The oxidative stress imbalance in the prostate tumor Gearing the journey to cancer

The development of cancer is a complex process. Cancer cells associate, both in primary as well as in secondary colonization sites with resident stromal fibroblasts, smooth muscle cells, macrophages, endothelium, neurons and migrating cells at metastatic niches and phenotypically and genotypically activate them, triggering different signaling mechanisms. During this process, the cancer cells and cells in the cancer microenvironment "co-evolve" in part due to oxidative stress, and acquire the ability to mimic other cell types (which can be termed osteomimicry, vasculomimicry, neuromimicry and stem cell mimicry), and undergo transition from epithelium to mesenchyme with definitive behavioral modifications. Prostate cancer cells co-evolve in their genotypic and phenotypic characters with stroma and acquire osteomimetic properties allowing these cells to proliferate and survive in the skeleton as bone metastasis [45]. ROS, RNS and other factors implicated in oxidative and nitrosative stress alters the homeostatic milieu, affecting macromolecules and damaging cell membranes, altering organelles permeability and function. Thus co-targeting different players in this complex scenario will be an effective treatment alternative for prostate cancer progression.

2.2.1. The prostate and its oxidative defense barriers

The normal prostate epithelium consists of prostatic ducts that contain basal cells, stem cells, secretory luminal cells and neuroendocrine cells. The stromal component consists of smooth muscle, fibroblasts, vascular endothelial cells, nerve cells, inflammatory cells, insoluble matrix and soluble factors. Inflammation is clearly associated to the early stages of prostate car-cinogenesis [46]. The macrophages in the tumor microenvironment produce ROS and RNS. The increase in reactive radicals such as superoxide (O2^-), hydrogen peroxide (H2O2), hy-droxyl radical (HO^), etc. produces DNA damage, causes genetic mutations and initiates/ promotes cancer progression. Some molecules implicated in prostate atrophy include p53 and AR mutations, hypermethylation of the CpG island of the promoter of gluthathione S tranferase-P1 (GSTP1), decreased activity of manganese superoxide dismutase (MnSOD) and increased expression of NADPH oxidase 1, which initiate high grade prostatic intraepi-thelial neoplasia (PIN) and progressive prostate cancer [45].

The prostate gland depends on the androgen/AR signaling for growth. Activation of this axis in advanced prostate cancer has been attributed to various mechanisms, including AR hy-persensitivity, de novo intraprostatic androgen synthesis, promiscuous AR activation via adrenal androgens, non-androgenic steroids and non-canonical AR activation via growth factors and cytokines through intracellular signal-transduction pathways [47]. These mechanisms may result from abnormalities in the AR status (e.g., mutation, splice variants) and/or in the levels of its co-regulators. Furthermore, some AR splice variants have been identified with constitutive effects in the absence of ligands [48].

ROS are endogenously generated during cellular metabolic processes. It can also come from external sources. Thus, excessive ROS production or impairment of antioxidant defense systems can induce oxidative stress. This increase in ROS levels may contribute to the initiation and 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. However, little is known about the exact molecular machinery that mediates ROS function in the tumori-genic process. Several transcription factors that regulate AR activity/transcription are implicated in oxidative stress, among them, NF-kB, c-Myc, CREB, Sp1 and Foxo3a [49]. Interestingly, castration-induced oxidative stress in prostate cancer cell lines increased AR levels through the overexpression of an oncogene member of the basic helix-loop-helix transcription factor Twist 1, which regulates the expression of AR by binding to E-boxes in its promoter, resulting in a gain of castration resistant phenotype [50] and being responsible of metastasis [51]. Evidently, there is a connection between oxidative stress and androgen deprivation in prostate cancer, which is also supported by previous observations of increased oxidative damage associated to the development of malignancies [52]. Of interest, when comparing the expression profile of castration resistant prostate cancer gene with the genetic landscape of hormonal sensitive tumors, the endogenous antioxidant defense system is clearly repressed, in particular MnSOD, which regulates ROS production by converting superoxide to a less reactive species, acting as a ROS scavenger. Hence, MnSOD in advanced prostate cancer could be mechanistically linked to AR reactivation. An array for transcription factor DNA binding activity showed that AR (among other transcription factors) binds to DNA after MnSOD knocked-down [53]. These findings correlate with a clear transcriptional repression of stress-related genes [54].

