Clock-cancer connection in non-Hodgkin’s lymphoma
Introduction
Currently, non-Hodgkin’s lymphomas (NHL) is among the most rapidly increasing malignancies, increasing to a point where it accounted for 4% of all new cancer cases in 2005 in the United States [1]. Despite tremendous efforts to improve our understanding of this cancer, its etiology remains largely unknown with the only well-established risk factor for NHL being immune deregulation [2]. Given that several essential components of the innate immune system are influenced by the 24-hour circadian rhythm [3], [4], [5], we speculate that circadian disruption might play a role in lymphomagenesis by detrimentally affecting immune activity. Furthermore, we hypothesize that genetic variations in genes responsible for maintaining circadian rhythm might act as a novel panel of biomarkers associated with an individual’s susceptibility to NHL.
Section snippets
Clock-cancer connection: epidemiological evidence
The vast majority of organisms experience a 24-hour oscillation of many essential biochemical, physiological and behavioral processes. This oscillation arises from an ancient adaptation to the rotation of the earth and is one of the fundamental components of our biological world. Disruptions of this critical rhythm have the potential to significantly affect our health, and may play a significant role in tumor development [6].
A connection between cancer development and the circadian cycle has
Clock-cancer connection: genetic evidence
To date, there have been nine core circadian genes identified: Clock, casein kinase Iε (CKIε), cryptochrome 1(Cry1), cryptochrome 2 (Cry2), Period1 (Per1), Period2 (Per2), Period3 (Per3), Bmal1, and NPAS2. A model of transcription–translation feedback loops of these circadian genes has been proposed to explain the molecular clockwork [17] in which cell functions are regulated through the expression of clock-controlled genes. It has been estimated that 2–10% of all mammalian genes are
Possible mechanisms: clock-controlled immune function
Circadian rhythms have been observed in immune activities, including in natural killer (NK) cells, which are an essential component of the innate immune system that responds to infections and cancerous growth [3]. The expression of NK cells oscillates throughout a 24 h period, with peak expression occurring in the early morning [4]. Numerous other components of the immune system, such as T-helper, T-suppressor and splenic B-cells, also display a 24-hour oscillation similar to that of the NK
Hypothesis
Given the established association between immune deregulation and non-Hodgkin’s lymphoma (NHL), we speculate that circadian rhythm might play a role in lymphomagenesis by affecting immune activity. For example, increased exposure to light at night will disrupt circadian rhythms and consequently elevate the risk of NHL. Furthermore, genetic and epigenetic variations in circadian genes may result in deregulation of circadian rhythms and other biological processes regulated by these genes. We
Testing the hypothesis
From an epidemiological perspective, a well-designed population-based case-control study would provide evidence for the role of circadian disruption in NHL. In this type of study, the questionnaire for assessing environmental light exposures and sleeping patterns must be carefully designed in order to ensure meaningful results. Additional studies involving nocturnal occupational groups, such as shift workers (e.g. nurses), would also test this hypothesis in NHL.
Genetic and epigenetic analyses
Conclusions
We propose that some NHL cases could be explained by light-induced circadian disruptions and/or genetic/epigenetic variations in circadian genes and/or gene-environment interactions between these two factors. We also propose that the clock-regulated immune activities might be one potential mechanism involved in lymphomagenesis. These hypotheses are testable in a molecular epidemiological study and could lead to the development of novel circadian risk and prognostic biomarkers for NHL.
Acknowledgements
We thank Derek Leaderer for editorial assistance. This work was supported by the US National Institutes of Health (Grants CA122676, CA110937, and CA108369).
References (37)
- et al.
Twenty-four-hour rhythms in immune responses in rat submaxillary lymph nodes and spleen: effect of cyclosporine
Brain Behav Immun
(1996) - et al.
Selective circadian rhythm disturbance in cerebral lymphoma
Sleep Med
(2003) - et al.
Circadian variation in the expression of cell-cycle proteins in human oral epithelium
Am J Pathol
(1999) - et al.
The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo
Cell
(2002) - et al.
Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders
Endocrinol Metab Clin North Am
(2002) - et al.
Casein kinase I delta (CKIdelta) is involved in lymphocyte physiology
Eur J Cell Biol
(2003) - et al.
Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia
Blood
(2005) - (2005) Cancer facts and figures 2004. Atlanta, American Cancer...
- et al.
Primary immunodeficiencies: genetic risk factors for lymphoma
Cancer Res
(1992) - et al.
Evidence supporting a circadian control of natural killer cell function
Brain Behav Immun
(2005)
Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells
J Immunol
The circadian clock: pacemaker and tumour suppressor
Nat Rev Cancer
Light in the built environment: potential role of circadian disruption in endocrine disruption and breast cancer
Cancer Cause Control
Increased breast cancer risk among women who work predominantly at night
Epidemiology
Night shift work, light at night, and risk of breast cancer
J Natl Cancer Inst
Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study
J Natl Cancer Inst
Cancer incidence among 10,211 airline pilots: a Nordic study
Aviat Space Environ Med
Prospective cohort study of the risk of prostate cancer among rotating-shift workers: findings from the Japan collaborative cohort study
Am J Epidemiol
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