The molecular circadian clock within the suprachiasmatic nuclei beats throughout each day employing 9 core clock genes, arranged in interacting negative and positive auto-regulatory feedback loops, whose circuit measures out daily time. This clock receives environmental light information through the eyes and disburses timing cues throughout the body by way of the autonomic nervous system, hormone production and release, and timing daily behavior such as sleep and activity. These same core clock genes beat similarly within peripheral tissues coordinating cell, tissue and organ functions within the day through tissue specific, circadian timed expression of clock-controlled genes. We have shown that these circadian clocks beat within cancer cells coordinating tumor growth, DNA synthesis and cell division throughout the day, along with the circadian susceptibility to anticancer agents targeting these processes. Per2 is a core circadian clock gene in the positive loop, a proposed tumor suppressor gene. A functionless Per2 mutation is associated with deregulated clock gene and c-myc over-expression, defective apoptosis pathways and increased cancer risk. Because we are interested in the balance between the host and cancer, we studied the growth of two apparently Per2 replete transplantable cancers (colon 38 and Lewis lung) in wild type C57BL/6 mice and in Per2m/m mutant mice on the same genetic background. Male or female wild type or Per2m/m mutant mice housed on 12 hr light:12hr dark regimen, either 1 per cage with access to a running wheel or four per cage without a running wheel, were injected subcutaneously with tumor cell fragments (colon 38) or tumor cells (low metastatic Lewis lung cell line). Tumors were measured twice each day at the beginning of daily sleep and activity over several weeks. Both subcutaneous colon 38 tumors and Lewis lung tumors in Per2m/m mutant mice grew at half the rate of those in wild type mice regardless of their sex, age, or housing condition (p<0.001). The Per2 gene of the host, either through its clock functions or other molecular function, slows subcutaneous tumor growth in two different transplanted tumors. This demonstrates the essential cooperativity between the host and tumor, and that the host Per2 clock gene is relevant to the host-cancer balance. Modulation of the circadian clock governing cancer cell proliferation presents a novel therapeutic and preventive strategy.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]