Biomarkers for Inflammation in BPH

Inflammation has important association with the pathogenesis, symptoms, and progression of BPH. Then, discovery of a biomarker would be invaluable for monitoring the progress of the disease. There are a number of early candidates and many others are currently being assessed by international research groups. A small study [115] suggested that measurement of serum malondialdehyde (MDA), an index of inflammation and oxidative stress, may be a useful marker in BPH. Serum MDA levels were analyzed in 22 BPH patients and 22 healthy donors showing an increase in levels in the BPH patients and a positive correlation with PSA. To our knowledge, this association has not been replicated.

The association of serum C-reactive protein concentration, a nonspecific marker of inflammation, and LUTS, suggestive of BPH, was examined in 2,337 men who participated in the Third National Health and Nutrition Examination Survey between 1988 and 1994 [116]. They found that men with a C-reactive protein concentration above the limit of detection (>3.00 mg/L) were 1.47 times more likely to have three or more symptoms than men with a C-reactive protein concentration below the detection limit (not statistically significant).

Cytokines and chemokines, inflammatory mediators, are also believed to be important in the pathogenesis of prostatic inflammation. Increased expression of IL-8 is noted in BPH tissue culture [117], which by direct and indirect mechanisms could promote proliferation of no senescent epithelial and stromal cells. This enhanced proliferation contributes to the increased tissue growth seen in BPH. Such processes may lead to the discovery of potential biomarkers for prostate inflammation in BPH. Seminal plasma levels of 8 cytokines and 9 chemokines were evaluated in 83 men (20 healthy controls, 9 men with CP/CPPS IIIA [inflammatory], 31 with CP/CPPS IIIB [non-inflammatory], and 23 men with BPH) [118]. Prostate specimens from 13 BPH patients were analyzed to detect interleukin-8 (IL-8) producing cells and to characterize inflammatory infiltrates. IL-8 concentration in seminal plasma was positively correlated with symptom scores in both the CP/CPPS patients and BPH patients.

Although a number of potential markers (C-reactive protein, IL-8, markers of oxidative stress) have been evaluated, these markers are generally nonspecific for prostate or BPH. However, it opens the search for biomarkers that could be used to stratify patients as to risk of developing BPH or related BPH adverse outcomes, monitor symptoms, and response to medical therapy for BPH.

Inflammation is a complex phenomenon consisting of a humoral (cytokines) and cellular (leukocytes, monocytes, and macrophages) components [119, 120], Cytokines that promote inflammation and act to make disease worse are called proin-flammatory cytokines, whereas other cytokines that serve to reduce inflammation and promote healing are called anti-inflammatory cytokines [121]. Inflammation is usually a self-limited event, with initial proinflammatory cytokines and growth factor release and angiogenesis followed by anti-inflammatory cytokine-mediated resolution [122]. In normal tissues, anti-inflammatory cytokines are synchronically upreg-ulated after the proinflammatory cytokines are produced, leading to inflammation resolution [123]. In chronic inflammation, mainly composed of chronically activated T cells and mononuclear phagocytes (monocytes and macrophages), there are persistence of promoters or a failure in the required mechanisms to resolve inflammation. This may release more progrowth cytokines as well as various growth factors and attract additional immune cells to the inflammation site which amplifies the inflammatory response [122, 124]. Prostate has a fully active immunologic response and involves a broad spectrum of immune responses against foreign antigens. Moreover, prostate contains scattered stromal and intraepithelial endogenous inflammatory cells such as T and B lymphocytes, macrophages, and mast cells [104, 125], T cells increase with age, which correlates with the incidence of prostate inflammation during the aging process [126]. T cells are known to release factors that stimulate matrix formation and secrete potent epithelial and stromal mitogens, which could promote prostate stromal and epithelial proliferation/hyperplasia [127],

Stromal-epithelial prostate interactions play a pivotal regulatory role in the maintenance of homeostasis in health and development of disease [126, 128]. Prostate cell can induce inflammation reaction by expressing antigen presenting cells (APCs) and all of the TLRs. These expressions can produce proinflammatory cytokine and activate immune responses [104, 121, 129-131]. Konig et al. found a different expression pattern of the TLR in BPH and PC tissue. Most of the BPH tissues showed a strong expression for the TLR 4, 5, 7, and 9, whereas in PC increased expression was obtained for TLR 1, 2, and 3 [132]. But it is still unknown how it will influence the inflammatory process in both diseases.

