Here we summarise a recent review, published in Genome Biology, that presented the hypothesis that internal and external ecological variations induced by biological cycles can also influence or be exploited by cancer cells.
Holobionts
Since the early 1940s, multicellular organisms have been considered “holobionts,” meaning assemblages composed of the host and its associated commensal microorganisms and parasitic taxa. Interestingly, multicellular organisms also have a long history of living with other entities – cancer cell communities (oncobiota).
Holobiont components are usually prisoners of their host. Their environment consists of two different ecological dimensions – the host and the host habitat. The first dimension refers to the host’s physiological, genetic and phenotypic characteristics. The second dimension is due to the biotic and abiotic factors that characterise the host’s ecosystem. These variables and their interactions contribute to the selective landscape in which holobiont members survive.
Biological cycles
Research has begun to explore the influence of biological rhythms on holobiont members. For example, several studies have demonstrated the relevance of these biological cycles in host-parasite relationships. While hosts can use biological rhythms to defend themselves against parasites, parasites can also manipulate the host clock to their own advantage.
Conversely, little is known about whether and how malignant cells are influenced by and/or can exploit biological rhythms. Like many parasitic organisms, malignant cells depend on their host to survive, proliferate and disperse. Therefore, some of the adaptations that have arisen from host-parasite interactions may be also relevant for cancer progression and dissemination. These adaptations may be relevant for clinical applications, such as liquid biopsy.
Factors implicated in circadian rhythms
The movement of the Earth around the Sun and on its own axis have been major contributors to geophysical rhythms that result in biological cycles. Alterations to these cycles can directly or indirectly increase vulnerability to various infectious and or chronic pathologies. All biological cycles and rhythms share similar physiological mechanisms. However, they can be divided according to the environmental factors associated with them, e.g. sunlight, gravity, exercise and eating patterns. These cues are called zeigebers. One of the most studied zeitgebers is the diel cycle, which is the fluctuation between day and night. The diel cycle dictates the biology of the circadian rhythm, with a direction of 24-26 hours.
The impact of biological cycles on cancer development
Biological cycles influence nearly all physiological and biological aspects of an organism. Researchers have found that alterations of circadian rhythms are linked to various health issues and diseases. For example, studies have found that circadian system disturbance by exogenous factors (night shift work and exposure to light at night) is associated with higher cancer incidence and poor prognosis. Additionally, other studies investigating the effect of sleep duration on cancer risk, have shown that short sleep duration is correlated with high cancer risk and the development of more aggressive tumours. Whereas longer sleep duration reduces the risk of breast cancer.
Cancer initiation and progression can be influenced by circadian cycle components through:
- Direct or indirect regulation of different genes
- Interaction of circadian cycle proteins with other proteins
- Changes in redox state, cofactors and post-translational modifications
- Regulation of secreted factors with paracrine or endocrine function
These regulations have an effect on cellular processes. These processes include nutrient metabolism, cell cycle, DNA repair, redox regulation, cellular secretion, protein folding and autophagy.
The circadian cycle is not the only rhythm that influences the organismal physiology. For example, the menstrual cycle lasts between 24 and 38 days and is linked to a higher risk of breast cancer in women with higher number of cycles. Annual cycles are another example, e.g. the seasonality of sunlight exposure and vitamin D synthesis, that might directly influence the risk of cancer.
The impact of biological cycles on the neuroimmune-endocrine system
All cells and tissues have some molecular clocks. These peripheric biological clocks strongly modulate the neuroimmune-endocrine system. Circadian cycles heavily influence the immune system through various hormonal and molecular pathways. For example, both the hypothalamus-pituitary-adrenal axis (HPAA) and sympathetic nervous system (SNS) are downregulated during the early sleep period when different hormones, such as leptin, melatonin, growth hormone and prolactin, reach their peak. These hormones have synergic pro-inflammatory actions. Most importantly, melatonin effectively inhibits EMT, which is a main mechanism for cancer dissemination.
Furthermore, the immune performance of an organism is reduced by circadian cycle alterations. For example, researchers have found that sleep deprivation for just 24 hours can decrease the efficacy of the hepatitis A vaccine. This effect can be explained by the presence of two different immune environments during the day and night. As a result, circulating tumour cells (CTCs) must adapt and elude the immediate immune response that is more active during daytime and evade the adaptive immune response during the night.
Interestingly, researchers have observed that circadian variations can predispose to higher platelet activation and coagulation. Consequently, promoting CTC survival. For example, cardiovascular events have day/night patterns with peaks in the morning. This suggests a potential link with the endogenous circadian clock that controls platelet activation. This could have important implications for CTC use in liquid biopsy as most studies on CTCs do not report the sampling time.
Conclusions
It is clear from this review that considering biological rhythms is important when studying cancer. Circadian rhythms influence host defence efficiency against cancer. It is important to determine whether malignant cells can acquire features, like parasites and microbiota, that allow them to exploit their host’s circadian rhythm and/or manipulate it to improve their proliferation and dispersal. Most importantly, researchers must consider the whole holobiont in which these malignant adaptations could occur. Only such an integrative approach will provide an accurate assessment of the context in which malignant cells that can exploit/manipulate the host biological rhythms are selected.
Image credit: Image by Gerd Altmann from Pixabay.