2.2.2. Is oxidative stress governing the co-regulators of nuclear receptors?

Co-regulators of transcription orchestrate the action of nuclear receptors. Each tissue has a "quantitative finger print" of co-activators based on the relative inherited concentrations of these molecules. When the cellular concentration of a co-activator is altered, genetic dysfunction usually leads to a pathologic outcome. Co-regulators contain the potential to efficiently promote cellular pathologies by coordinately misdirecting multiple independent functions such as oncogenesis. During the development and progression of prostate tumors there are a misregulation of AR co-activators, many of them play a critical role in redox maintenance protecting cells from cytotoxicity produced by oxidative stress. That is the case with peroxiredoxin (Prx), a gene elevated in cancer with anti-oxidant capacity. Prx1, a co-activator that facilitates the binding of androgen to the AR, is regulated by nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2), a transcription factor also induced by oxidative stress. Another member of this family, Prx2, is also regulated by oxidative stress but in this case through Foxo3a, another transcription factor implicated in AR transcription and cellular responses to oxidative stress and overexpressed in the castrate resistant-disease. Remarkably, the subcellular distribution of co-regulators seems to be relevant in the regulation of the AR activity. While cytoplasmic Prx2 enhances AR transactivation, its nuclear localization decreases the receptor activity, suggesting that the redox status of the nucleus and cytoplasm might affect AR signaling through this co-regulator [55].

2.2.3. Oxidative stress and tumor-stroma co-evolution

Since the initial seed and soil hypothesis elaborated by Paget in 1889 [56], the relevance of the tumor microenvironment in the carcinogenic process is continuously on scene. Tissue recombination experiments with mixed prostate stromal/epithelial cell xenografts surprisingly revealed that transformation of epithelial cells is accompanied by a transdifferentiation of fi-broblasts. Prostate stroma is mainly composed of fibroblasts and smooth muscle cells, and an intermediate cell type described as myofibroblast. The highly proliferative stromal cells immediately surrounding malignant glands have been described as "reactive stroma" or "carcinoma-associated fibroblast" (CAF) [57]. Wound repair exhibits a fibroblastic switch to a myofibroblast-like phenotype, with the subsequent extracellular matrix (ECM) remodeling through angiogenesis and increased protease activity [58]. The "reactive stroma" of a malignant tumor may parallel the granulation tissue of a healing wound in many ways, behaving as wounds that never heal. This "reactive stroma" comprises multiple cell types, which have been altered from their original state to become permissive of prostate cancer cell progression. In human prostate cancers, the "reactive stroma" displays increased number of myofi-broblasts, amplification of ECM proteins, and increased local vascular density, properties almost identical to those seen in granulation tissue. Intriguingly, there is still no effective marker of "reactive stroma" available. The receptors activated by serine proteases (PARs) are good candidates as PARs play key roles in tissue remodeling and cancer invasion. Other key signaling mediators also involved in the "reactive stroma" phenoptype include tumor growth factor beta (TGFp), partly responsible for fibroblast transdifferentiation. Other fibro-blastic and smooth muscle markers participate in the transformation phenomena, such as vi-mentin and smooth muscle a-actin. However, TGFp also affects the cancer cell itself, accomplishing contrary roles in the different stages of cancer evolution. Even in precancer-ous PIN lesions elevated TGFp expression was detected in epithelial cells. In addition to TGFp, chronic inflammation has also been the focus in the development of prostate cancer. Several characteristics of chronic inflammation are increased, such as the induction of the proinflammatory enzyme COX-2 and production of ROS and RNS. In turn, the infiltration of macrophages and leukocytes together with COX-2 activation, further enhances the burst of oxidative stress, promoting a more aggressive phenotype.