T cells, prostatic stromal, and epithelial cells simultaneously secrete higher proinflammatory cytokines such as interleukins (IL-1, -1a, -2, -4, -6, -7, -8, and -17), the CXC-type chemokine, and their receptors in BPH and PC tissues compared to normal prostate tissue [121, 128, 130, 133] . These cytokines were thought to induce fibromuscular growth and proliferation of prostatic stromal or epithelial cell by an autocrine or paracrine loop or via induction of COX-2 expression [44, 127, 133], IL-1 a produced by epithelial cells induces fibroblast growth factor-7 (FGF-7) in prostate stromal cells that can induce benign growth of the prostate. IL-17 upregu-lates the secretion of other proinflammatory cytokines, such as IL-8 and -6 as well as of TGF-p. IL-8 and -6 are recognized as two potent growth factors for prostatic epithelial and stromal cells, with IL-8 playing a major role in stromal proliferation by the induction of FGF-2 [130, 134] . The expression of proinflammatory cytokines was different between BPH and PC. Mechergui et al. [121] and Konig et al. [132] found IL-6 and -8 were more overexpressed in PC tissue compared to BPH tissue. IL-6 regulates the growth of prostate carcinoma and activates the androgen receptor-dependant gene in prostatic cancer cells in the absence of androgen [121],

Chronic inflammation continuously produces COX-2 [123, 135, 136]. COX-2 increases production of prostaglandin (PG) E2 (an adhesion to the extracellular matrix) and concentrations of Bcl-2 (proapoptotic genes) and reduces the E-cadherin protein (with consequent loss of cell-to-cell adhesion). COX-2 also modulates production of angiogenic factors to induce angiogenesis.

Lastly, COX-2 increases the carcinogenic potential of cells through the oxidation of procarcinogens to carcinogens, increased cell growth, decreased apoptosis, as well as decreased immune response to abnormal or cancer cells matrix metallopro-teinase overexpression with an associated increase in invasiveness [134, 137-139]. COX-2 is upregulated in a variety of malignancies including prostate cancer, throughout the tumorigenic process from early hyperplasia to metastatic disease [123,140]. Many studies showed more overexpression of COX-2 in prostate cancer compared to that in BPH. COX-2 overexpression was also higher in PIN and poorly differentiated tumors [122, 132, 136, 140]. Chronic inflammation also produces a free radical substance/oxidative stress such as inducible nitric oxide (iNOS)/reactive nitric species (RNS) and various reactive oxygen species (ROS) [119, 123, 135, 141, 142] , These oxidative stresses can induce vascular tissue damage, protein structural and functional damage, and genomic damages and cause posttranslational modifications including those involved in DNA repair and apoptosis [119]. These can lead to oxidative DNA damage such as point mutations, deletions, or rearrangements and reduce DNA repair. These oxidative stresses also alter the stem cell population. Genomic alterations in cellular DNA result in the modulation of an imbalance between cell proliferation and cell death. A change in the normal regulation of programmed cell death leads to hyperplastic or precancerous transformation [122, 124, 143]. All of these active factors production also induce repetitive tissue damage and repair with the release cytokines, growth factors, and oncogenes, leading to increase of epithelial or stromal cell proliferation ] 143]. Normally, these highly oxidative stresses are removed by natural protective mechanism, the superoxide dismutase enzyme system, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) enzyme [119] , Human prostatic tissue is vulnerable to oxidative DNA damage due to more rapid cell turnover and fewer DNA repair enzymes [144]. Balance between oxidative stress and antioxidant component of the cells has a role in developing prostate disease [144]. There are increases in the oxidative stress and decrease in the antioxidant mechanisms in prostate disease. Sciarra et al. [119] characterized NOS expression in the human prostatic tissue and in particular for the iNOS-increased immunostaining in the epithelial cells of BPH and even more with HGPIN and PC than that of normal tissue. Khandrika et al. [144] also found increasing ROS generation for more aggressive phenotype in PC cell lines. Prostate cancer cell expresses lower levels of antioxidant enzymes or almost total inactivation of prooxidant scavenging enzyme than BPH [139]. Compared with normal prostate, the activity of antioxidant enzymes is decreased in BPH [139, 145-149].

