121If hyperinsulinemia occurs due to ONOO−-mediated nitrosylation of IR/LR,
insulin resistance and even type II diabetes would take place. The synovial pan-
nus, an earliest symptom of RA, should be a tumor-like hyperplasia in the articu-
lar synovium. Hyperglycemia can initiate Warburg effects for enhanced glycolysis,
ROS burst, and nitrosylation, accompanying with the inactivation of tumor sup-
pressors responsible for DNA repair and DNMT responsible for DNA meth-
ylation. Eventually, genetic mutation and epigenetic modification could occur
(malignant tumor conversion).
Multiple receptors/enzymes have been implicated as the mediators linking
hyperglycemia to cancer. An in vitro study suggested that glucose transporters,
including GLUT1 and GLUT3, are regulated by hyperglycemia in choriocarci-
noma cells (Hahn et al. 1998 ). In a hyperglycemic medium supplemented with
25 mM d-glucose, GLUT1 and GLUT3 are upregulated, and glucose uptake is
enhanced. It was observed that the levels of epidermal growth factor (EGF) and its
corresponding receptor (EGFR) that promote oncogenesis are augmented by high-
level glucose in pancreatic cancer cells (Han et al. 2011 ). Similarly, hyperglyce-
mic conditions was found to induce peroxisome proliferator-activated receptors
(PPARs) in breast cancer cells (Okumura et al. 2002 ), and high levels of PPAR-α
and PPAR-γ that influence lipid metabolic pathways accelerate cell proliferation
(Mueller et al. 1998 ). Additionally, high glucose promotes the cell cycle through
cyclin-dependent kinase 2 (CDK2), E2F, cyclin A, and cyclin E, resulting in
abnormal proliferation (Masur et al. 2011 ).
Furthermore, hyperglycemic conditions were also noticed to augment the levels
of glial cell line derived neurotophic factor (GDNF) in human pancreatic cancer
cells (Liu et al. 2011 ). GDNF, a cytokine related to the transforming growth factor-β
family, can enhance the survival, growth, and differentiation of midbrain dopamin-
ergic neurons, which promote cell proliferation and invasion in pancreatic cancer
(Lin et al. 1993 ; Veit et al. 2004 ). Taken together, these data highlighted that hyper-
glycemia serves as a contributing factor to enhanced cell proliferation and cancer.
In breast cancer, the family-transmitted BRCA1 mutation is linked to estro-
gen receptor α negative (ERα−) with unknown reasons. It was suggested that
17 β-estradiol or estrogen-ERα− influences BRCA1 expression, and BRCA1 inhib-
its ERα activity through a monoubiquitination mechanism, implying the existence
of a negative feedback mechanism that regulates functional interaction between
ERα and BRCA1 in breast cancer cells (Manavathi et al. 2013 ). However, this
suggested model is unable to explain why BRCA1 mutation is often accompanied
with triple negative, i.e. ERα−, progesterone receptor negative (PR−), and human
epidermal growth factor receptor 2 negative (HER2−).
It has been noted that loss of BRCA1 results in impaired DNA double-strand
break repair and activated TP53-mediated apoptosis (Shukla et al. 2011 ; Pao
et al. 2014 ). So I assumed that breast cells carrying BRCA1 mutation might be
destroyed by TP53-mediated apoptosis, which should lead to the undetection of
abovementioned receptors. In contrast, if TP53 is also mutated, the newly prolifer-
ated breast cancer cells with Brca1 mutation should be survived, and all receptors
could be detectable, i.e. receptor positive.
7.3 The Origin of CSC: Next Breakthrough on Tumorigenesis/Carcinogenesis?