Infections and inflammatory responses are linked to 20% - 300% of all deaths from cancer worldwide. Inflammatory responses play crucial roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Several studies point to an important role of inflammation in prostate growth, although the contribution of inflammation to benign prostate cancer is not completely understood. The basic and clinical research in the area, trying to understand the etiology of prostatic inflammation and its signaling pathway may help to develop the novel therapeutic interventions against prostate cancer development triggered by inflammation.
Inflammation is a fundamental physiological process that can arise in any tissue in response to infectious, post-ischemic, toxic, or autoimmune injury. In the setting of tissue damage resulting from microbial pathogen infection or other noxious stimuli, these processes lead to eradication of pathogens, clearing of debris, epithelial regeneration and stromal remodeling. Inflammation induces cellular and genomic damage and promotes cellular turnover associated with a sustained inflammatory microenvironment that provides a constant supply of a variety of reactive nitrogen and oxygen species, reactive aldehydes, cytokines, chemokines, and growth factors, which can alter crucial biological processes responsible for maintaining normal cellular homeostasis, leading to uncontrolled proliferative response and genomic instability and risk of prostate cancer development [
There is a poorly understood, but longstanding, observation and epidemiologic link between inflammation and cancer. It was in 1863 that Rudolf Virchow reported for first time leucocytes in neoplastic tissues and made a connection between inflammation and cancer. He suggested that the “lymphoreticular infiltrate” reflected the origin of cancer at sites of chronic inflammation. Recent estimates suggest that about 20% of all human cancers are caused by chronic infection or chronic inflammatory states [
Prostate cancer remains a significant health concern for men throughout the world. Recently, there has developed an expanding multidisciplinary body of literature suggesting a link between inflammation and prostate cancer [
Inflammation is a process that involves both an innate and adaptive immune response following infection or injury. The innate immune system initiates the inflammatory response by producing a large number of cytokines, reactive oxygen (ROS), and nitrogen species (RNS) [
Chronic or recurrent inflammation is responsible for the development of many human cancers, including those affecting the liver, esophagus, stomach, large intestine, and urinary bladder [
Oxidative damage to DNA and other cellular components accompanying chronic or recurrent inflammation may connect prostate inflammation with prostate cancer. In response to infections, inflammatory cells produce a variety of toxic compounds designed to eradicate microorganisms. These include superoxide, hydrogen peroxide, singlet oxygen, as well as nitric oxide that can react further to form the highly reactive peroxynitrite [
Inflammation involves the induction of complex, coordinated chemical signals and associated physiological processes following injury that promote “healing” of damaged tissues [
The molecular mechanisms that prime the pathogenesis of cancer-related inflammation are complex and involve a delicate interplay between tumor and its microenvironment. To address the details of transition from inflammation to cancers and the further development of inflammation-associated cancers, it is necessary to investigate specific roles of key regulatory process involved in this process. Constant activation of NF-κB has been found in several cancers including PCa. NF-κB might be linked to tumour development through induction of pro-inflammatory cytokines, such as IL-6, TNF-α, and COX-2, and may also contribute to genomic instability by promoting release of ROS and RNS.
1) The oxidative stress imbalance in the prostrate tumor, and
2) The cytokine & chemokine orchestration in prostate cancer.
The oxidative stress associated with infection and inflammation has also been regarded as a possible cause of prostate carcinogenesis because the induction of iNOS (inducible nitric oxide synthase) might activate reactive nitrogens and oxygen reactive species that are released during the inflammatory response.
At the site of inflammation, caused by either wounding or infection, phagocytic cells (e.g. neutrophils and macrophages) generate reactive oxygen and nitrogen substances, but these cells also synthesize and secrete large quantities of growth factors and a number of potent angiogenic factors, cytokines, and proteases, all of which are important mediators in the tissue regeneration, but can also potentiate neoplastic tumorigenesis. Prostaglandins, cytokines, nuclear factor NF-κB, chemokines and angiogenic factors are the main molecular players that link inflammation to genetic alterations. However, free radical species derived from oxygen (ROI) and nitrogen (RNI) are the main chemical effectors [
Human cells have three main systems for protection and repair during the oxidative stress: 1) direct antioxidant enzymes (superoxide dismutase (SOD), catalase, peroxidises), 2) proteases and phospholipases activated by oxidative modification of membranes, 3) lipid and water soluble antioxidants [
The macrophages in the tumor microenvironment produce ROS and RNS. The increase in reactive radicals causes DNA damage, 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 intraepithelial neoplasia (PIN) and progressive prostate cancer [
ROS are endogenously generated during cellular metabolic processes. It can also come from external sources. The 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 [
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity.
