Circadian coordination of cancer growth and metastatic spread

To understand whether mammalian circadian time structure measurably affects the host-cancer balance, we studied tumor-take frequency after s.c. tumor cell inoculation and: the number of pulmonary tumor nodules after i.v. tumo r cell injections at each of 6 equispaced times of day. We employed 2 genet ically distinct mouse strains and 2 different tumor model systems, a methyl cholanthrene A-induced fibrosarcoma of C(3)HeJ mice and 2 B-16 melanoma cel l lines of vastly different metastatic efficiency in C57 Black/6 mice. Fibr osarcoma cells were injected s.c. in 1 of 8 different doses, at 1 of 8 perm utated anatomic sites and at I of 6 equispaced circadian times, in 96 femal e C(3)HeJ mice maintained under a synchronizing schedule of 12 hr light alt ernating with 12 hr dark. Regardless of tumor cell dose and inoculum locati on, tumor-take frequency depended strongly upon the circadian stage of tumo r cell inoculation. Injections of between 2,000 and 50,000 live tumor cells inoculated near the daily sleep/wake interface resulted in the lowest inci dence of tumor take compared with inoculation at other times of day. In the experimental i.v. B-16 melanoma metastatic model (N = 110), the capacity o f both high and low metastatic potential clones to successfully metastasize to lung depended, to a large extent, upon when in the day each of these cl ones was injected. Similar to the fibrosarcoma data, the dairy sleep/wake b oundary was the time of day associated with the greatest resistance to meta static spread. Published 1999 Wiley-Liss, Inc dagger.