Articles on Inflammation & Prostate Disorders

Macrophage inhibitory cytokine-1: possible bridge molecule of inflammation and prostate cancer. [Review] [35 refs] Karan D. Holzbeierlein J. Thrasher JB. Cancer Research. 69(1):2-5, 2009. There is emerging evidence that inflammation may lead to prostate cancer development. Although inflammation is an essential response to injury or infection, chronic inflammation is harmful and causes tissue damage. Increasing evidence suggests that inflammation leads to the development of epithelial cancers; however, studies on inflammation-targeted genes that might contribute to the development of cancer are at the beginning stage. Here, we describe macrophage inhibitory cytokine-1, which provides a potential link between inflammation and prostate cancer. Understanding the regulation of macrophage inhibitory cytokine-1 in response to inflammation may have potential for novel therapeutic strategies.

Inflammation and prostate cancer. [Review] [86 refs] Vasto S. Carruba G. Candore G. Italiano E. Di Bona D. Caruso C. Future Oncology. 4(5):637-45, 2008. Prostate cancer remains a major health concern for the male population throughout the Western world. It is today widely accepted that inflammation has a role in many human cancers. In fact, inflammation is thought to incite carcinogenesis by causing cell and genome damage, promoting cellular turnover and creating a tissue microenvironment that can enhance cell replication, angiogenesis and tissue repair. Accordingly, there is a body of literature suggesting a link between chronic inflammation and prostate cancer, in which prostate inflammation may contribute to the promotion of prostate cancer development. On the other hand, high levels of endogenous gonadal steroids are considered as risk factors for prostate cancer. Interestingly, it is clear that elevation of estrogens in the presence of testosterone results in a prostate-specific inflammatory response. Thus, it is possible that early inflammatory events stimulated by sex hormones serve as a prerequisite for the onset of prostate cancer.

The interleukin-8 pathway in cancer. [Review] [58 refs] Waugh DJ. Wilson C. Clinical Cancer Research. 14(21):6735-41, 2008. Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface, G protein-coupled receptors (CXCR1 and CXCR2). Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. The induction of IL-8 signaling activates multiple upstream signaling pathways that (a) impinge on gene expression via regulation of numerous transcription factor activities, (b) modulate the cellular proteome at the level of translation, and/or (c) effect the organization of the cell cytoskeleton through posttranslational regulation of regulatory proteins. As a consequence of the diversity of effectors and downstream targets, IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and infiltrating neutrophils at the tumor site. Accordingly, IL-8 expression correlates with the angiogenesis, tumorigenicity, and metastasis of tumors in numerous xenograft and orthotopic in vivo models. Recently, IL-8 signaling has been implicated in regulating the transcriptional activity of the androgen receptor, underpinning the transition to an androgen-independent proliferation of prostate cancer cells. In addition, stress and drug-induced IL-8 signaling has been shown to confer chemotherapeutic resistance in cancer cells. Therefore, inhibiting the effects of IL-8 signaling may be a significant therapeutic intervention in targeting the tumor microenvironment.

Multi-faceted roles for CXC-chemokines in prostate cancer progression. [Review] [74 refs] Waugh DJ. Wilson C. Seaton A. Maxwell PJ. Frontiers in Bioscience. 13:4595-604, 2008. CXC-chemokines play an essential role in co-ordinating the function of the immune system. Increasingly, these small signaling molecules are recognized in facilitating communication between multiple cell types within the tumor microenvironment. This review will summarize the role of two members of this family, CXCL12 (stromal cell derived factor-1) and CXCL8 (interleukin-8) in promoting the disease progression of prostate cancer, the most prevalent non-cutaneous cancer in men in western society and the second leading cause of death from cancer in men. Evidence for a role of these chemokines in underpinning the development and progression of this disease is supported by examination of prostate tissue and serum samples from prostate cancer patients, from biochemical and molecular investigations conducted on representative cell-based models of this disease and from observation of CXC-chemokine promoted growth and systemic dissemination of human prostate tumors in experimental in vivo models. The future potential of employing strategies to attenuate chemokine expression or alternatively to selectively block chemokine receptor signaling to effect greater long-term control or enhanced therapeutic response in this disease is also discussed.

