Do malignant cells sleep at night?

Abstract

Biological rhythms regulate the biology of most, if not all living creatures, from whole organisms to their constitutive cells, their microbiota, and also parasites. Here, we present the hypothesis that internal and external ecological variations induced by biological cycles also influence or are exploited by cancer cells, especially by circulating tumor cells, the key players in the metastatic cascade. We then discuss the possible clinical implications of the effect of biological cycles on cancer progression, and how they could be exploited to improve and standardize methods used in the liquid biopsy field.

Keywords: Chronobiology; Circadian cycle; Circulating tumor cells; Disease ecology; Phenology; Tumor dissemination.

Fig. 1

Liquid biopsy. In cancer, the liquid biopsy term describes the minimally invasive analysis of analytes released by or related to the primary and/or metastatic tumors. These analytes can be found in any physiological or pathological body liquid (e.g., blood, ascites) [20]. This is an extension of the tissue biopsy, and many cancer biomarkers of clinical utility can be found also in liquid biopsy samples. Moreover, new biomarkers can be easily identified in liquid biopsy analytes because they are thought to represent more accurately cancer progression (i.e., the metastatic cascade), and cancer heterogeneity than tissue biopsy samples [21]. Some examples of liquid biopsy analytes are: circulating tumor cells (CTCs), circulating-free nucleic acids (cfNA: DNA or RNA), extracellular vesicles (EVs), tumor-educated platelets, and their possible combination with other protein tumor makers [22]. Although all these analytes have biological significance during the metastatic cascade and provide useful clinical information, currently, the most studied analytes are CTCs and cfNA. As CTCs are the main drivers of the metastatic cascade, it is reasonable to suggest that the biological cycles might influence their biological behavior, as observed in cancer. Consequently, these observations have implications for the current and future clinical applications of CTCs as liquid biopsy

Fig. 2

The circadian clock system is a complex transcriptional–translational autoregulatory network with activating and inhibitory components. Brain Muscle Arnt-Like protein-1 (BMAL1), the major component of the endogenous clock, heterodimerizes with Circadian Locomotor receptor Cycles Output Kaput (CLOCK) or Neuronal PAS domain protein 2 (NPAS2) to generate active transcription factor heterodimers. Binding of these dimers to the Enhancer-box (E-box) elements of their target genes leads to the expression of genes that encode the transcription repressors Cryptochrome (CRY1 and CRY2) and Period (PER1, PER2, PER3) [30, 31, 33, 34]. CRY and PER complexes inhibit CLOCK/BMAL1 transcriptional activity. CLOCK/BMAL1 dimers also drive the transcription of the nuclear receptors REV-ERBα and retinoid-related orphan receptor α (RORα) that represses and activates BMAL1 transcription, respectively [35]. Clock genes regulate the expression of clock-controlled regulators and also of genes that can be implicated in tumorigenesis. Therefore, their dysregulation might affect several cancer-related processes such as cell-cycle control, apoptosis, metabolic regulation, and DNA damage response. Circadian rhythm disruption might play a more critical role in tumor formation and progression than genetic factors [36]. Aberrant expression of circadian genes has been observed in different human cancers: head and neck squamous cell carcinoma, leukemia, ovarian, oral, and prostate cancer [–41]

Fig. 3

Circadian rhythms and cancer. This figure shows some examples on how circadian rhythm alterations contribute to the appearance of cancer hallmarks. a Circadian rhythms and cell cycle: DNA replication and cell cycle present a specific circadian pattern. Indeed, the expression of regulators of DNA replication and cell cycle shows circadian rhythms [–70]. Moreover, circadian cycle genes play an important role in the regulation of some cell cycle genes [71, 72]. b Circadian rhythms and DNA repair: DNA repair, DNA damage response, and the circadian cycle are tightly connected. As observed for cell cycle regulators, the expression (mRNA and protein) of DNA repair genes shows circadian patterns [69]. Reciprocally, DNA damage can affect the circadian clock [73, 74]. c Circadian rhythm and metabolism: The circadian rhythm influences a wide range of metabolic processes, such as the mitochondrial, glucose, amino acid, and lipid metabolisms as well as the Krebs cycle [75, 76]. As the metabolic needs of cancer cells are different from those of normal cells, the impact of circadian disruption should be taken into account when studying their metabolism in the tumor environment. The hypoxic tumor microenvironment and the activation of hypoxia-inducible factors (HIFs) play a regulatory role in tumor-linked metabolism and angiogenesis [65, 77]. d Circadian rhythm and apoptosis: alterations of circadian clock components influence the expression of apoptosis-related genes

Fig. 4

Circadian cycle influence on cancer cell dissemination. The circadian rhythm influences the neuroimmune-endocrine system, with clear differences between day and night. These observations can be summarized as two synergic “immune environments”. Disruptions of these biological cycles can facilitate cancer progression and dissemination of circulating tumor cells (CTCs). Therefore, cancer cells must adapt to efficiently progress through the metastatic cascade. Potential influence of the a normal and b disrupted circadian cycle on CTCs and cancer dissemination