This series of three articles on the circadian rhythm will present a perspective on the importance of its temporal cadence in regulating and maintaining the harmony and balance of the body’s metabolic processes, and the effects of its disruption on cancer development and progression.

Beneath the surface of sunrise, with waking and alertness and sunset with preparation for sleep and rest there exists an internal daily 24 hour cycle, the circadian rhythm (CR). It acts as our central clock, regulated by day and night light signals and synchronized to the brain's master time keeper, the suprachiasmatic nucleus (SCN). 

The suprachiasmatic nucleus, SCN, coordinates the actions and timing of multiple biological and behavioral pathways using neurotransmitters and hormones to regulate the specific timed expression of local “clock” genes in organs and tissues. Each system’s activities operate on an individual synchronized timed feedback loop, coordinated by the SCN, requiring that each to pardon the pun, “run like clockwork” if survival and equilibrium within the body is to occur. 

And it is when these rhythms become disrupted that the body’s balance and harmony become negatively impacted setting the stage for disease.But maintaining lifestyle patterns that mimic and synchronize circadian rhythms appears to reduce cancer recurrence and progression.

Understanding the Global Circadian Rhythm in Health and Its Impact on Cancer When Disrupted (Part 1)

The Cycle

Fluctuations in environmental light signals govern the global circadian cycle. Light sensitive photopigments in the retina called melanopsins activate retinal ganglion cells which are connected directly to the central nervous system via the optic nerve, bypassing customary visual cues. Its stimulation then activates the 20,000 neurons of the suprachiasmatic nucleus, SCN, the master regulator, located in the hypothalamus of the brain that activate the neuropeptide hormones, vasoactive intestinal peptide (VIP),Gastrin-Releasing Peptide (GRP) and arginine Vasopressin( AVP). These hormones trigger cellular activity in local “clock genes”. located in peripheral organs and tissues to produce proteins which regulate thousands of metabolic activities, based on the specific time sequences needed for each organ’s essential functions. 

A metaphor used to describe the circadian rhythm and its interactions is described by Drs Assis and Oster in the journal, Cellular Molecular Life Science, 03/2021, as an orchestral model in which the SCN acts as the conductor which provides the hormonal or nervous system information (music) to each member of the orchestra (organ or tissue) allowing them to play their instruments (pathways) to control and regulate their individual biologic and behavioral processes, but always within the context of the overall musical composition (CR), orchestrated by the conductor (SCN) directing the entire ensemble. 

This regulation of the circadian rhythm is considered so important that The International World Health Organization has recently categorized disruption of the circadian rhythm as a probable carcinogen linked to development of cancers of the breast, prostate, colon, liver, ovary and pancreas, as well as being associated with earlier cancer deaths and reduced effects from cancer treatments.

This Master SCN Clock specifically interacts with the rhythmic light patterns regulating the sleep wake cycle, coordinating complementary local clocks. However, societal cues affecting sleep/wake cycles and modern variabilities of activity levels and eating schedules can misalign this synchronization.

Cancer studies using cell tissues, in the lab, show that chronic circadian desynchronization encourages multiple cancer pathways that promote cancer proliferation. Similar data has also been validated in clinical patient research, showing that decades of CR disruption in shift work patterns of overnight working, very early morning or late evening work schedules appear to be associated with increased cancer risk and other chronic diseases.

And now this pattern of increased cancer risk is being seen in students and many working 9-5 jobs that have adopted lifestyles that mimic shift worker schedules that promote circadian rhythm disruptions.

The Normal Circadian Rhythm Regulated Stages of Sleep

  • Non Rapid Eye Movement Sleep (NREM) is our restorative sleep, which is divided into three stages: (1) passing from wakefulness to light sleep, then into (2) true sleep with diminished awareness of surroundings, the lowering of body temperature and the slowing of the heart. It is here that memory consolidation and information processing from the day occur. The last part (3) is deep sleep, essential for our restoration and recovery from the day. It is here that tissue repair, muscle recovery, and immune system strengthening occurs. It is also during this cycle that hormones and metabolism are harmonized and balanced over its 90-minute cycle.

