The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 234

senescence (explained later in this review). Together with the findings
that Bmal1 -null mice display normal skin regeneration and aggressive hy-
perplastic growth in bone at a young age as well as increased lymphoma
development after g -radiation, and that targeted silencing of Bmal1 in
tumors induces immune suppression and accelerated tumor growth in
mice, 29,125,149,168 the studies described earlier suggest that cellular senes-
cence resulting from hyperplastic growth, oncogenic activation, and accu-
mulated free radical-induced DNA damage is intrinsic to Bmal1 / somatic
cells. However, in tumors and somatic tissues that can overcome the barriers
of cellular senescence and reactive oxygen species (ROS)-induced apoptosis,
loss of Bmal1 only accelerates tumor initiation and growth. 22,29,166,168
Bmal1 / mice are specially distinct from other circadian gene-mutant mouse
models in that they lack circadian homeostasis even when kept in 24-h LD
conditions. 169 This severe disruption of endogenous homeostasis may also
contribute to increased senescence at the organismal level. However, if
Bmal1- null mice can overcome aggressive aging, they are likely cancer prone.
3.4. Cellular-based studies using mouse primary cells
lacking core circadian genes
The role of core circadian genes in controlling cell proliferation and
DNA damage response has also been studied using various types of
primary cells isolated from different circadian gene mouse models
in vitro . 19,29,124,128,129,149,170 The results obtained from these studies should
be explained with caution. For example, primary MEFs cultured in vitro
behave very differently from somatic cells in tissues prone to tumor devel-
opment. MEFs are known to be resistant to g -radiation-induced aopotosis
regardless of genotypes and, therefore, should not display a high rate of
apoptotic death after a sublethal dose of g -radiation in the absence of
aberrant oncogenic activation. 128,171,172 In addition, the cell cycle clock is
different from the molecular clock in that it does not free run
( Fig. 9.1 ) . 173,176 Therefore, the serum shock protocol for setting free-
running status of the molecular clock in cultured MEFs is not suitable for
studying the role of a core circadian gene in cell cycle control because this
protocol requires confluent cell culture condition and only provides growth
factor-containing serum for a few hours at the initial serum shocking stage,
which leads to uncoupling of the cell cycle clock from the molecular clock
due to growth arrest induced by contact inhibition and lack of proper
extracellular signals to induce immediate early genes essential for G1 cell
cycle progression after the first day of the experiment. 19,177,178