The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 257

signaling pathways including the PI3K/AKT/mTOR, MAPK, and JAK3/
STAT pathways that are often aberrantly activated in tumors. 463-465 Obesity
also promotes chronic inflammation by increasing circulating free fatty acids,
proinflammatory cytokines IL-1 b , IL-6, TNF- a , and monocyte chemo-
attractant protein-1, stimulating type 2 macrophage polarization, and acti-
vating NF- k B-mediated proinflammatory and proproliferation
pathways. 462,466-468 Such changes in tissue microenvironment lead to tissue
damage due to increased cell necrosis induced by constant stress of increasing
in biosynthesis, oxidative stress, and DNA damage, which in turn stimulates
tissue regeneration that needs active cell proliferation to support. However,
the deregulation of multiple oncogenic and tumor suppression pathways as
well as immunosuppression due to circadian disruption would result in an
increased risk of neoplastic growth that would accelerate cancer develop-
ment in obese subjects. 469-471
5. ANTICANCER CHRONOTHERAPY
Chemotherapy using one or more cytotoxic drugs in conjunction
with radiation therapy or surgery is one of the most common procedures
for anticancer therapy. Since chemotherapeutic drugs indiscriminately tar-
get both cancerous cells and normal host cells in renewable tissues, these
drugs often generate intolerable side effects that impair the treatment. 472
The “targeted” anticancer therapy developed in recent years is aimed at
blocking the growth of cancer cells via monoclonal antibodies recognizing
tumor-specific antigens on the tumor cell surface or small molecules that
block intracellular tyrosine kinase signaling including MARK/ERK,
JAK, PI3K, CDKs, estrogen receptor (ER), epithelial growth factor recep-
tor (EGFR), and vascular endothelial growth factor receptor-controlled
pathways. 473 However, since these signaling pathways are also important
for mediating neuroendocrine functions in host tissues, these small inhib-
itors also potentially increase the risk of fatal side effects among cancer
patients. 474 Thus, to maximally increase tumor targeting efficiency and
protect normal host tissues are the biggest challenges for successful antican-
cer treatments.
Tumors are derived from host tissues after regaining the properties of rapid
self-renewing and dedifferentiation phenotypes. Most biological processes
supporting tumor growth are also essential for normal physiological functions
of the host except that the biological processes in normal host tissues are prop-
erly controlled and integrated with the daily physiology. Thus, anticancer