2.2.4. Oxidative stress triggers metabolic reprogramming

Mounting evidence recollected in the last paper of Hanahan and Weinberg [59] display compelling data on oxidative stress as a scaffold of the well-established hallmarks of cancer. Oxi-dative stress players are expressed abnormally in tumors, positively affecting compulsory stages of the carcinogenic process, by stimulating cell proliferation and anchorage independent cell growth, causing insensitivity to apoptosis, sustaining de novo angiogenesis, and by altering the migration/invasion program through metabolic and epigenetic mechanisms. ROS mediates ligand-independent transactivation of receptor tyrosine kinase and ERK activation affecting proliferation, promoting tissue invasion and metastatic dissemination due to MMP secretion/activation. Furthermore, ROS induce the release of VEGF and angiopoie-tin promoting angiogenesis and evading apoptosis/anoikis [60-62].

In cancer cells, high levels of ROS can result from increased basal metabolic activity, mito-chondrial dysfunction due to hypoxia or mitophagy, peroxisome activity, uncontrolled growth factor of cytokines signaling and oncogene activity, as well as from enhanced activity of known ROS sources as NADPH oxidase, COX or lipoxygenases [62]. It is well accepted that the activity of oxidants on tumors depends on their mutagenic potential, their capacity to rule the intracellular signaling pathways governing cellular homeostasis and their recognized role in stromal reactivity, mandatory for cancer development and dissemination [63, 64].

Cell vulnerability appears as a consequence of the oxidative status of their constituents promoting spontaneous and therapy induced cell death. Thus, resistance to oxidative stress is positioned as a major mechanism of tumor chemo- and radio-defense.

The tumor hypoxic microenvironment as well induces this "reactive stroma", affecting the cancer cells motility, and consequently generating a more aggressive tumor, which can met-astasize to the bone. Hypoxia generates ROS production and likewise anti-oxidants agents have shown to suppress hypoxia induced epithelial to mesenchymal transition (EMT), impairing the metastatic phenotype [65]. The "reactive stroma" recruitment to the cancer foci begins early during carcinogenesis and its co-evolution is predictive of human cancer progression, which is facilitated by tumor-stroma interactions.

It is of particular significance that many genes, which are regulated by oxidative stress, are targets of NF-kB [66]. NF-kB is constitutively activated in human prostate carcinoma and correlates with disease progression [67]. NF-kB is an inducible transcription factor that belongs to the Rel/NF-KB family. Increasing evidence suggests that inhibition of NF-kB activity in prostate cancer cells can suppress angiogenesis, invasion and metastasis by down-regulating the expression of NF-kB downstream target genes, such as VEGF, plasminogen activator type urokinase and MMP-9 [68]. Additionally, heme-oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, confers cytoprotection against oxi-dative stress and inflammation [69]. This protein exerts vital metabolic functions limiting the axis of heme degradation and maintaining the cellular homeostasis. Several signaling molecules are implicated in the cytoprotection conferred by HO-1, including NF-kB and PI3K/Akt [70]. Although classical recognized as a microsomal protein, its presence has been detected in other subcellular compartments [71, 72]. Recent studies have reported that HO-1 suffers a proteolytic degradation in its hydrophobic C-terminal domain, which would facilitate its entrance to the nucleus [73]. It has been proposed that HO-1 possesses in the nucleus a non-catalytic canonical function participating in the regulation of the activity of several nuclear transcription factors and also regulating its own transcription [72,

73]. Moreover, it has been documented HO-1 nuclear expression in human primary prostate carcinomas [71]. It has also been reported that it impairs prostate tumor growth in vivo and down-regulates the expression of target genes associated with inflammation and angiogenesis [74, 75]. However, clinical data demonstrated a statistically significant difference in HO-1 epithelial expression between benign, high-grade PIN, localized prostate cancer, and advanced prostate cancer, where castration resistant disease presented the highest HO-1 expression followed by benign tissue. This work provides experimental evidence for a cross talk between epithelial HO-1 expression and PTEN deletions, which are associated with adverse clinical outcome [76].

Altogether these findings may indicate that the oxidative stress imbalance may strongly influence the prostate carcinogenic process and may also cooperate in the bone homing of prostate cancer, the most clinically significant aspect of this disease. The stromal-epithelial interaction gains therapeutic relevance, as prostate carcinoma cells must induce the hospitality of bone cells in order to take up residence in an osseous microenvironment.

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