Dr. David E. Blask, Professor and Head of the Laboratory of Chrono-Neuroendocrine Oncology in the Dept. of Structural & Cellular Biology at TUSOM, is an internationally-recognized leader in research on the chronobiological and neuroendocrine mechanisms by which the central circadian system in the brain regulates human cancer growth and metabolism and the host/cancer balance via the nighttime circadian production and actions of the pineal gland hormone melatonin. His research with co-workers has led to the discovery of a novel metabolic pathway by which the nocturnal circadian melatonin signal inhibits the growth of human cancers via the suppression of cAMP-dependent tumor uptake of dietary linoleic acid and its metabolism to its mitogenic metabolite 13-hydroxyoctadecadienoic acid. His research has also uncovered melatonin's ability to suppress the tumor uptake of glucose and the production of lactic acid, a process known as aerobic glycolysis or the Warburg effect. Furthermore, his laboratory has demonstrated that the host/cancer balance in metabolism and tumor growth is a dynamic circadian-regulated process mediated by the nocturnal melatonin signal that is disrupted by exposure to light at night-induced melatonin suppression. His research with co-workers has pioneered the perfusion of tissue-isolated human cancer breast cancer xenografts with blood collected from human female subjects collected at different times of the day and night to demonstrate the circadian melatonin signal to be the first circadian anti-cancer signal in humans to directly inhibit tumor growth and metabolism. Moreover, he and his colleagues have shown for the first time that exposure of human female subjects to bright polychromatic light at night induces circadian disruption by suppressing the nocturnal melatonin signal leading to the stimulation of human cancer growth progression and metabolism. Dr. Blask has received a number of awards recognizing his research accomplishments, most notably, the Aaron B. Lerner (discoverer of melatonin) Pioneer Medal for Outstanding and Sustained Contributions to Melatonin Research.
- Melatonin/Circadian Regulation and Light at Night Circadian Disruption of Cancer Growth
Tulane Cancer Center Program Member
For the past 35 years I have dedicated my research career to understanding the mechanisms by which the central circadian system of the brain regulates human breast cancer growth and metabolism via the nighttime circadian production of the pineal gland hormone melatonin. Melatonin is arguably the most important output signal of the central circadian clock in the suprachiasmatic nucleus (SCN) and has very potent direct oncostatic actions on a variety of human cancer cells and xenografts including breast, prostate, colorectal, squamous cell head/neck, cervical, urothelial and mesenchymally-derived cancers such as leiomyosarcoma. Using a unique tissue-isolated human cancer xenograft/nude rat model system developed in our laboratory, we discovered a highly novel pathway by which the nocturnal circadian melatonin signal inhibits human cancer growth in vivo. This pathway involves the ability of melatonin to suppress cAMP-activated tumor uptake of dietary linoleic acid (LA), an essential omega-6 fatty acid, and its conversion to its mitogenic metabolite 13-hydroxyoctadecadienoic acid (13-HODE) as well as decreased tumor glucose uptake and lactate production (e.g., Warburg effect). This results in a down-regulation in the activation of ERK1/2 and AKT signaling pathways leading to severely curtailed tumor growth at night while, in the absence of melatonin during the daytime, these mechanisms are fully active resulting a very high proliferative rate. Circadian disruption/suppression of the nocturnal melatonin signal by exposure of tumor-bearing animals to light at night leads to constantly up-regulated LA uptake/metabolism and the Warburg effect and culminates in runaway tumor growth. In studies paralleling those performed in our animal model, we have also demonstrated, by perfusing tissue-isolated human breast cancers with blood collected from human subjects during different times of the day and night, that the nocturnal circadian melatonin signal in adult female human subjects inhibits tumor metabolic signaling and proliferative activity. Furthermore, exposure of human subjects to bright light at night suppresses the nocturnal circadian melatonin signal resulting in high, daytime-like rates of tumor metabolism and growth. I am a Professor in the Dept. of Structural & Cellular Biology, Head of the Laboratory of Chrono-Neuroendocrine Oncology, and Associate Director of the Tulane Center for Circadian Biology in the Tulane University School of Medicine. I am also a member of the Tulane Cancer Center and Louisiana Cancer Research Consortium and the Tulane Center for Aging. My work has been funded over the years by multiple RO1 grants from NIH/NCI, NIH/NCCAM, and NIEHS.
Hill SM, Cheng C, Yuan L, Mao L, Jockers R, Dauchy B, Frasch T, Blask DE. Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin. Breast Cancer Res Treat. 2010 Jun 12. [Epub ahead of print]
Dauchy, R.T., Blask, D.E., Dauchy, E.M., Davidson, L.K., Tirrell, P.C., Greene, M.W., Tirrell, R.P., Hill, C.R., and Sauer, L.A. Antineoplastic effects of melatonin on a rare malignancy of mesenchymal origin: melatonin receptor-mediated inhibition of signal transduction, linoleic acid metabolism and growth in tissue-isolated human leiomyosarcoma xenografts. J Pineal Res., 47:32-42, 2009.
Blask, D.E. Melatonin, sleep disturbance and cancer risk. Sleep Med. Revs. 13:257-264, 2009 (Invited).
Blask, D.E., Dauchy, R.T., Brainard, G.C., and Hanifin, J.P. Circadian stage-dependent inhibition of human breast cancer metabolism and growth by the nocturnal melatonin signal: consequences of its disruption by light at night in rats and women. Integ. Cancer
Therap. 8:347-353, 2009 (Invited).
Block, K.I., Hrushesky, W., and Blask, D. In this issue: circadian disruption and cancer. Integ. Cancer Therap. 8:295-297, 2009 (Invited).
Dauchy RT, Dauchy EM, Davidson LK, Krause JA, Lynch DT, Tirrell PC, Tirrell RP, Sauer LA, Van der Riet P, Blask DE. Inhibition of fatty acid transport and proliferative activity in tissue-isolated human squamous cell cancer xenografts perfused in situ with melatonin or eicosapentaenoic or conjugated linoleic acids. Comp Med. 2007 Aug;57(4):377-82.