118 7 Prospective
how it acts on, directly or indirectly, maturated cells or stem sells remains obscure.
Nevertheless, we could still anticipated that the origin of tumor/cancer should at
least engage the following effectors: (1) NO-driven hypoxia. Sustained NO burst
due to chronic inflammation may cause hypoxia, angiogenesis and hyperplasia
that are seen in the benign tumor. (2) ONOO−-mediated mutagenesis and modi-
fication. The concomitant occurrence of high-level NO and O 2 − promotes the for-
mation of ONOO− and enables the denaturation of proteins and DNA, which are
frequently seen in either benign or malignant tumor/cancer. (3) NO-confered cyto-
protection. Tumor/cancer cells are characterized by extreme longevity, and there
must be an association of NO with antiapoptosis, antiautophagy, antisenescence,
and anticytotoxicity in tumor/cancer cells.
Hypoxia promotes tumor development through multiple mechanisms includ-
ing initiating tumor angiogenesis (Choi et al. 2003 ), causing genome mutagen-
esis (Papp-Szabo et al. 2005 ), maintaining anaerobic metabolism (Gillies and
Gatenby 2007 ), and modifying acidic microenvironment (Fang et al. 2008 ; Chen
et al. 2010 ; Hjelmeland et al. 2011 ). Early in 1998 , Wink et al. had reviewed that
chronic inflammation can lead to the de novo production of many kinds of chemi-
cal intermediates, among which ONOO− that mediates nitrogen stress is able
to make DNA damage. Previously, it was detected that purine and pyrimidines
deamination, strand breaks and purine modification, and nitroguanine adduction
can occur upon exposure of DNA to ONOO− (Yermilov et al. 1995 ; Zingarelli
et al. 1996 ). Usually, DNA damage necessarily leads to DNA repair by tumor sup-
pressors, thereby uneasily leading to genetic mutagenesis. Surprisingly, why are
genetic mutations not rare in tumor/cancer? The most possibility is that ONOO−
inactivates DNA repair responsible enzymes such as tumor suppressors, p53
and BRCA1, via nitrosylation/nitration. Therefore, genes are highly prone to be
mutated when DNA repair responsible tumor suppressor genes have been mutated.
Indeed, evidence for ONOO−-mediated p53 modification in human gliomas had
been declared (Cobbs et al. 2001 ).
An investigation on the genetic disease Laron’s syndrome (dwarfism) that is
resulted from the deficiency of growth hormone receptors has revealed a very low
risk of suffering cancer and diabetes among patients. It is believed that the syn-
chronously generated growth hormone (GH) and insulin-like growth factor (IGF)
might be the enhancers promoting tumor proliferation (Leslie 2011 ). Furthermore,
it has been documented that insulin and IGF facilitate the transport of glucose
into cells through activating PI3K, which is antagonisted by the tumor suppressor
PTEN. When PI3K is overactivated due to PTEN mutation, cells prone to uptake
a large quantity of glucose for anaerobic respiration (Warburg effects), with which
the metabolic activity increases for 10–20 folds. As the consequence, more ROS is
released and more DNA damaged, hence leading to a higher frequency of tumori-
genesis/carcinogenesis (Taubes 2012a). Interestingly, the diabetes pill metformin
can decrease the cancer rate for 25–40 % via activating AMPK and decreasing
blood insulin levels, thereby supporting the notion that high-level insulin increases
the risk of cancer (Taubes 2012b).