119Why does tumor cell prefer to glycolysis-based substrate phosphorylation
(with the generation of only one mole of ATP) rather than citrate cycle-coupled
oxidative phosphorylation (38 moles of ATP) even in an aerobic condition? This
might be inflammation activates iNOS but inactivates eNOS, which should block
NO-driven mitochondrial biogenesis. So the deficiency of functional mitochon-
dria of tumor cells are forced to utilize glucose and other carbohydrates depending
on the ineffective metabolic pattern, i.e. in aerobic respiration. If those possi-
bilities could be confirmed, the unsolved issue on the origin of CSC should be
readily solved, and a next breakthrough on the pathogenesis of cancer might be
anticipated.
More enthusiastically, there have been most recent achievements to support
such anticipation: (a) inflammasome-mediated dysbiosis regulates the progres-
sion of nonalcoholic fatty liver disease (NALFD) and obesity (Henao-Meijia et al.
2012 ); (b) hyperresponsibility to low-does endotoxin LPS during progression to
nonalcoholic steatohepatitis (NASH) is regulated by leptin-mediated signaling
(Imajo et al. 2012 ); (c) obesity-induced gut microbial metabolite promotes liver
cancer through senescence secretome (Yoshimoto et al. 2013 ); and (d) obesity,
rather than diet, drives epigenomic alterations in colonic epithelium resembling
cancer progression (Li et al. 2014 ).
There seems a plausible association of HFD with NASH, during which the
obesity-induced leptin plays a crucial role through inducing the hepatic expres-
sion of CD14 and increasing the cellular hyper-reactivity to low-dose LPS (Imajo
et al. 2012 ). A large entity of literature has indicated that type II diabetes might be
associated with an increased incidence of pancreatic cancer, hepatic cancer, colon
cancer, bladder cancer, and breast cancer, suggesting a mitogenic effect of hyper-
insulinemia (Joost 2014 ). Obesity has been identified as a cause for oesophageal,
colon, uterine, kidney and postmenopausal breast cancers, and also as a signifi-
cant risk factor for prostate cancer, pancreatic cancer, and non-Hodgkin lymphoma
(Gong et al. 2014 ).
A hyperglycemic environment has been supposed to contributes to tumor pro-
gression through multiple pathways (Ryu et al. 2014 ). Cancer cell proliferation
is promoted by the upregulation of glucose transporters (GLUT1 and GLUT3),
growth factors and receptors, and other growth promoting signals. The levels of
HIF-1α, prolyl hydroxylase, and cytochrome c regulated by hyperglycemia are
associated with antiapoptotic activity of cancer cells. As a possible mechanism
underlying insulin-driven cancer, it has been summarized that an increase of insu-
lin levels is correlated with an increase of the bioavailable IGF, which promotes
cellular proliferation and inhibits apoptosis in many tissue types (Suh and Kim
2011 ). Previously, it was found that many cancer cells have an increased content
of insulin receptor (IR) (Papa et al. 1990 ) and an predominant expression level
of the isoform A of IR (IR-A), whose activation elicits mitogenic effects (Frasca
et al. 1999 ). By binding to the overexpressed IR-A, insulin may favor cancer pro-
gression and facilitate tumor growth.
7.3 The Origin of CSC: Next Breakthrough on Tumorigenesis/Carcinogenesis?