biologia - Studia

M. C. ALUPEI, R. M. MAXIM, M. BANCIU
pathway involved for tumor cell proliferation (Denko, 2008). Although the secondary
effects of oncogenes are not fully understood, oncogenes have a major contribution for
the increased accumulation of HIF-1α (Brahimi-Horn and Pouyssegur, 2007).
Mitochondrial ROS ensure HIF-1α stabilization by blocking the activity of prolyl
hydroxylase involved in mechanisms of recognition HIF-1α for proteasomal
degradation (Denko, 2008).
Besides this positive effect exerted by ROS on HIF-1, several studies have
been shown that ROS can decrease HIF-1α levels by signaling an increase in prolyl
hydroxylase activity (Denko, 2008, Qutub and Popel, 2008).
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Involvement of oxidative stress in tumor angiogenesis
Tumor angiogenesis – is a key process in tumor progression (Miller et al.,
2009). Angiogenic mechanisms are activated by various cellular stress factors, such
as hypoxia, low pH, nutrient deprivation and ROS (Eichhorn et al., 2007).
Endothelial cells are responsible for high ROS generation, such as O 2 - and H 2 O 2 ,
involved in different pathophysiological responses. The primary source of ROS in
endothelial cells is the activity of NADPH oxidase. In low concentrations ROS can
act as signalling molecules that mediate endothelial cell proliferation and migration,
facilitating angiogenesis (Ushio-Fukai, 2006).
In tumor cells, oxidative stress increases the production of angiogenic factors.
The hypoxic states present during tumor development generate a high amount of
ROS (Sihvo et al., 2003). Hypoxia also activates HIF-1 expression, the main regulator
of vascular endothelial growth factor (VEGF) and of other pro-angiogenic proteins.
ROS is also responsible for activation of NF-kB, a transcription factor capable to
upregulate HIF-1 (Xia et al., 2007). Moreover, ROS, in particularly H 2 O 2 , have been
demonstrated to directly stimulate angiogenesis in tumor cells and endothelial cells
by enhancing the production of VEGF (Miller et al., 2009). Even more important, it
is widely known that H 2 O 2 is increased in cancer cells due to the lack of catalase
activity (Chung-man Ho et al., 2001).
Inflammation – role in tumor angiogenesis
Since 1863, Virchow has shown the relation between inflammation and
cancer, suggesting that tumors tended to occur at sites of chronic inflammation.
Moreover, epidemiologic studies presented that chronic inflammatory diseases are
frequently associated with increased risk of cancers (Balkwill and Mantovani, 2001).
Chronic inflammation is involved in all stages of carcinogenesis. Recent findings have
proven that the tumor development from inflammation might be a process driven by
inflammatory cells as well as a variety of mediators, including cytokines, chemokines,
and enzymes, which altogether could create an inflammatory microenvironment
(Coussens and Werb, 2004). After „angiogenic switch” in tumor cells, the inflammatory
cells infiltrating the tumor fully participate in the angiogenic process by recruitment,