Inflammation, infection, and prostate cancer. [Review] [16 refs] Klein EA. Silverman R. Current Opinion in Urology. 18(3):315-9, 2008 PURPOSE OF REVIEW: Recent evidence suggesting that inflammation and infection play a role in the etiology of prostate cancer, and the discovery of a novel virus in men with a genetic susceptibility to prostate cancer is reviewed. RECENT FINDINGS: Almost 20% of visceral cancers worldwide have proven infectious causes. There is substantial histologic, molecular genetic, and epidemiologic evidence that infections and inflammation are also important in the pathogenesis of prostate cancer. The R462Q allelic variant in RNASEL, an antiviral gene important in the innate immune response to viral infections, increases susceptibility to prostate cancer while resulting in vitro in deficient antiviral defenses, suggesting that prostate cancer could be caused by a virus. The study of R462Q carriers led to the discovery and biologic characterization of a novel retrovirus, xenotropic murine leukemia-related virus, isolated and cloned from prostate tissue of affected men. Biologic studies of this virus show that it is sensitive to inhibition by interferon and its downstream mediator, RNaseL, and that its DNA has integrated into the DNA of some men with prostate cancer. SUMMARY: Inflammation triggered by infection and other causes underlies the development of prostate cancer, and xenotropic murine leukemia-related virus is a candidate etiologic agent. Ongoing studies seek to define its oncogenic potential and pathogenesis.

Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome. [Review] [139 refs] Dandona P. Dhindsa S. Chaudhuri A. Bhatia V. Topiwala S. Mohanty P. Current Molecular Medicine. 8(8):816-28, 2008. Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Araldi EM. Dell'aica I. Sogno I. Lorusso G. Garbisa S. Albini A. Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer. [Review] [107 refs] Current Cancer Drug Targets. 8(2):146-55, 2008. Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths in Western countries. The extraordinary biological heterogeneity, the increasing incidence of this disease, and the presence of putative premalignant conditions make prostate cancer a crucial pathology to study and test pharmacological or nutritional chemopreventive strategies. It has been demonstrated that the incidence of prostate cancer is lower in Asian people, and that it increases in Asian men living in Western countries; these data point to a pivotal role of diet in the onset of prostate cancer. A large amount of work has been done in investigating chemopreventive properties of dietary compounds widely used in Asian countries (i.e. soy, soybeans, green tea, fish) in respect of the oxidants- and meat-rich diet typical of Western people, particularly of central and northern Europe. Some dietary products appear promising as chemo-preventive agents for prostate cancer, because they display both anti-oxidant and anti-inflammatory activity - and inflammation is crucial for the aetiology of adeno-carcinoma of the prostate. There is increasing evidence for close correlation between inflammation, the microenvironment and tumour-associated neo-angiogenesis causing the adverse outcomes of prostate cancer. It may thus be useful to develop new strategies to couple the treatment of inflammation-related prostate cancer and the generation of angiopreventive or antiinflammatory molecules to prevent this disease. The search for compounds with few or no adverse effects - particularly cardiovascular - as compared with the agents currently in use is therefore of greatest relevance.

David Stock, Patti A. Groome, D. Robert Siemens. Inflammation and Prostate Cancer: A Future Target for Prevention and Therapy? Urologic Clinics of North America 35;117-130, 2008. Given its long natural history, prostate cancer has become an ideal model for the clinical and basic science study of neoplastic disease in distinct pathologic phases: tumor initiation, progression, invasion, and metastasis. Chronic or recurrent acute inflammation, a product of infectious agents or other sources, has potential promotional roles in each of these phases. Nonsteroidal anti-inflammatory drugs (NSAIDs), because of their ability to attenuate inflammation, as well as possibly direct anti-cancer properties associated with the inhibition of stromal cyclooxygenase-2, are potential candidates for clinical use in prostate cancer. Though epidemiologic evidence indicating a reduced risk of prostate cancer for NSAID users supports a chemoprotective benefit, observational assessment and clinical trials of these agents among large cohorts of prostate cancer patients are needed to determine their value in prostate cancer management. 

Haverkamp J. Charbonneau B. Ratliff TL. Prostate inflammation and its potential impact on prostate cancer: a current review. [Review] [51 refs] Journal of Cellular Biochemistry. 103(5):1344-53, 2008. Recent studies have identified a role for inflammation in the development and progression of several cancers, such as liver, stomach and the large intestine. Data from several studies has shown correlations between soluble inflammatory mediators, such as cytokines, chemokines and growth factors. However, a direct relationship between inflammation and prostate cancer has yet to be identified. Two major hurdles currently exist which limit the study of this relationship are first that animal models available for studying prostate inflammation are limited, and secondly that relatively little is known about the inflammatory response in the prostate. Here we first review the data demonstrating a correlation between inflammation and prostate cancer as well as review what is currently known about the inflammatory response in the prostate and the impact this inflammation has on the prostate tissue.

