The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 221

CHAPTER NINE

The Circadian Clock in Cancer
Development and Therapy

Loning Fu * , † , { , Nicole M. Kettner * , †
* Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's
Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA
† Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
{ Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA

Contents
1.

Introduction 222

2. Circadian Dysfunction Promotes Cancer Development in Humans 224

2.1 Circadian disruption is an independent cancer risk factor for humans 224

2.2 Circadian disruption is associated with poor prognosis and early mortality
of cancer patients

224

2.3 Disruption of the molecular clockworks in human cancers 225

2.4 Central clock dysfunction increases cancer risk in humans 229

3. Circadian Disruption Promotes Cancer Development in Animal Models 229

3.1 The central clock suppresses tumor initiation and progression in animal
models 229

3.2 Variation in cancer phenotypes reported for circadian gene-mutant mouse
models

230

3.3 The molecular clock suppresses tumor development in mice 231

3.4 Cellular-based studies using mouse primary cells lacking core circadian genes 234

4. The Role of the Mammalian Circadian Clock in Tumor Suppression 236

4.1 The role of peripheral clock in tumor suppression 236

4.2 Tumor suppression in vivo is a clock-controlled physiological function 247

5. Anticancer Chronotherapy 257

6. Conclusions 259

Acknowledgments 259

References 259

Abstract
Most aspects of mammalian function display circadian rhythms driven by an endoge-
nous clock. The circadian clock is operated by genes and comprises a central clock in the
brain that responds to environmental cues and controls subordinate clocks in peripheral
tissues via circadian output pathways. The central and peripheral clocks coordinately
generate rhythmic gene expression in a tissue-specific manner in vivo to couple diverse
physiological and behavioral processes to periodic changes in the environment.