Abstract
Altered circadian rhythms predicted for poor survival in patients with metastatic colorectal or breast cancer. An increased incidence of cancers has been reported in flying attendants and in women working predominantly at night. To explore the contribution of circadian structure to tumor growth we ablated the 24-h rest-activity cycle and markedly altered the rhythms in body temperature, serum corticosterone and lymphocyte count in mice by complete stereotaxic destruction of the suprachiasmatic nuclei (SCN) or by subjecting the mice to experimental chronic jet-lag. Such disruption of circadian coordination significantly accelerated malignant growth in two transplantable tumor models, Glasgow osteosarcoma and Pancreatic adenocarcinoma. The mRNA expression of clock genes per2 and reverb-α in controls displayed significant circadian rhythms in the liver (Cosinor, p=0.006 and p=0.003, respectively) and in the tumor (p=0.04 and p<0.001, respectively). Both rhythms were suppressed in the liver and in the tumor of jet lagged mice. This functional disturbance of molecular clock resulted in down regulation of p53 and overexpression of c-Myc, two effects which may favor cancer growth. Conclusions:These results indicate that circadian system could play an important role in malignant growth control. This should be taken into consideration in cancer prevention and therapy.
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References
Rusak B, Zucker I (1979) Neural regulation of circadian rhythms. Physiol Rev 59:449–526
Klein DC, Moore RY, Reppert SM (eds) (1991) The Suprachiasmatic Nucleus. The Mind’s Clock. Oxford University Press, Oxford, New York
Lévi F, Zidani R, Misset JL (1997) For the international organization for cancer chronotherapy. Randomized multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350:681–686
Mormont MC, Lévi F (2003) Cancer chronotherapy: principles, applications and perspectives. Cancer 97:155–169
Mormont MC, Waterhouse J, Bleuzen P, etal. (2000) Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res 6:3038–3045
Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D (2000) Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst 92:994–1000
Schernhammer ES, Laden F, Speizer FE, etal. (2001) Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst 93:1563–1568
Schernhammer ES, Laden F, Speizer FE, etal. (2003) Night-shift work and risk of colorectal cancer in the nurses’ health study. J Natl Cancer Inst 95:825–828
Pukkala E, Aspholm R, Auvinen A, etal. (2002) Incidence of cancer among Nordic airline pilots over five decades: occupational cohort study. BMJ 325:567–571
Rafnsson V, Tulinius H, Jonasson JG, Hrafnkelsson J (2001) Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes Control 12:95–101
Reynolds P, Cone J, Layefsky M, Goldberg D, Hurley S (2002) Cancer incidence in California flight attendants (United States). Cancer Causes Control 13:317–324
Maywood ES, Smith E, Hall SJ, Hastings MH (1997) A thalamic contribution to arousal-induced, non-photic entrainment of the circadian clock of the Syrian hamster. Eur J Neurosci 9:1739–1747
De Prins J, Hequet B (1992) Data processing in chronobiological studies. In: Touitou Y, Haus E (eds) Biologic Rhythms in Clinical and Laboratory Medicine. Springer-Verlag, Berlin, pp 90–113
Mikkelsen JD, Larsen PJ, Sorensen GG, etal. (1994) A dual-immuncytochemical method to localize c-fos protein in specific neurons based on their content of neuropeptides and connectivity Histochemistry 101:245–251
Hastings MH, Best JD, Ebling FJP, etal. (1996) Entraiment of the circadian clock. Brain research III Hypothalamic integration of circadian rhythms. In: Buijs RM, Kalsbeek A, Romijn HJ, Pennartz CMA, Mirmiran M (eds) Progress in Brain Research. 111, Elsevier Science BV, Amsterdam, pp 147–174
Li XM, Liu XH, Filipski E, etal. (2000) Relationship of atypical melatonin rhythm with two circadian clock outputs in B6D2F1 mice. Am J Physiol 278:R924–R930
