Clinical reviewMelatonin, sleep disturbance and cancer risk
Introduction
Remarkably little is known about the actual purpose(s) of sleep even though roughly one-third of our existence on planet earth is spent asleep, primarily during the night. The 24-h sleep/wake cycle in humans is probably the most obvious manifestation of our inherent biological rhythmicity and time-keeping mechanisms.1 Humans have evolved over millions of years such that endogenously generated daily oscillations in our physiology, metabolism and behavior are synchronized to the solar day.2 Prior to the industrial age, humans were exposed to bright, full spectrum sunlight during the day and to complete darkness during the night (firelight, candle light, oil lamp light, gas light, moonlight and star light notwithstanding). Since the advent of electric light just a little over a 120 years ago, human daily exposure to healthful natural light and darkness has been largely compromised such that in fast-paced “24/7” westernized societies, our evolutionary heritage of bright days and dark nights has been flipped like a light switch.3, *4, 5 Now, daytime exposure to dim indoor lighting and nighttime exposure to bright lights are increasingly the rule at home, at work and in places of leisure and entertainment. As an unforeseen consequence of these societal changes, disturbances in sleep manifested primarily as sleep deprivation and accompanying disruptions in circadian synchronization have been linked to the development of cardiovascular and gastrointestinal diseases as well as metabolic disorders such as insulin resistance, type II diabetes and obesity.*6, 7 More recently, however, studies reveal that unadapted night shift workers exposed to light at night experience circadian dysregulation, including phase shifts and suppression of the chronobiotic/anticancer hormone melatonin,a in addition to sleep disturbances. In fact, both night and early morning shift workers sleep two or more hours less than day shift workers with accompanying reductions in sleep efficiency and quality.8, 9, 10, 11 In epidemiological studies it has been reported that both female and male night shift workers are at a significantly increased risk of developing a number of different malignancies including breast,12, 13, 14, 15 colon,16 prostate17 and endometrial cancer.18 There are currently no experimental model systems that can directly address the hypothesis that sleep disturbance by itself promotes the development and growth of cancer. Therefore, this article will focus on current experimental and epidemiological evidence that indirectly supports a link between light at night-induced disturbances in physiological melatonin production, circadian/homeostatic sleep regulation and immune function and cancer.
Section snippets
Melatonin production, physiology and pathophysiology
Derived from the essential amino acid tryptophan, melatonin is an indoleaminea molecule that is found widely throughout nature. Melatonin is synthesized and immediately secreted into the blood vascular system and cerebrospinal fluid by the pineal glanda during the night whereas the daytime production of melatonin is virtually nil. The surge of melatonin during dark nights represents a biological timing signal that is internally driven by the activity of a central pacemaker in the
Melatonin and sleep
The coincidence of pineal melatonin production and the occurrence of sleep during the night indicate an important relationship between the two processes. The fact that sleep propensity during the night increases in concordance with the evening increase in blood levels of melatonin implies but does not prove the existence of a causal link.26, 27 While the occurrence of sleep is not necessary for the nocturnal production of melatonin, the presence of darkness during the night is an absolute
Melatonin and cancer
In experimental rat models of chemical carcinogenesis the physiological melatonin signal suppresses the initiation phase of tumorigenesis. One mechanism by which this may be accomplished is via melatonin's ability to suppress the accumulation of DNA adducts (the resulting complex when chemicals bind to DNA) formed by carcinogens that cause damage to and permanent alterations in DNA (i.e., mutations and amplifications), which lead to neoplastic transformation. This may be accomplished directly
Light at night, melatonin suppression and cancer risk
The risk of developing breast cancer is up to five times higher in industrialized nations than in underdeveloped countries. Overall, nearly 50% of breast cancers cannot be accounted for by conventional risk factors.44, *45 Westernized nations have increasingly become 24-h per day societies with greater numbers of people being exposed to more artificial light during the night both at home and particularly in the workplace.3, *4, 5, *6 It has been postulated that light exposure at night may
Melatonin, sleep disturbance, immune function and cancer
The immune system is a double-edged sword in that it has both the capacity to suppress the development of malignancies via protective, immunosurveillance mechanisms and also promote cancer pathogenesis under certain circumstances. Through complex mechanisms collectively referred to as “immunosculpting”, tumors may induce immune tolerance and suppression in response to immune effectors. This mechanism provides a means by which cancer cells can escape from the immunosurveillance activity of the
Sleep duration and cancer risk
It is well known that fatigue and disturbances in sleep are among the most common side-effects reported by patients suffering form cancer. Sleep disorders including difficulties in sleep initiation and maintenance, poor sleep efficiency and quality, early awakening and excessive daytime sleepiness are often seen in cancer patients in response to the presence of cancer and/or to anticancer therapy.62 On the other hand, the question of whether sleep disturbances or alterations in sleep patterns
Concluding remarks
The development, growth progression and spread of cancer comprise a complex multistage process that involves intricate molecular and biochemical interactions that cause somatic cells to depart from their normally differentiated functions in situ and become transformed into rapidly proliferating tumors with the capacity for unlimited expansion and eventual invasion and metastasis into distant organs that ultimately lead to the death of the host. The environment has been implicated in the vast
Glossary
- Melatonin
- an indoleamine neurohormone in vertebrate species produced by the pineal gland and secreted into the bloodstream and cerebrospinal fluid during the night.
- Pineal gland
- a small, pea-sized and pine cone-shaped gland located deep within the middle of the human brain between the two halves of the cerebral cortex; produces the neurohormone melatonin.
- Suprachiasmatic nucleus (SCN)
- a region in the hypothalamus of the brainstem that consists of small, bilaterally paired clusters of nerve cells
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