Stock D. Groome PA. Siemens DR. Inflammation and prostate cancer: a future target for prevention and therapy?. [Review] [117 refs] Urologic Clinics of North America. 35(1):117-30; vii, 2008. Given its long natural history, prostate cancer has become an ideal model for the clinical and basic science study of neoplastic disease in distinct pathologic phases: tumor initiation, progression, invasion, and metastasis. Chronic or recurrent acute inflammation, a product of infectious agents or other sources, has potential promotional roles in each of these phases. Nonsteroidal anti-inflammatory drugs (NSAIDs), because of their ability to attenuate inflammation, as well as possibly direct anti-cancer properties associated with the inhibition of stromal cyclooxygenase-2, are potential candidates for clinical use in prostate cancer. Though epidemiologic evidence indicating a reduced risk of prostate cancer for NSAID users supports a chemoprotective benefit, observational assessment and clinical trials of these agents among large cohorts of prostate cancer patients are needed to determine their value in prostate cancer management.

Caruso DJ. Carmack AJ. Lokeshwar VB. Duncan RC. Soloway MS. Lokeshwar BL. Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence. Clinical Cancer Research. 14(13):4111-8, 2008. PURPOSE: Lack of reliable biomarkers limits accurate prediction of prostate-specific antigen biochemical recurrence (disease progression) in prostate cancer. The two inflammatory chemokines, osteopontin and interleukin-8 (IL-8), are associated with tumor angiogenesis and metastasis. We investigated whether osteopontin and IL-8 expression in prostate cancer correlates with disease progression. EXPERIMENTAL DESIGN: Archival prostatectomy specimens (n = 103) were obtained from patients with minimum 72-month follow-up. Osteopontin and IL-8 expression was evaluated by immunohistochemistry and graded for intensity and the area. Association of osteopontin and IL-8 staining with biochemical recurrence was evaluated by univariate and multivariate models. RESULTS: In tumor cells, osteopontin and IL-8 staining was higher in the recurred group (203.2 +/- 78.4; 181.1 +/- 89.3) than in the nonrecurred group (122.7 +/- 76.6; 96.4 +/- 85.6; P < 0.001). Higher osteopontin and IL-8 staining was also observed in benign areas adjacent to tumor in the recurred group, than in nonrecurred group. In univariate analysis, except age, all preoperative and postoperative variables and osteopontin and IL-8 staining scores were significantly associated with biochemical recurrence (P < 0.05). In multivariate analysis, margin status and osteopontin staining independently associated with biochemical recurrence within 72 months. Osteopontin, either alone or with IL-8 and seminal vesicle invasion, was a significant variable in predicting biochemical recurrence within 24 months. Osteopontin and IL-8 staining predicted recurrence with high sensitivity (75.5%; 73.6%) and specificity (76%; 70.6%). CONCLUSION: In prostatectomy specimens, osteopontin expression is independently associated with biochemical recurrence. Both osteopontin and IL-8 may be predictors of early disease progression.

Patel MI. Kurek C. Dong Q. The arachidonic acid pathway and its role in prostate cancer development and progression. [Review] [53 refs] Journal of Urology. 179(5):1668-75, 2008. PURPOSE: The arachidonic acid pathway incorporates phospholipase, cyclooxygenase, lipoxygenase and epoxygenase enzymes. This pathway has been shown to have a major role in the development and progression of a number of cancers, including prostate cancer. We discuss the current status of research of this pathway in the area of prostate cancer, ranging from preclinical in vitro studies to human clinical trials. MATERIALS AND METHODS: We performed an online search of the current and past peer reviewed literature on prostate cancer and arachidonic acid, phospholipase, cyclooxygenase, lipoxygenase, epoxygenase, platelet activating factor, prostaglandin and eicosanoid. We retrieved and evaluated all full-length articles published in English from the 1980s to January 2007. RESULTS: Epidemiological evidence suggested that nonsteroidal anti-inflammatory drugs may decrease the risk of prostate cancer. This effect, presumably through the inhibition of cyclooxygenase-2, has been validated in preclinical studies. Cyclooxygenase-2 inhibition has also decreased the rate of prostate specific antigen increase in men with biochemical recurrence after treatment for prostate cancer. Although lipoxygenase and secretory phospholipase A2 inhibition was also effective for decreasing prostate cancer growth in preclinical studies, to our knowledge these strategies have not yet been used in clinical trials. Cytosolic phospholipase A2, platelet activating factor and epoxygenase need further investigation to determine a role in prostate cancer. CONCLUSIONS: Evolving data suggest a significant role for some areas of the arachidonic acid pathway in prostate cancer. Inhibiting 1 or a number of these enzymes in combination may hold promise for future prostate cancer treatment.  

