

Background

Numerous published studies on cellular and animal models offer remarkable evidence for the circadian clock's direct role in cancer development. Novel research reveals an unanticipated, growing significance of the circadian rhythm in cancer metastasis.

Since metastasis is the leading cause of mortality in cancer patients, studies have taken a particular interest in circulating tumor cells (CTCs) that initiate the metastatic cascade. The influence of the circadian clock on CTC spread and metastasis formation may present an opportunity to discover vulnerabilities and create innovative anti-metastasis therapies.

Cancer and the circadian clock

Studies have shown that night-shift work is associated with circadian misalignment, sleep deprivation, and lifestyle changes like irregular meals, alcohol consumption, lack of physical activity, and smoking, all of which have a chance of posing additional risk factors for cancer susceptibility.

Additionally, shift workers often are in a worse socioeconomic position. Socioeconomic disparities are frequently reflected in lifestyle disparities, including nutrition, associated with cancer risk. Consequently, additional, better-defined epidemiological investigations are necessary to guide public health decisions and future research.

Genetic and non-genetic methods of disrupting the circadian rhythm in mice have demonstrated a link between the circadian clock and the onset or progression of tumors. For instance, genetic deletion of genes Per2 or Bmal1 accelerated lung cancer in mutant mice, resulting in elevated c-Myc protein levels, thus accelerating cancer proliferation and metabolic reprogramming.

Additionally, Cry2 mutation promotes the development of aggressive lymphoma in Eu-Myc models. Also, physiologically perturbing circadian rhythms by chronic jet lag or suprachiasmatic nucleus (SCN) ablation considerably accelerated tumor onset and progression among wild mice, tumor-bearing mice, and tumor-prone mutant mice in multiple mouse cancer models. Cancer models included hepatocellular carcinoma, breast cancer, and lung cancer.

Time-dependent characteristics that affect metastasis

Recent advancements in the study of CTC have proven that tumor microenvironment (TME) modulates CTC intravasation. Studies have also highlighted that hypoxia can upregulate cell-cell junction proteins and cause intravasation of clusters of hypoxic CTCs with improved metastatic characteristics relative to normoxic CTCs.

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Moreover, the interaction between cancer-associated fibroblasts (CAFs) and cancer cell clusters increases the primary tumor's collective invasion. In addition, the interaction between cancer cells and perivascular tumor-associated macrophages (TAMs) generates transitory vascular permeability and cell intravasation by activating the vascular endothelial growth factor-A (VEGF-A) expression.

CTCs acquire resistance mechanisms to defend themselves from hemodynamic-related deterioration via interactions with CAFs and activation of the RhoA–myosin II axis and formins. When CTCs collaborate with neutrophils, their proliferative condition improves, and more effective metastatic development has also been noted. Lastly, dynamic crosstalk between the cancer cells and the TME influences consequent steps in the metastatic cascade, promoting cancer cell colonization and metastasis establishment.

Several investigations have indicated that the CTC formation exhibits diurnal patterns, suggesting that the circadian rhythm regulates metastasis. Recent research indicates that the circadian clock governs the CTC intravasation from breast cancer patients and animal models.

Additionally, the circadian rhythm governs the establishment of the metastatic niche by controlling the biology and functioning of the TME. The production of lung metastasis due to melanoma cells follows a circadian pattern. Neutrophils that collect in the lungs following a time-dependent way regulate the duration of this process.

Utilizing chronotherapy as a possible therapeutic technique

Chronotherapy entails the appropriate timing of drug delivery at a certain phase of the circadian cycle to maximize efficacy and safety. This strategy is based on three significant considerations. Firstly, each pharmacological target's activity and/or expression may fluctuate throughout the day.

Secondly, the generation of adverse impacts and toxicity may be governed by the circadian rhythm. Lastly, the drug's pharmacodynamics and pharmacokinetics may change depending on the time of day. Since most protein-coding genes go through circadian cycling, this strategy is well evidenced.

Along with chronochemotherapy, chronoimmunotherapy is developing as a potentially superior cancer treatment. A recent study found that stage IV malignant melanoma patients who received infusions including immune checkpoint inhibitors nivolumab, ipilimumab, and/or pembrolizumab before 16:30 noted a survival rate that was nearly double as compared to those who received the therapy after 16:30.

These results may suggest that adaptive immune reactions are lesser when initially triggered in the evening than throughout the day. In addition, the median progression-free and overall survival of nivolumab-treated non-small-cell lung cancer patients before 12:45 were tripled compared to patients treated after 12:45.

Conclusion

The study findings showed that while robust characterization of the molecular elements involved in the circadian clock processes in various cell types and tissues exists, additional research should focus on the synchronization of the central pacemaker and peripheral organs.

At the cellular level, future studies should focus on comprehending the crosstalk between canonical and non-canonical clock processes to identify the important and redundant elements defining the circadian rhythm's maintenance. In addition, future research should also assess the role of this crosstalk on the genesis and progression of cancer.

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.