title: 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.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute , Buffalo, NY , USA .
authors.forename: Maria
authors.initials: M
authors.lastname: Comas
authors.forename: Karen K
authors.initials: KK
authors.lastname: Kuropatwinski
authors.forename: Michelle
authors.initials: M
authors.lastname: Wrobel
authors.forename: Ilia
authors.initials: I
authors.lastname: Toshkov
authors.forename: Marina P
authors.initials: MP
authors.lastname: Antoch
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D056950:Period Circadian Proteins / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases
keywords: Bmal1-driven luciferase; Circadian clock; Per2-driven luciferase; food restriction; in vivo imaging; p53-/-; sarcoma; tissue explants; xenografts