Uemura H. Ishiguro H. Ishiguro Y. Hoshino K. Takahashi S. Kubota Y. Angiotensin II induces oxidative stress in prostate cancer. Molecular Cancer Research: MCR. 6(2):250-8, 2008. Angiotensin II has been shown to be a cytokine especially acting as a growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of angiotensin II seems to be similar in prostate cancer, as we previously reported. In the present study, we explored the biological role of angiotensin II in oxidative stress of prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related proteins (p47phox, manganese superoxide dismutase 2, glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with angiotensin II and/or an angiotensin II receptor type 1 blocker, candesartan. To examine DNA damage induced by angiotensin II, 8-hydroxy-2'-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint proteins including p53, Chk2, and cdc2. Immunocytochemical studies of inducible nitric oxide synthase and superoxide anion radical (O(2)(-)) were done in LNCaP cells stimulated with angiotensin II. The phosphorylation of Akt was induced by angiotensin II treatment and inhibited by candesartan, as well as by LY294002, an inhibitor of phosphoinositide 3-kinase. Oxidative stress-related proteins were up-regulated by angiotensin II and inhibited by pretreatment with candesartan or catalase. The level of 8-hydroxy-2'-deoxyguanosine was increased by angiotensin II and conversely decreased by candesartan. Immunocytochemical studies showed that angiotensin II enhanced an inflammatory marker, inducible nitric oxide synthase, and the production of O(2)(-) radical. The hypothesis that angiotensin II has the potential to induce oxidative stress, which may be implicated in carcinogenesis of the prostate gland through long-term exposure to chronic inflammation is proposed.

Rebbeck TR. Rennert H. Walker AH. Panossian S. Tran T. Walker K. Spangler E. Patacsil-Coomes M. Sachdeva R. Wein AJ. Malkowicz SB. Zeigler-Johnson C. Joint effects of inflammation and androgen metabolism on prostate cancer severity. International Journal of Cancer. 123(6):1385-9, 2008. Multiple pathways of prostate carcinogenesis have been proposed, including those involving androgen metabolism and inflammation. These pathways are not independent, and may act together in prostate cancer etiology: androgens promote both inflammatory processes and serve as mitogens in prostate tumor growth. To explore the possible joint effects of these pathways in prostate cancer severity, we studied 1,090 Caucasian prostate cancer cases to evaluate whether tumor severity is influenced by a history of benign prostatic hyperplasia (BPH) interacting with genotypes involved in inflammation or androgen metabolism including MSR1, RNASEL, AR, CYP3A4, CYP3A43, CYP3A5 and SRD5A2. We observed a statistically significant interaction between a number of genotypes and BPH. After considering the potential for false positive associations, the only remaining significant associations involved CYP3A43 P340A genotypes and history of BPH on both Gleason grade (interaction p-value = 0.026) and tumor stage (interaction p-value = 0.017). These results suggest that androgen metabolism may act in concert with inflammatory phenotypes such as BPH in determining prostate cancer severity.

Hsing AW. Sakoda LC. Chua S Jr. Obesity, metabolic syndrome, and prostate cancer. [Review] [84 refs] American Journal of Clinical Nutrition. 86(3):s843-57, 2007. Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.