  • Rapid Eye Movement Sleep (REM) describes sleep in which eye movements beneath the closed eyelids occur. It implies an awakened, active brain that is creating vivid, complex dreams. During this time, the voluntary muscles in the body become temporarily paralyzed while the brain is active, as measured by its increased oxygen consumption and its metabolism. During this cycle, emotions are processed, memories consolidated, and creative solutions revealed, and daily experiences are moved into long-term storage for future retrieval.

External Factors That Cause Imbalances That Disrupt of Circadian Rhythms

Sleep Disruption, Insomnia

Insomnia is a sleep disturbance that causes chronic issues with sleep initiation,night waking or reduction in sleep duration, which fragments and reduces needed restorative and repair time. Disruption of the sleep/wake cycle is the primary initiator of circadian rhythm dysregulation – creating a domino effect; affecting the SCN, the peripheral clock genes, tissue and organ rhythms and ultimately the body’s biologic pathways. 

Please see the following article on ways to correct sleep imbalances.

Chronically, Sleep disruptions negatively affect:

  • Cellular DNA repair

  • Autophagy, recycling of components

  • Apoptosis, protective programmed cell death 

  • Immune functions

  • Sleep regulation

  • Digestion and Appetite

  • Inflammatory responses

  • Glucose control

  • Detoxification

  • Impaired storage of daily experiences into memory 

  • Hormonal imbalances 

  • Overall metabolism

Lifestyle Disruptors 

Artificial Light’s Impact On Sleep

For centuries, activities occurred in the daylight until darkness. Summer expanded daylight hours and winter brought darkness and shelter at an early hour. But today, exposure to ubiquitous artificial blue light from street lights, home LED light bulbs and fluorescents, along with blue lighting on phones, tablets and laptops, and the enhanced and continuous bright lightning in work spaces, homes and schools create prolonged daylight conditions which contribute to the dysregulation of normal circadian sleep wake rhythms.

International data states that 80% of the world’s population is exposed to light at night.

Twenty percent of the work force is engaged in night shift work. These people are working hours distinctly opposite the common daytime “9-5”. Some adjust to this lifestyle and shift their circadian rhythm. However, one third have difficulty falling and staying asleep during daylight hours, and then remaining alert and awake at night when the body is geared to be winding down. Studies show these people have diminished focus and concentration, irritability and increased risks of accidents or injury. But importantly, this pattern of work is associated with cardiovascular disease, metabolic syndrome, obesity and cancer.

Solutions to Reduce Exposure

  •  Utilizing blue light free bulbs or soft white and fluorescent bulbs emit less blue light. 

  • If late evening or night screen time is needed, adding an orange filter to reduce blue light will improve sleep quality. There are multiple screen protectors or glasses available.

  • If using blue light bulbs, shield the light, direct its focus downward. 

  • Using motion and light sensors allows light exposure only when needed.

  • In urban areas outside illumination can produce significant exposure to artificial blue light. Sleep areas benefit from window coverings or a night mask.

A 2023 analysis of studies of multiple databases demonstrated that night exposures to light increases the risk of breast cancer, especially in Asian women.

Food Availability, Late-Night Eating and Sleep

In modern contemporary life food is available, whenever someone wants to eat, at any time,day or night.

And night eating can offer pleasurable ways of coping with daily life. If the day is stressful, and carried home, emotional eating can be a source of comfort. With constant stimulation in our busy lives, lack of activities at night can lead to eating from boredom, or stimulation from media or TV, with their constant advertising of food can seduce some people to go out to grab a taco bell.

Rhythmic signals and appetite normally extend from morning to early evening being coordinated by two hormones, ghrelin and leptin. Ghrelin is a hormone produced by intestinal/endocrine cells, primarily in the stomach, that helps regulate energy balance and signals the brain to trigger hunger, with increased appetite and the desire to eat. Once food is consumed, another hormone,Leptin, produced in fat cells, signals the brain that there is enough energy absorbed and produces feelings of satiety or fullness. Late-night eating lowers leptin creating extended feeling of continued hunger, while at the same time raising ghrelin levels, increasing appetite.

So what happens with late-night eating?

  • Melatonin's production is delayed interfering with sleep initiation

  • Cortisol levels are stimulated, increasing inflammation. 

