The oxidative stress associated with infection and inflammation can cause prostate carcinogenesis through the induction of iNOS (inducible nitric oxide synthase), leading to reactive nitrogens and oxygen reactive species activation.

At the site of inflammation phagocytic cells (e.g. neutrophils and macrophages) generate reactive oxygen and nitrogen species. These cells also synthesize and secrete large quantities of growth factors and potent angiogenic factors, cytokines, and proteases. These are important mediators in the tissue regeneration process, but can also potentiate neoplasia. Prostaglandins, cytokines, nuclear factor NF-κB, chemokines and angiogenic factors are the main molecular mediators and free radical species derived from oxygen (ROS) and nitrogen (RNS) are the main chemical effectors [17] [18].

Human cells have the following coping mechanisms: direct antioxidant enzymes, proteases, phospholipases, and lipid and water-soluble antioxidants [19] [20]. Inflammation can cause proliferation within prostatic tissue through compensatory cellular proliferation with resulting hypertrophy. Prostatic inflammation generates free radicals (ROS, NOS) through macrophages and neutrophils which can induce hyperplastic transformations [21] [22].

The macrophages in the tumor microenvironment produce reactive radicals causing DNA damage and genetic alterations such as; p53 and AR mutations, hypermethylation of the CpG island of gluthathione S tranferase-P1 (GSTP1) promoter, decreased activity of manganese superoxide dismutase (MnSOD) and increased expression of NADPH oxidase 1 [23].

ROS are endogenously generated during cellular metabolic processes but can also come from external sources. Excessive ROS production or impairment of antioxidant defense systems can induce oxidative stress and promote development of various cancers, including prostate cancer, because oxidative stress regulates cellular fate in various systems. ROS are considered to be tumor initiators/promoters given the potential for induction of DNA damage. Furthermore, signaling pathways in response to intracellular changes in ROS levels may trigger proliferation, apoptosis and senescence, events highly implicated in all the stages of the carcinogenic process [24] (Figure 1).

The NF-κB family of transcription factors is critical in carcinogenesis [25] through modulation of genes involved in cell survival, proliferation, angiogenesis, and invasion [26]. NF-κB is a dimer formed by proteins of the Rel family (RelA/p65, RelB, c-Rel, NF-κB1/p50, and NF-κB2/p52) that is retained in the cytoplasm as a complex with inhibitory IκB proteins that is subsequently trans-located into the nucleus where it binds specific elements in the promoters of NF-κB-responsive genes [27]. Hyperactivation of NF-κB is a hallmark of chronic inflammation and has been widely linked to cancer. As mentioned before inflammation contributes to prostate cancer development via multiple mechanisms such as oxidative stress, genomic instability, and DNA damage. Indirectly it increases levels of proinflammatory factors such as tumor necrosis factor α (TNFα) [27]. NF-κB hyperactivation results from enhanced production of tumorpromoting cytokines, stimulation of growth factor receptors, and aberrant activation of upstream NF-κB kinases such as IKK and NF-κB-inducing kinase (NIK).

Several lines of evidence suggest NF-κB pathway is dysregulated in prostate cancer and has been implicated in the progression to the lethal androgen-independent state. Constitutive NF-κB activation has been reported in several prostate tumors and since nuclear NF-κB is predominantly observed in organ-confined tumors, it suggests it to be an early event in prostate cancer development [28] [29]. NF-κB mediates the effect of proinflammatory cytokines such as TNFα, IFNγ, and IL-1β [30]. Binding of TNFα to its receptor, leads to the recruitment of adaptor proteins, that ultimately regulates NF-κB activation and transcriptional activation of inflammatory, and anti-apoptotic genes.

Overall, available evidence confirms that NF-κB activation is a key event in PCa pathogenesis and aggressiveness through EMT induction (see next section). Constitutive or induced activation of NF-κB is critical in providing a positive feedback signal to immune cells in the tumour microenvironment. This increases the production of molecular mediators such as various proinflammatory cytokines & chemokines, which contribute to carcinogenic and inflammatory processes (Figure 2).

Cytokines are a family of cell-signaling molecules (proteins, peptides, or glycoproteins) that are secreted by various cell types in the tumor microenvironment, are used extensively in intercellular communication and can impact prostate cancer growth [31].

Cytokines, including TNF-α, IL, growth factors, and differentiation factors (colonystimulating factors), contribute to the progression of prostate tumors of altered cells at the inflammatory site [32].

Several evidences suggest that TNF and chemokines are mediators of inflammation and prostate cancer [33]. TNF, product of activated macrophages and tumor cells, binds to membrane-bound receptors and plays a critical role in both tissue destruction and damage recovery. Thus, it helps in maintaining the reversibility of microenvironments, stimulating cellular change, and tissue remodeling [33].

In relapsing cancers TNF-α is not released from prostate cancer cells rather from associated macrophages and in hormone-refractory cases serum TNF-α levels are higher than untreated patients [34] [35]. While the relationship between TNF-α and hormone responsiveness has not been explored, androgen-insensitive prostate cancer cells have proven to be TNF-α insensitive [36]. The recent publication from Davis et al. [37] explains the dichotomy of TNF-α effect on the control of apoptosis in prostate cancer cells through proposed physiologic role for TNF-α in prostate regression after androgen withdrawal.

Inflammatory cytokines have also been reported to facilitate the spectrum of prostate tumor development particularly IL-6, which is a multifunctional cytokine, produced by not only by inflammatory cells, but also osteoblasts and even prostate cancer cells. Several lines of clinical and experimental evidence suggest that IL-6 contributes to prostate cancer progression. Both, early and advanced prostate cancer display high expression levels of IL-6 [38]. There is accumulating evidence linking IL-6 levels to prostate cancer stage as IL-6 serum levels were found to be strongly elevated and positively correlated to tumor load [39] [40]. In other study Shariat et al. showed that LNCaP cells continuously exposed to IL-6 develop increased invasiveness as assessed by chamber-based migration assay develop neuroendocrine features when exposed to IL-6 [41] [42].

It is important to note IL-6 modulates the growth of hormone-refractory PCa cells, but not of hormone-de- pendent cell lines [43].

IL-6 has also been implicated in other aspects of prostate cancer pathophysiology such as tumorigenesis in the prostate microenvironment through the activation of Janus kinase (JAK) and signal transducers and activators of transcription (STAT), signaling [44]. IL-6 also stimulates autocrine activation of insulin-like type I growth factor receptor (IGF-IR) to confer tumorigenesis. Furthermore IL-6 can also signal through MAPK and phosphatidylinositol-3 kinase (PI3K) pathways [44]-[48].

Cytokines like IL-8 and IL-17 are also involved in prostate cancer as, IL-8, an inflammatory chemokine, promotes progression of human solid tumors by its ability to regulate the expression of matrix metalloproteinases (MMPs) [49]. Numerous studies have demonstrated a correlation between MMPs, IL-8, and CPa as increased levels were associated with high Gleason scores and metastatic disease. High levels of IL-8 lead to an increase in MMP-9 expression, which directly increases the tumor grade and metastasis [49] [50].

Steiner et al. have shown that 58% of human malignant prostate tissues have an increased level of IL-17 mRNA implying that IL-17 acts directly on the prostate tumor cells and promotes tumorigenesis.

Taken together, experimental studies have validated the crucial role of various pro/anti-inflammatory cytokines in prostate cancer progression and development.