biologia - Studia

OXIDATIVE STRESS AND INFLAMMATION-KEY PLAYERS IN TUMOR ANGIOGENESIS
proliferation, migration and activation of the endothelial cells as well as by production
of the majority of proangiogenic factors: vascular endothelial growth factor (VEGF),
hepatocyte growth factor (HGF), matrix metalloproteinase-2 (MMP2) and interleukin-
8 (IL-8) (Albini et al.,2005; Banciu, 2008; Balkwill et al., 2005; Naldini and Carraro,
2005; Zou, 2005). For that reason this step of angiogenesis is also called tumor
inflammatory angiogenesis (Albini et al., 2005; Banciu, 2008; Naldini and
Carraro, 2005). Consequently, inflammation-dependent angiogenesis seems to be a
central force in tumor growth and expansion, a concept supported by the observation
that the use of anti-inflammatory drugs leads to angiogenesis inhibition (Albini et
al., 2005; Banciu, 2008).
Key cell players in tumor inflammation
The inflammatory microenvironment of neoplastic tissues include neutrophils,
T cells, neutrophils, eosinophils, monocytes that expressed Tie-2 receptors, dendritic
cells, macrophages, and mast cells. All these cell types possess the capacity to produce
cytokines, cytotoxic mediators like ROS, serine and cysteine proteases, metalloproteinases
(MMPs) and membrane perforating agents (Balkwill and Mantovani, 2001; Coussens
and Werb, 2002; Nakayama et al., 2004).
The innate immune cells contribute to cancer development through direct and
indirect mechanisms. The direct mechanisms are: DNA damage induced by generation
of ROS and regulation of intracellular pathways via activaition of transcription factors
such as NF-κB and HIF-1. The indirect mechanisms include promotion of angiogenesis
and tissue remodeling by the production of growth factors, cytokines, chemokines and
matrix metalloproteinases; COX-2 upregulation; suppression of antitumour adaptative
immune responses. The adaptive immune cells also contribute to modulation of cancer
by direct and indirect mechanisms. The direct mechanisms comprise: inhibition of
tumor growth by antitumor cytotoxic-T-cell activity and inhibition of tumor growth by
cytokine-mediated lysis of tumour cells (de Visser et al., 2006).
Among the immune cell populations present in tumor tissue, tumor-associated
macrophages (TAM) seem most important in promoting and coordinating tumor
growth (Banciu et al., 2008). TAM are a major component of tumor leukocyte
infiltrate, being recruited by chemokines i.e. monocyte chemotactic protein (MCP).
Chronic inflammation induced by TAM represents a source of reactive oxygen species
(ROS) which, depending of their level, could modulate the immune system, and affect
cell proliferation, stimulating angiogenesis by activation of oxidative stress enzymes
responsible for stabilization of HIF-1α (Fruehauf and Meyskens, 2007). ROS generated
in TAM but also in neutrophils via a plasma membrane bound nicotinamide adenine
dinucleotide phosphate, reduced form (NADPH)-oxidase deliver a sublethal oxidative
stress to tumor cells. Tumor cells exposed to sublethal oxidative stress will have a
higher capacity of metastasis due to the reduction of tumour cell adhesion to basement
membrane components (Brown and Bicknell, 2001). TAM are an important source of
pro-inflammatory cytokines and chemokines (TNF α (tumor necrosis factor α),
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