The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 253

lifestyle change is associated with a dramatic increase in the risk of sporadic
cancers ( Fig. 9.4 ). 401

4.2.2 Circadian control of cancer immune surveillance
The current concept of cancer immuno-editing is based on the evidence of
sequential steps of elimination of transformed cells in vivo by the immune
system. 402 When transformed cells accumulate above a threshold, they are
recognized by lymphocytes including Nature Killing T, Nature Killing
(NK), and gamma delta T cells that are stimulated by transformed cells to
produce interferon g (IFN- g ). This triggers a cascade of innate immunity
including the induction of chemokines CXCL9, 10, and 11 to block
neovascularization in the tumor and the recruitment of NK cells, dendritic
cells, macrophages, and other immune effector cells to the tumor site. The
antiproliferative effects of IFN- g on transformed cells and the cytocidal
activities of macrophages and NK cells result in the death of tumor cells,
which are ingested by dendritic cells and trafficked to the draining lymph
node, where the tumor-specific CD4 þ and CD8 þ T lymphocytes are devel-
oped. These tumor-specific T lymphocytes are then directed to the tumor
site along a chemokine gradient, where they act together with NK cells and
activated macrophages to recognize and destroy tumor cells. 402,403 Mice
deficient in cancer immuno-editing display a significantly higher risk of
spontaneous tumor development in the immune, digestive, respiration,
and reproductive organs. 404-408 Cancer immuno-editing is usually abolished
by cancer-induced immunosuppression in human cancer patients. 402,403
The mechanisms of cancer immunosuppression include deregulation or
loss of expression of cancer cell surface markers leading to the lack of rec-
ognition of transformed cells by cytotoxic T lymphocytes, resistance to cell
death induced by cytotoxic T lymphocytes due to deregulation of apoptotic
factors and death receptors, production of immunosuppressive factors

representative intracellular signaling pathways directly or indirectly controlled by the
central clock shown in the figure include the c-AMP/PKA/CREB/AP1, Ras/MARK/JNK/
ERK, and PI3K/AKT/b-catenin/TCF/LEF pathways essential for c-Myc activation and cell
cycle progression , 386-388 the PI3K/AKT/mTOR signaling controlling biosynthesis and
drug resistance , 389,390 the GPCR/ATM signaling for p53 activation , 29 the GPCR/PKC/
NF-kB pathway that regulates stress and immune response, 391 the JAK/STAT pathway
controlling apoptotic response , 392 and the GR and ERa signaling pathways cross-talking
with the AP1 signaling . 393,394 These signaling pathways also control the expression and
function of circadian genes leading to a coupled activation of the molecular clock with
tissue-specific function in vivo including cell proliferation, metabolism, apoptosis, DNA
repair, biosynthesis, secretion, and senescence. 395-398