Halberg F, Albrecht PG, Bittner JJ (1959) Corticosterone rhythm of mouse adrenal in relation to serum corticosterone and sampling. Am J Physiol 197:1083–1087
Haus E (1992) In: Touitou Y, Haus E (eds) Biologic Rhythms in Clinical and Laboratory Medicine. Springer-Verlag, Berlin, pp 504–526
Filipski E, King VM, Li XM, etal. (2002) Host circadian clock as a control point in tumor progression. J Nat Cancer Inst 94:690–697
Glasgow LA, Crane JL, Kern ER (1978) Antitumor activity of interferon against murine osteogenic sarcoma cells. J Natl Cancer Inst 60:659–663
Corbett TH, Roberts BJ, Leopold WR, etal. (1984) Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL6 mice. Cancer Res 44:717–726
Reddy AB, Field MD, Maywood ES, Hastings MH (2002) Differential resynchronisation of circadian clock gene expression within the suprachiasmatic nuclei of mice subjected to experimental jet lag. J Neurosci 22:7326–7330
Filipski E, Delaunay F, King VM, etal. (2004) Effects of chronic jet lag on malignant growth in mice. Cancer Res 64:7879–7885
Hastings MH, Field MD, Maywood ES, Weaver DR, Reppert SM (1999) Differential regulation of mPER1 and TIM proteins in the mouse suprachiasmatic nuclei: new insights into a core clock. J Neurosci 19:RC11
Yamazaki S, Numano R, Michikazu A, etal. (2000) Resetting central and peripheral circadian oscillators in transgenic rats. Science 288:682–685
Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M (2001) Entrainment of the circadian clock in the liver by feeding. Science 291:490–493
Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U (2000) Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Development 14:2950–2961
Hara R, Wan K, Wakamatsu H, etal. (2001) Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus. Genes Cells 6:269–278
Wu MW, Li XM, Xian LJ, Lévi F (2004) Effects of meal timing on tumor progression in mice. Life Sciences 75:1181–1193
Scheving LE, Burns ER, Pauly JE, Tsai TH (1978) Circadian variation in cell division of the mouse alimentary tract, bone marrow and corneal epithelium. Anat Rec 191:479–486
Bjarnason GA, Jordan R (1999) Circadian variation in the expression of cell-cycle proteins in human oral epithelium. Am J Pathol 154:613–622
Smaaland R, Laerum OD, Lote K, Sletvold O, Sothern RB, Bjerknes R (1991) DNA synthesis in human bone marrow is circadian stage dependent. Blood 77:2603–2611
Granda TG, Lévi F (2002) Tumor-based rhythms of anticancer efficacy in experimental models. Chronobiol Int 19:21–41
Fu L, Pelicano H, Liu J, Huang P, Lee CC (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50
Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H (2003) Control mechanism of the circadian clock for timing of cell division in vivo. Science 302:255–259
Fu L, Lee CC (2003) The circadian clock: pacemaker and tumor suppressor. Nature Rev Cancer 3:350–361
Granda TG, Liu XH, Cermakian N., et al. (2004) Circadian regulation of cell cycle and apoptosis proteins in mouse bone marrow and tumour. FASEB, published on line, Nov 15
Hofsethh LJ, Hussain SP, Harris CC (2004) P53/25 years after its discovery. Trends Pharmacol Sci 25:177–181
Pasquale Innominato, Elisabeth Filipski, Xiao Mei Li, Francis Lévi. Effects of experimental chronic jet-lag on clock and cell cycle gene expression. Proc. 9th Meeting Soc. Res. Biol. Rhythms, June 24–26, 2004, Whistler, BC, Canada
Petit LM, Jerry DJ, Bittman EL, Harrington ME. (2004) Effects of circadian rhythm disruption on radiation-induced apoptosis. Proc. 9th Meeting Soc. Res. Biol. Rhythms, June 24–26, Whistler, BC, Canada, Abstract 154
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Filipski, E., Li, X.M. & Lévi, F. Disruption of Circadian Coordination and Malignant Growth. Cancer Causes Control 17, 509–514 (2006). https://doi.org/10.1007/s10552-005-9007-4
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DOI: https://doi.org/10.1007/s10552-005-9007-4