  • Neurotransmitters, dopamine and serotonin become dysregulated potentially affecting moods and behavior as well as quality of sleep. 

  • Digestive disturbances causing upset stomach and acid reflux and poor absorption of nutrients.

  • Slowing of metabolism and caloric burn along with blood sugar elevation combine to promote fat storage and increased risk of obesity.

  • Late-night eating is also associated with elevated blood pressure and increased risk of cardiovascular disease.

The recognition that erratic or late eating contributes to cancer development prompted research documenting that 

  • Women who eat during the day for 11-12 hours and then fast for 12 hours reduce their breast cancer risk 

  • Studies from European countries show that avoiding late evening dinners reduces both breast and prostate cancer risk.

The Circadian Rhythm and Hormone Balance

Cortisol

Cortisol is an important hormone for the modulation of inflammation and for its effect on the regulation of the sleep cycle, both of which impact the repair and recovery from the effects of cancer treatment, and can potentially reduce the risk of recurrence. 

The hypothalamic-pituitary axis, the HPA, regulates cortisol through the stimulation of the hypothalamus secretion of corticotropin-releasing hormone, CRH.

The normal cortisol cycle activates in the early morning from the blue light spectrum, rises till mid afternoon, declines toward evening and reaches its lowest point in the night. Its normal rhythmic effects modulate day time inflammation by suppressing immune responses , assists in blood glucose regulation, affect lipid and protein metabolism and regulates salt and water metabolism.

The classic response to acute danger or a perceived threat results in a series of instinctual spontaneous reactions. In acute situations, whether physical or emotional, there is a transient surge of cortisol, which results in its transient elevation to mobilize glucose energy stores for preparation of fight or flight.

Chronic situations that cause persistent elevations of cortisol disrupt this normal sleep wake cycle and include stressors, chronic pain, lack of exercise, inappropriate diet, persistent nighttime light exposure and for cancer patients, the side effects of treatment or charged triggers associated with living with a cancer diagnosis. This continued cortisol production chronically raises cortisol levels resulting in

  • Poor sleep initiation

  • Night waking

  • Daytime sleepiness as relative levels do not increase, but at night remain elevated with people feeling wired but tired.

  • Restlessness

  • Lower sleep efficiency, or the time that you stay in bed

  • Fatigue, with minimal or no relief even with napping 

Melatonin, N-Acetyl-5-Methyoxytryptamine

Is a neurohormone synthesized from serotonin and secreted by the pineal gland, as daylight diminishes. It reminds the body it is time to sleep,improves initiation and quality of sleep. It has a significant interrelationship with cortisol; for as cortisol levels dip,melatonin levels rise allowing restorative sleep. And as morning approaches with increased blue light, melatonin decreases and cortisol starts to rise. Persistent chronic elevated cortisol levels suppress melatonin release and reduce its effect on sleep.

While melatonin is associated with the regulation of the sleep wake cycle, other less familiar effects on cancer include

  • Enhancement of T cell function and immune responses to fight cancer while diminishing the effect of regulatory T cells, tumor associated macrophages, cancer associated fibroblasts, and myeloid derived suppressive cells all of which drive cancer cell growth. 

  • Modulates of tumor suppressor genes

  • Regulates apoptosis

  • Antioxidant effects

Growth Hormone

Growth hormone is regulated by the circadian rhythm, being intermittently released throughout the night, seemingly corresponding to cycles of slow wave sleep. Its effects support energy metabolism and utilization, support of structural components in the body, the muscle and bone density. Its dysregulation with sleep disruption increases risks for obesity and metabolic syndrome.

Medications Affecting Sleep

Multiple classes of pharmaceuticals have the potential to disrupt sleep rhythm 

  • B Blockers used for cardiac arrhythmias and hypertension decrease melatonin

  • Steroids increase cortisol 

  • Diuretics increase night awakening to urinate

  • Antidepressants can affect people differently, and for some are stimulating, and might be taken in the morning instead

  • Dementia drugs have an alertness effect and can disrupt sleep

  • Opioids affect onset of sleep and staying asleep

  • ADHD drugs lengthen the time it takes to go to sleep

  • Asthma inhalers, for acute use, are stimulating

Cytokines

 Are immune modulator proteins that are secreted during the night, in two phases, and regulate inflammatory responses and immune activity.