Age was also one of contributing factors for changing the oxidant/antioxidant balance which is shifted towards oxidative stress [144]. Production of ROS and free radicals in the mitochondria is increased during aging [150]. There are also a down-regulation and/or underexpression of antioxidant with increasing age [151] . Therefore, oxidative stress can activate the transcription factor NF-kB (nuclear factor kappa-lightchain—enhancer of activated B cells) by TNF-a/AP-1 transduction pathway and NIK transduction pathway. NF-kB is known as a master inflammatory transcriptional regulator and is highly active in macrophages. Targets of NF-kB include genes regulating immune response, inflammation, cell proliferation, cell migration, and apoptosis. The nuclear translocation of NF-kB can activate target genes involved in carcinogenesis [137]. NF-kB potentially can lead to the amplification of the inflammatory response in the tumor environment. Dysregulation of the transcription factor NF-kB has been proposed as a putative molecular mechanism leading to chronic inflammation and cancer.

In a chronically inflamed tumor environment, it is difficult to distinguish whether the aberrant NF-kB activation originates from tumor cells or from immune infiltrates.

Wong et al. found that the exposure of prostatic epithelial cells to proinflammatory-soluble mediators directly activated NF-kB and induced local production of proinflammatory cytokines in the prostate epithelial cells. Narayanan et al. [120] and Wong et al. [124] found significant increased NF-kB in the prostatic specimen which has PIN and adenocarcinoma histopathology. The IL-1b-induced NF-kB pattern of intraprostatic chemo-attractive signals might have a capability for maintaining the chronic inflammation and PIA in the prostate, which are recognized as putative precursor lesions in the development of prostate cancer [152] . In normal prostate, the transduction pathway from NIK to NF-kB seems to be inactive in BPH. There is increasing TNF-a/AP-1 transduction pathway and also follows by increasing apoptotic pathway to inhibit uncontrolled cell proliferation [120] . In PC, the proapoptotic effect of TNF-a/AP-1 pathway was found decreased and also nuclear translocation of NF-kB increased which are an active form to stimulate prostate cancer cell proliferation [120, 124],

Induction of anti-inflammatory factors such as MIC-1 is an early response due to inflammation in the prostate [153]. MIC-1 was downregulated in BPH tissues compared to normal prostate tissue [44, 134, 154]. However, in PC, there are up-regulation and overexpression of MIC-1 in higher grade and more aggressive prostate cancers [153, 154]. Gene expression analysis between normal peripheral zones and transition zones of the specimens obtained from patients with prostate cancer revealed a preferential expression of MIC-1 in the peripheral zone (predominant site of tumor occurrence) compared with the transition zone (site of BPH) [154]. MIC-1 in tumor environment is assumed to reduce the tumor killing (functional) activity of macrophage [154].

Another factor that differentiates between BPH and PC was gene polymorphism. Polymorphisms in innate and adaptive immune genes may affect the nature and the extent of the immune response within the prostate, including the likelihood of persistent prostatic infection and chronic inflammation. There is much evidence that BPH has only rare genetic abnormalities [155]. Recently, multiple genes with regulatory roles on inflammatory pathways have been associated with prostate cancer risk, including Ribonuclease L (RNASEL), macrophage scavenger receptor 1 (MSR1), macrophage inhibitory cytokine-1 (MIC-1), interleukins (IL-8, -10), vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM), ELAC2/HPC2, Machropaghe Scavenger Receptor (SR-A/MSR1), CHEK2, Breast Cancer gene 2 (BRCA2), Paraoxonase 1 (PON1), 8-oxoguanine glycosylase (OGG-1), TLRs, and COX-2 promoter. These genes are linked to cellular defenses against inflammation and oxidative stress, and defects in their function may lead to the inability to prevent tumor formation by this pathway [125, 136, 156-160],

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