About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease.

/pdf/inflammation-in-prostate-carcinogenesis-1hvbel1p7j.pdf

Inflammation in prostate carcinogenesis

Tumor-specific Th17-polarized cells eradicate large established melanoma

Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-beta towards Treg and IL-6 and TGF-beta towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORgammat for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-gamma and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2249.2007.03356.x

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.20408

Human prostate cancer risk factors.

Chronic inflammation is now known to contribute to several forms of human cancer, with an estimated 20% of adult cancers attributable to chronic inflammatory conditions caused by infectious agents, chronic non-infectious inflammatory diseases and/or other environmental factors. Indeed, chronic inflammation is now regarded as an 'enabling characteristic' of human cancer. The aim of this review is to summarize the current literature on the evidence for a role for chronic inflammation in prostate cancer aetiology, with a specific focus on recent advances regarding the following: (i) potential stimuli for prostatic inflammation; (ii) prostate cancer immunobiology; (iii) inflammatory pathways and cytokines in prostate cancer risk and development; (iv) proliferative inflammatory atrophy (PIA) as a risk factor lesion to prostate cancer development; and (v) the role of nutritional or other anti-inflammatory compounds in reducing prostate cancer risk.

Prostate cancer and inflammation: the evidence.

INTRODUCTION AND OBJECTIVES

To investigate factors involved in inflammation of the prostate besides IL-15, we screened prostatic cells and tissues for IL-17 and IL-17 receptor expression



METHODS

Normal prostate (n = 1), BPH (n = 19), and carcinoma (CaP, n = 12) specimens were screened for IL-17, IL-17 receptor, CD45, IL-6, and IL-8 mRNA expression The carcinoma cell lines DU145, PC3, LNCaP, and BPH-epithelial (EC), stromal cell (SC) preparations, and BPH-T-cell lines were analyzed for IL-17 production by RT-PCR and ELISA The effect of IL-17 on IL-6, IL-8, TGF-β1, and fibroblast growth factor (FGF-2) mRNA expression and/or release of SC was analyzed using real-time PCR and/or ELISA Immunohistochemistry was used to localize both IL-17 and IL-17 receptor



RESULTS

In the normal prostate, IL-17 expression was very weak and restricted to lymphocytes In 79% of BPH and 58% of CaP specimens, IL-17 mRNA and protein expression was increased IL-17 mRNA expression could be shown for activated BPH-T-cells and to some extend for BPH-EC Expression of IL-17 receptor was ubiquitous Release of IL-17 was shown only for activated BPH-T-cells IL-17 stimulated expression of IL-6 (13-fold) and IL-8 (26-fold) by prostatic BPH-SC In situ, however, the amount of IL-17mRNA in BPH-tissue did not correlate with the amount of IL-6 and IL-8 mRNA In CaP tissue, significant correlation was found only between the amount of IL-6 and IL-8 mRNA



CONCLUSIONS

Activated BPH-T-cells abundantly express IL-17 The increase of IL-17 in BPH-tissues goes hand in hand with elevated levels of IL-15, a pro-inflammatory cytokine with T-cell growth factor properties A clinical relevance of increased IL-17 expression under pathological conditions is suggested by the demonstration of significant upregulation of IL-6 and IL-8 production of prostatic SC by IL-17 Prostate 56: 171–182, 2003 © 2003 Wiley-Liss, Inc

Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate.

BACKGROUND
Benign prostatic hyperplasia (BPH) frequently exhibit infiltration of CD4 +/CD45RO + memory-T-lymphocytes. Expression and impact of lymphocyte-derived growth factors on prostatic stromal cell (PSC) growth were investigated.

METHODS
Lymphokine synthesis in normal prostate tissues (n = 3), BPH-tissues (n = 13), BPH-derived T-cells (n = 6), BPH-derived epithelial cells (BPH-EC) (n = 5), normal prostate-derived (n = 3) and BPH-derived stromal cell lines (BPH-SC) (n = 6), and prostate cancer (CaP) lines (n = 3) was analyzed by RT-PCR and Southern-blotting. The effect of interleukin (IL)-2, -4, -7, and interferon-γ (IFN-γ) on normal and BPH-SC growth was investigated by 3H-thymidine incorporation assays.

RESULTS
All BPH-tissues and, to a lesser degree, normal prostates, expressed significant amounts of IFN-γ mRNA. However, only BPH-tissues contained IL-2 and IL-4 mRNA (ratio: 10:13). BPH-T-cell lines were heterogenous in composition and expressed significant amounts of IFN-γ, IL-2, and IL-4 mRNA. Low level expression of these lymphokines was also observed in BPH-EC, CaP lines, and PSC lines. IL-2, -7 and IFN-γ stimulated the proliferation of BPH-PSC lines but not that of normal PSC, while IL-4 inhibited BPH-PSC growth.

CONCLUSIONS
Chronic inflammation may induce an increased growth pattern of fibromuscular tissue in BPH similar to that of wound healing. Prostate 52: 43–58, 2002. © 2002 Wiley-Liss, Inc.

Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation.

Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue.

Background

Pro-inflammatory interleukin (IL)-15 plays a major role in host defense and chronic inflammation by stimulating T-lymphocyte recruitment and growth. Expression of IL-15 and IL-15 receptor (IL-15R) in human prostate was examined.



Methods

Normal and benign hyperplastic (BPH) prostate specimens (n = 23) were analyzed for IL-15 and IL-15Rα-chain expression by immunohistochemistry and Real-Time-PCR/RT-PCR. Regulation of prostatic stromal cell (PSC) IL-15 mRNA and effect of IL-15 on prostatic cell growth were analysed in vitro.



Results

In normal prostate, anti-IL-15 and anti-IL-15Rα-chain reactivity were restricted to smooth muscle and stromal cells. However, in BPH, in addition epithelial cells frequently exhibited discrete anti-IL-15R and often intense, membranous anti-IL-15 reactivity. IL-15/IL-15R mRNA were detected in all prostatic cells types. In BPH tissues, IL-15 mRNA content was variable (15-fold). IL-15 mRNA synthesis of PSC was significantly up-regulated by IFN-γ. Furthermore IL-15 strongly stimulated the growth of BPH-T-lymphocytes and weakly that of carcinoma cell lines, but not of stromal cells.



Conclusions

Overexpression of IL-15 and IL-15Rα-chain in BPH and massive proliferation of BPH-T-lymphocytes induced by IL-15 suggest a role for IL-15 in prostatic inflammation. Since IFN-γ, a T-lymphocyte product, stimulates prostatic IL-15 production; chronic inflammation might be triggered by this paracrine loop. Prostate 49:251–262, 2001. © 2001 Wiley-Liss, Inc.

Differential expression of interleukin-15, a pro-inflammatory cytokine and T-cell growth factor, and its receptor in human prostate.

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Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate.

Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation.

Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue.

Differential expression of interleukin-15, a pro-inflammatory cytokine and T-cell growth factor, and its receptor in human prostate.