Sciarra A. Di Silverio F. Salciccia S. Autran Gomez AM. Gentilucci A. Gentile V. Inflammation and chronic prostatic diseases: evidence for a link?. [Review] [36 refs] European Urology. 52(4):964-72, 2007. OBJECTIVES: Emerging evidence indicates that prostatic inflammation may contribute to prostate growth either in terms of hyperplastic (benign prostatic hyperplasia [BPH]) or neoplastic (prostate cancer [PCa]) changes. We propose two questions: Does prostate inflammation represent a significant factor for the development and the progression of both BPH and PCa? Are data available now to sustain the identification of prostate inflammation as a risk factor for prostate diseases? METHODS: We reviewed the recent international literature using a PubMed search to analyze new findings supporting a role for inflammation in BPH and PCa growth and progression. RESULTS: On histologic examinations from patients with BPH, inflammatory aspects are present in approximately 40% of cases. The men with inflammatory aspects inside the prostate have a significantly higher risk for BPH progression and acute urinary retention. Evidence shows that a cyclooxygenase-2 (COX-2) inhibitor can increase the apoptotic activity in human BPH tissue. Analyses on the bacterial colonization in PCa and normal prostate tissue showed a highly suggestive correlation between bacterial colonization/chronic inflammation and the diagnosis of PCa. Evidence from genetic studies supports the hypothesis that prostate inflammation may be a cause of PCa development. Proliferative inflammatory atrophy has been considered as an early histologic precursor to prostatic intraepithelial neoplasia and PCa. CONCLUSION: The concept that inflammation can promote chronic prostatic diseases, such as BPH or PCa, is actually supported by several new significant findings; however, no specific oncologic surveillance for these cases is justified at the moment.

Bonfil RD. Chinni S. Fridman R. Kim HR. Cher ML. Proteases, growth factors, chemokines, and the microenvironment in prostate cancer bone metastasis. [Review] [11 refs] Urologic Oncology. 25(5):407-11, 2007. The arrival of cancer cells in the marrow upsets the delicate homeostatic nature of the bone microenvironment. Cell surface or secreted factors brought in by cancer cells perturb the web-like communication network between different bone cell types and bone matrix. Chemokines not only attract cancer cells from the circulation into the marrow, they also stimulate a cell signaling process leading to attachment, invasion, and further stimulation of bone matrix turnover. Cancer cell surface-associated proteases have also been associated with tumor growth and bone matrix turnover. Recent data indicate that autocrine proteolytic shedding of cell surface chemokines further promotes osteoclastogenesis. Proteases also contribute to autocrine and paracrine shedding of growth factors, another mechanism of promoting growth and expansion of the metastatic deposit. Studies of the bone microenvironment have thus revealed multiple potential targets of intervention with regard to the expanding metastatic deposit.

De Marzo AM. Platz EA. Sutcliffe S. Xu J. Gronberg H. Drake CG. Nakai Y. Isaacs WB. Nelson WG. Inflammation in prostate carcinogenesis. [Review] [158 refs] Nature Reviews. Cancer. 7(4):256-69, 2007. 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.

Kramer G. Mitteregger D. Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease?. [Review] [89 refs] European Urology. 51(5):1202-16, 2007. OBJECTIVES: Chronic inflammation has been documented for years in benign prostatic hyperplasia (BPH), but only now has it become evident as a major factor in disease progression. This review highlights the immunologic key features of chronic inflammation in BPH and the present interpretation of these changes in the development and progression of BPH. RESULTS: Almost all BPH specimens show inflammatory infiltrates at histologic examination, but correlation to bacterial or other foreign antigens has not been established. Recognition of prostate secretion products by autoreactive T cells and animal models on experimental prostatitis demonstrate an autoimmune component to chronic inflammation. The infiltrate consists predominantly of chronically activated CD4(+) T lymphocytes, which are permanently recruited to prostate tissue via elevated expression of interleukin 15 (IL-15) and interferon gamma (IFN-gamma), proinflammatory cytokines produced by smooth muscle and T cells, respectively. With the appearance of infiltrates, T cell-derived cytokine production of IFN-gamma, IL-2, and transforming growth factor beta increases, the former two ultimately reaching 10-fold and the latter 2-fold higher levels in fully developed BPH than in normal prostates. As "mature" BPH nodules develop, IL-4 and IL-13 expression increases >2-fold, corresponding to a T-helper (Th)0/Th2 cytokine pattern. Dysregulation of the immune response in BPH may occur via elevated expression of proinflammatory IL-17, which stimulates a multifold production of IL-6 and IL-8, key executors of stromal growth in BPH. CONCLUSIONS: These data strongly suggest that BPH is an immune inflammatory disease. Unravelling the specific nature of immune dysregulation may help design novel drugs with these specific targets in mind.