  •  Early at night, TH1 cytokines stimulate an immune cellular response to remove foreign antigens. Overactivity imbalances can stimulate autoimmune responses.

  • Later at night, Th2 cytokines are stimulated which act to convert B cells into plasma cells that make antibodies. Overactivity is associated with allergy. 

 In situations of disruption of the circadian rhythm these phases can become imbalanced and are associated with tumor development.

Lipid Metabolism

Clock gene activity is diurnal and essential for lipid metabolism of fatty acids, cholesterol, phospholipids and triglycerides. It is now recognized in epidemiologic studies, the study of the combined factors influencing the presence of a disease, that dysregulation of the circadian rhythm is associated with increased risk of abnormal lipid synthesis, transport, absorption and storage which impairs normal cell membrane lipid repair and maintenance. 

Local Clock Disruptions

SCN, suprachiasmatic nucleus input, based on light fluctuations, regulates cyclic release of neurotransmitters and hormones to create genetic signaling to the peripheral clocks initiating their activities. These alterations, called epigenetic responses, leave DNA unchanged affecting only the genetic expression. These same types of effects can come from sources unrelated to the circadian rhythm producing responses that are out of sync with the normal rhythms and capable of disrupting the overall body balances.

The SCN activates multiple peripheral clock genes, BMAL1, Clock, PER1(period) and PER2, CRY (cryptochrome) and TIM (timeless) which are actually the time keepers that respond to day and night cycles. Each has a unique regulatory effect on cancer affecting the timing, interval of action and strength of response of physiologic responses. 

CRY Clock gene places a role in maintenance of circadian rhythms.

Currently there is ongoing research to evaluate various molecules that can target clock genes to improve cancer treatment and outcomes. Many studies of clock gene targeted compounds are being conducted,one example:

CRY proteins can be appropriated by cancer and used to increase its growth.

  • A new compound, SHP 1705 activates the CRY clock epigenetically, specifically in glioblastoma. In preclinical studies , it impairs its stem cells while not affecting normal cells. 

Other clock genes 

When downregulated 

  • PER1 inhibits cancer cell invasion

  • PER 2 inhibits cancer cell replication and invasion

  • BMAL1 suppresses cancer spread

When upregulated 

  • TIM inhibits cancer cells

  • CLOCK strengthens cancer stem cells

Environmental Disruptors

Recent information now recognizes environmental pollutants, including benzene, tobacco smoke, heavy metals, microplastics and pesticides, as capable of imbalancing the clock genes. Their overexpression or repression of physiologic activities are associated with increased cancer risk for Renal Cell carcinoma progression,Liver cancer development,Breast cancer, Colon cancer.

Exercise

Exercise is closely related independently to skeletal muscle clock genes without involving the SCN.

  •  Studies indicate peak levels of performance and muscle strength are achieved in the late afternoon or early evening. At those times the muscles power, force and maximum oxygen utilization are increased.

However 

Physical activity in the morning is useful to augment daytime alertness but when excessive, and especially in the late evening can postpone melatonin release and sleep induction.

  • A recent study of Chinese college students examined the relationship between physical activity and depression based on its epigenetic effect on DNA methylation in the expression of PER2 and CRY1 clock genes.

Two patterns of physical activity were seen and followed for two years, those with a continued high level of exercise and those with a gradual low level. The students performing long term low levels of exercise in terms of intensity and duration had moderate to severe depressive symptoms. In the high intensity group, these symptoms appeared to be dampened by methylation effects on these clock genes.

So it appears that this is another aspect of exercise that suggests benefit that may add quality of life to cancer survivors.

The Gut Microbiome, Immunity and Pathogens

These areas are shown, in mice models, to be influenced by the circadian rhythms activation of the peripheral clock genes,

The microbiome within the gut is influenced by the circadian rhythm’s control of gastric acid, intestinal motility, gut absorption and mucosal protection, and the timing of food intake, its quality and quantity.

Within the intestine there are thousands of microbial species which influence immune functions.

  • Commensal or beneficial bacteria produce short chain fatty acids (SCFA) from the fermentation of fiber, helping regulate immune function, enhancing T cell function. reducing inflammation, supporting a strong barrier and reducing leaky gut. Changes in peripheral clock expression affects SCFA levels.

