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. tumor cell injections at each of 6 equispaced times of day. We employed 2 genetically distinct mouse strains and 2 different tumor model systems, a methylcholanthrene A-induced fibrosarcoma of C(3)HeJ mice and 2 B(16) melanoma cell lines of vastly different metastatic efficiency in C57 Black/6 mice. Fibrosarcoma cells were injected s.c. in 1 of 8 different doses, at 1 of 8 permutated anatomic sites and at 1 of 6 equispaced circadian times, in 96 female C(3)HeJ mice maintained under a synchronizing schedule of 12 hr light alternating with 12 hr dark. Regardless of tumor cell dose and inoculum location, tumor-take frequency depended strongly upon the circadian stage of tumor cell inoculation. Injections of between 2,000 and 50,000 live tumor cells inoculated near the daily sleep/wake interface resulted in the lowest incidence 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 of 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 clones was injected. Similar to the fibrosarcoma data, the daily sleep/wake boundary was the time of day associated with the greatest resistance to metastatic spread.