120 7 Prospective
According to above results, we suggested here a mechanistic model involving
the origin of tumorigenesis and summarizing the conversion of benign tumor to
malignant tumor, as depicted in Fig. 7.3, in which the relevant overweight/obesity,
insulin tolerance/type II diabetes, and RA were also illustrated.
As described above, activation of proinflammation cytokines is derived from
endotoxinemia, which is an essential consequence of HFD-induced gut dysbiosis,
leading to the overgrowth of G− bacteria and the leakage of bacterial LPS into
the blood. Upon systemic, chronic and low-grade inflammation, both iNOS and
HO-1 are upregulated for overproducing NO and CO and leading to hypoxia.
Next, hypoxia-sensed HIF-1α, VEGF, and EPO are induced, thereby driving angi-
ogenesis, cell proliferation, and inflammatory infiltration (benign tumor forma-
tion). Upon the activation of iNOS, both eNOS and nNOS should be inactivated
due to the deprival of the NO precursor ARG by super activated iNOS. The lack
of eNOS-derived NO would impede mitochondrial biogenesis and lead to adipose
tissue whitening, i.e. BAT conversion to WAT, which remarkably decrease energy
expenditure, alters lipid storage/usage homeostasis, and eventually allows over-
weight and obesity.
Fig. 7.3 A mechanistic model of the origin of a malignant tumor from a benign tumor. ARG
l-arginine; CO carbon monoxide; DNMT DNA methyltransferase; eNOS endothenial nitric oxide
synthase; EPO erythropoietin; G− Gram negative bacteria; HIF-1α hypoxia inducible factor α;
HO- 1 heme oxygenase 1; IGF insulin-like growth factor; IGFR IGF receptor; iNOS inducible
nitric oxide synthase; IR insulin receptor; LPS lipopolysaccharide; LR leptin receptor; NF-κB
nuclear factor κB; nNOS neuronal nitric oxide synthase; NO nitric oxide; RA rheumatoid arthri-
tis; ROS reactive oxygen species; VEGF vascular endothelial growth factor. The plus symbol (+)
represents activation, and the minus symbol (−) represents inactivation