  • Recent research has shown circadian rhythm disorders change the gut microbiota and in some instances affects metabolic pathways that remove toxic metabolites in the gut affecting health.

  • The circadian rhythm affects the types and actions of the microbiome impacting immune T Helper Cells, T Regulatory cells needed for immune responses.Disruption of the sleep-wake cycle is reflected in a reduced immune response for gut protection from foreign pathogens.

  • Other immune responses are influenced by circadian rhythm control. The patterns of expression for different pathogen receptors including toll like receptors (TLR), Nod like receptors (NOD) which detect pathogens ,are reduced with CR disruption.

There is significant cross talk between the circadian rhythm, the intestinal microbiome and the immune system and these above are just a small sample of current research into these interactions.

Optimum immune protection and microbial balance require harmony of the the circadian rhythm. Adaption of a lifestyle that maintains the sleep wake cycle and dietary patterns can be a major contributor to overall health and prevention of illness.

It also offers potential approaches for enhanced immune responses and protection.

Circadian Disruption and its Effects on Cancer

Current research has shown a strong interplay between the circadian rhythm and cancer development and progression. In normal cells, peripheral circadian clocks, controlled by the SCN, exert strong control over DNA replication, immune related inflammation, activation of tumor suppression genes and limited oncogene activation pathways.

Cancer’s ability to disrupt this rhythm creating epigenetic modifications in clock gene expression allows them to escape regulation and to facilitate continued tumor growth and the conversion of normal cells to cancer cells.

The Immune System

It is important for Immune cells to mount a response to foreign substances, antigens, but it is also necessary to prevent over-expression that potentially could lead to autoimmune disease. One control mechanism is the presence of the PD-1, programmed cell death protein-1 receptors on the surface of T cells that plays an essential role in immune system down regulation to prevent overactivity.However, this action interferes with the immune system's antitumor killing and surveillance effects in response to cancer. 

The circadian rhythm, via clock genes, provides timed cycles of PD-L1, programmed cell death protein production. 

  • Currently, anti PD-I drugs are being used in several cancers, triple negative breast cancer, renal and bladder cancer , Hodgkin's lymphoma, melanoma and non-small cell lung cancer. These drugs act to prevent PD-1 action thereby taking the block off the immune system allowing the body’s own anti-cancer responses to be more aggressive.

The circadian rhythm affects the timing of production and activity of PD-1 proteins suggesting that if anti PD-1 therapies are aligned with the circadian cycle, less immune blockade would occur making treatment more effective

Studies have also shown the reverse, that in CR disruption, patients receiving anti PD-1 drugs in lung cancer have a worse prognosis and increased drug resistance

  • If the sleep wake cycle is disrupted, an imbalance between the timing of TH1 cytotoxic helper cell activity and TH2 antibody helper cell activity occurs potentially leading to chronic inflammation and tissue injury, a hallmark of cancer.

Epigenetic changes involving clock gene expression,while complex, have shown

  • The effects of environmental disruptions of the CR, light exposure, diet and nutritional changes and stress can cause abnormal expression of PER 1 & 2, disrupt DNA damage repair creating increased cancer risk.

  • P53 is a tumor suppressor protein whose replication and activity is controlled by BMAL1 and PER2. If these clock gene actions are disrupted P53 actions are affected adversely and are associated with increased risk of lung, liver and ovarian cancer.

  • Normal cells have a limited ability to replicate while cancer cells are considered immortal as they can continue to indefinitely replicate. Cancer is able to do what normal cells can't by activating the telomerase enzyme to add DNA sequences to the end of chromosomes, the telomeres. This prevents the normal telomere shortening seen in aging and senescent cells resulting in death.

Tumor Microenvironment

This environment consists of a terrain with immune reactive and suppressive cells, an extracellular matrix composed of collagen ,enzymes and structural support components and vascular endothelial cells that allow new blood vessel growth.

Cancer cells alter this environment to allow support of proliferation and spread.

In their totality, the multiplicity of interactions for protection and destruction of cancer cells versus and their growth and metastasis , while complex, and not completely understood, has been shown to be directly influenced by the balance of the circadian rhythm.