Furthermore, NF-κB has been recognized as the major transcription factor that involves prostate cancer initiation and progression [
The NF-κB family of transcription factors plays a crucial role in inflammation as well as in the development and progression of cancer. Extensive evidence indicates that the NF-κB pathway is implicated in controlling the expression of genes involved in cell survival, proliferation, angiogenesis, and invasion [
Several lines of evidence suggest that activation of NF-κB pathway is dysregulated in prostate cancer and has been implicated in the progression to the androgen-independent state that ultimately leads to patient death. Constitutive NF-κB activation has been reported in prostate tumors tumors [
Collectively, the available evidence confirms that NF-κB activation is a key event in PC pathogenesis. Constitutive or induced activation of NF-κB may lead to amplification of the inflammatory response by providing a positive feedback signal to immune cells present in the tumour microenvironment, thereby increasing the production of molecular mediators such as various proinflammatory cytokines & chemokines which contribute to carcinogenic and inflammatory processes (
Cytokines are a family of cell-signaling protein molecules that are secreted by various cell types and are a category of signaling molecules used extensively in intercellular communication. Cytokines can be classified as proteins, peptides, or glycoproteins. A variety of cytokines are secreted by cells in the tumor microenvironment and can impact on prostate cancer growth [
Cytokines, including TNF-α, IL, growth factors, and differentiation factors (colony-stimulating factors), are secreted or membrane-bound molecules that play a regulatory role in the growth, differentiation, and activation of immune cells (100). Cytokine signaling could contribute to the progression of prostate tumors of altered cells at the inflammatory site [
A large number of evidences suggest that TNF and chemokines are candidate linking molecules between inflammation and prostate cancer [
TNF-α is not released from prostate cancer cells themselves but from associated macrophages after a relapse in disease. Studies have shown that patients with hormone-refractory prostate cancer demonstrate high serum TNF-α levels as compared with untreated patients [
The recent publication from Davis et al. [
Moreover, inflammatory cytokines have also been reported to facilitate the spectrum of tumor development. For example, one of the most interesting mediators clearly implicated in prostate cancer is IL-6, a multifunctional cytokine, produced by inflammatory cells, osteoblasts and even prostate cancer cells. There are multiple lines of clinical and experimental evidence preponderantly showing that IL-6 contributes to prostate cancer progression. Both, patients with prostate cancer and patients with advanced metastatic disease display high expression levels of IL-6 and its soluble receptor in the circulating plasma [
In addition to the clinical observations, in vitro studies have provided evidence that IL-6 modulates prostate cancer cell growth of hormone-refractory cells, but had no effect on the growth of hormone-dependent cell lines [
IL-6 has also been implicated in other aspects of prostate cancer pathophysiology such as tumorigenesis in the prostate microenvironment. IL-6 foremost effect is the activation of Janus kinase (JAK) signaling and of signal transducers and activators of transcription (STAT) proteins, especially STAT3 [
The other cytokines like IL-8 and IL-17 are also involved in human prostate epithelial cells, growth and survival. It has been shown that Human IL-8, an inflammatory chemokine, promotes tumor cell growth and the progression of human solid tumors; this includes PCa, due largely to its ability to regulate the expression of matrix metalloproteinases (MMPs) [
Steiner et al. have shown that 58% of human malignant prostate tissues have an increased level of IL-17 messenger ribonucleic acid and both prostate tumor cells and prostate stromal cells treated with IL-17 in vitro have an increase in messenger ribonucleic acid and protein expression of both IL-6 and IL-8. These data suggest that IL-17 acts directly on the prostate tumor cells and promotes their growth and metastasis, or indirectly by increasing the level of inflammatory cytokines and growth factors released locally in the prostate.
Together above, experimental studies have validated the crucial role of various pro/anti-inflammatory cytokines in prostate cancer progression and development.
The evidence presented in this review provides a strong association between inflammation and prostate cancer but the whole story between inflammation and prostate cancer is still far from being completely understood. The question regarding the intriguing feedback loop between cytokines and NF-κB is which activation is the initial event during the prostate cancer. In addition, animal models for inflammation-derived cancers and combination to molecular approaches, such as specific gene knockout mouse, will be helpful and necessary to address the questions in this field. We believe that the better clarification of mechanisms linking inflammation and prostate cancer will be beneficial to the development of efficacious prevention and therapies of inflammation-associated cancers.