Temporal control of tumor growth in nocturnal mammals: impact of the circadian system

Abstract

Glioblastoma multiforme is the most aggressive brain tumor; however, little is known about the impact of the circadian system on the tumor formation, growth and treatment. We investigated day/night differences in tumor growth after injecting A530 glioma cells isolated from malignant peripheral nerve sheath tumor of NPcis (Trp53+/-; Nf1+/-) mice. Tumors generated in the sciatic nerve zone of C57BL/6 mice injected early at night in the light/dark cycle or in constant darkness, showed higher growth rates than in animals injected diurnally. Similar nocturnal increases were observed when injecting B16 melanoma cells or when mice received knocked-down clock gene Bmal1 cells. Moreover, treatment with a low-dose of the proteasome inhibitor Bortezomib (0.5 mg/kg) in tumor-bearing animals, displayed higher efficacy when administered at night. Results suggest the existence of a precise temporal control of tumor growth and of drug efficacy in which the host state and susceptibility are critical.