The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 247

and Per2 are found to inhibit cellular senescence in vivo possibly by distinct
mechanisms. Per2 mutation leads to AKT-dependent vascular senescence that
impairs endothelial progenitor cell function, while loss of Bmal1 promotes
senescence in vivo via a p53-independent mechanism. 23,194 The increased cel-
lular senescence found in circadian gene-mutant mice may be explained by
their inherent high risk of deregulation of oncogenic and tumor suppression
pathways, high intracellular levels of redox and its associated accumulation of
genomic DNA damage, and abnormal internal physiological environments
that promote oncogenic extracellular signaling. These abnormalities together
with a lack of proper control of gene expression could increase paracrine activ-
ities and loss of senescence surveillance, which leads not only to increased local
tissue damage and inflammation that stimulate cell regeneration but also to the
possibility of reentering the cell cycle of senescent cells. Since cancer is a
clonogenic disease in vivo , one or a few premalignant cells that successfully
escape senescence surveillance would be sufficient enough to promote cancer
development in vivo . 224,339

4.2. Tumor suppression in vivo is a clock-controlled
physiological function
Although an intact molecular clock can provide self-sustained circadian
oscillations in peripheral tissues, peripheral organs rely on daily entrainment
signals from the central pacemaker to maintain the synchrony of the internal
physiology. Disruption of central clock function leads to phase desynchrony
among peripheral tissues. 201 Such desynchronization of the internal circa-
dian homeostasis is closely related to increased risk of tumor development
and accelerates tumor progression in both humans and experimental animal
models. 34-49,54-59,117-122 The key entrainment signals from the central clock
include extracellular signaling controlled by the ANS and NES. 24 Loss of
homeostasis of ANS and NES disrupts circadian homeostasis of cancer
immune surveillance and energy balance as well as G1 cell cycle progression
in renewable peripheral

tissues, which synergistically promote tumor

development.
The mechanisms of SCN control of peripheral tissues have been dis-
cussed in detail in several recent reviews. 24,30-33,275,340 Briefly, via direct
and indirect targeting, the SCN clock controls brain centers, especially those
in the hypothalamus including the paraventricular nucleus (PVN), arcuate
nucleus (ARC), dorsomedial hypothalamus (DMH), lateral hypothalamus
(LHA), and endocrine neurons producing corticotropin-releasing hormone