Daily rhythms are retained both in spontaneously developed sarcomas and in xenografts grown in immunocompromised SCID mice

Abstract

The circadian clock generates and regulates many daily physiological, metabolic and behavioral rhythms as well as acute responses to various types of stresses including those induced by anticancer treatment. It has been proposed that modulatory function of the clock may be used for improving the therapeutic efficacy of established anti-cancer treatments. In order to rationally exploit this mechanism, more information is needed to fully characterize the functional status of the molecular clock in tumors of different cellular origin; however, the data describing tumor clocks are still inconsistent. Here we tested the status of clock in two models of tumors derived from connective tissue: sarcomas spontaneously developed in p53-deficient mice and human fibrosarcoma cells grown as xenografts in immunocompromised severe combined immunodeficient (SCID) mice. We show that both types of tumors retain a functional clock, which is synchronized in phase with normal tissues. We also show that spontaneously developed tumors are not only oscillating in the context of an organism where they receive hormonal and metabolic signals but continue oscillating ex vivo in tissue explants demonstrating that tumors have functional clocks capable of timing all their functions. We also provide evidence that similar to liver, tumors can be synchronized by food availability independent of the central pacemaker in the suprachiasmatic nuclei (SCN). These data provide the basis for the design of anticancer therapies that take into account the circadian metabolic and physiological patterns of both the tumor and normal tissues.

Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues

“…Currently, there are few studies on the circadian clock of cancers. The findings have ranged from cancer tissue being arrhythmic, to being rhythmic but out of phase with normal tissue, to being rhythmic and in phase with normal tissue (18,19,(39)(40)(41)(42)(43)(44). It is necessary to determine the circadian phase and amplitude relationships between cancer and normal tissues to develop truly mechanism-based chronotherapy regimens.…”

“…As a result, the TS and NTS of diurnally expressed genes are repaired out of phase. As it has been reported that cancers may have circadian rhythms in phase with the host (18) or out of phase with…”

The tumour suppressing role of the circadian clock

“…Not all studies, however, have shown suppressed circadian clock gene oscillations in cancer cells/tumour tissue. Comas et al found that fibrosarcoma cells and mouse sarcomas in vivo display significant rhythmic profiles of PER2 ‐ and BMAL1 ‐driven luciferase expression, similar to that found in normal tissues, although with slightly reduced amplitude . Moreover, U2OS osteosarcoma cells are often used as a cell line in which to study circadian rhythms due to the robust circadian oscillations observed in these cells .…”

Understanding the crosstalk of molecular factors and signaling pathways reveals novel biomarkers of cisplatin resistance in testicular germ cell tumors

“…Concerning circadian rhythms in oncological diseases, plentiful opposing, and tissue specific results can be found. Some studies report that tumors do indeed show rhythmic circadian gene expression [128], while others indicate that cancerous tissue either lacks rhythmicity or expression of clock genes is compromised [129,130]. Recent studies have declared absence of circadian rhythm in TGCTs, although some authors proposed that cyclic expression of clock genes in testes is suspended due to cellular differentiation during spermatogenesis [126,131].…”