Wang W. Bergh A. Damber JE. Increased expression of CCAAT/enhancer-binding protein beta in proliferative inflammatory atrophy of the prostate: relation with the expression of COX-2, the androgen receptor, and presence of focal chronic inflammation. Prostate. 67(11):1238-46, 2007. BACKGROUND: Proliferative inflammatory atrophy (PIA) in the prostate has been proposed to be a precursor to prostate cancer. CCAAT/enhancer-binding protein beta (C/EBPbeta) is an important transcription factor involved in cellular proliferation and differentiation. Activation of C/EBPbeta plays a crucial role during the initial stage of cyclo-oxygenase 2 (COX-2) induction by proinflammatory mediators. Overexpression of C/EBPbeta has been reported in several human tumors. Nevertheless, the C/EBPbeta expression and functions in human prostate tissue are basically unknown. METHODS: C/EBPbeta immunohistochemical staining was performed on 45 benign prostate hyperplasia (BPH) samples. The expression of C/EBPbeta in PIA lesions and normal-appearing acini was analyzed. In addition, by using double-IHC staining, C/EBPbeta expression and the association with chronic inflammatory cell density, co-expression of COX-2 and androgen receptor (AR) were also investigated. RESULTS: C/EBPbeta was occasionally observed in normal-appearing prostate acini (4.9% +/- 6.7%, Mean +/- SD) but was clearly overexpressed in PIA lesions (81.8% +/- 16.4%) (P < 0.0001). Atrophic glands with T-lymphocyte and macrophage inflammation expressed higher level of C/EBPbeta. Furthermore, C/EBPbeta correlated significantly with COX-2 expression. Downregulation of the AR was common in PIA and was also related to the C/EBPbeta overexpression. CONCLUSIONS: The data demonstrated that chronic inflammation appeared to play roles in the induction of C/EBPbeta expression in prostate epithelium, which was in turn associated with increased COX-2 expression and AR downregulation. In combining with other molecular alteration in the epithelium of PIA, it is suggested that these cells might be a kind of intermediate cells and involved in the pathogenesis of prostate cancer.

Prostate cancer prevention. [Review] [156 refs] Nelson WG. Current Opinion in Urology. 17(3):157-67, 2007 PURPOSE OF REVIEW: Prostate cancer, a common cause of morbidity and mortality in the developed world, ought to be a preventable disease. This review focuses on prostate cancer prevention in the context of new mechanistic insights into human prostatic carcinogenesis. RECENT FINDINGS: Evidence is accumulating to implicate infection and inflammation as contributors to prostate cancer development. Inherited prostate cancer susceptibility genes discovered thus far encode participants in host responses to infection. Proliferative inflammatory atrophy, a prostate cancer precursor lesion, ties inflammatory responses to prostatic carcinogenesis. Somatic epigenetic alterations, present in all prostate cancers, appear to arise in the setting of inflammation. Finally, a newly identified somatic genome change, involving a fusion between an androgen-regulated gene, TMPRSS2, and genes encoding members of the ETS family of transcription factors, may provide a clue as to why prostate cancer cells exhibit androgen dependence for growth and survival. SUMMARY: The contributions of infection and inflammation to the early development of prostate cancer suggest prevention strategies featuring prevention or eradication of infection, amelioration of inflammation, or attenuation of genome-damaging reactive oxygen and nitrogen species. The acquisition of androgen dependence later during prostate cancer pathogenesis suggests the use of approaches targeting androgen signaling, including inhibitors of 5alpha-reductase.

Lu Y. Cai Z. Xiao G. Keller ET. Mizokami A. Yao Z. Roodman GD. Zhang J. Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption. Cancer Research. 67(8):3646-53, 2007. Prostate cancer preferentially metastasizes to bone, resulting in high mortality. Strategies to inhibit prostate cancer metastasis include targeting both tumor-induced osteoblastic lesions and underlying osteoclastic activities. We and others have previously shown that blocking receptor activator of nuclear factor-kappaB ligand (RANKL) partially blocks tumor establishment and progression in bone in murine models. However, levels of RANKL in the cell lines used in these studies were very low, suggesting that soluble factors other than RANKL may mediate the cancer-induced osteoclast activity. To identify these factors, a human cytokine antibody array was used to measure cytokine expression in conditioned medium collected from primary prostate epithelial cells (PrEC), prostate cancer LNCaP and its derivative C4-2B, and PC3 cells. All prostate cancer cells produced high amounts of monocyte chemotactic protein-1 (MCP-1) compared with PrEC cells. Furthermore, levels of interleukin (IL)-6, IL-8, GROalpha, ENA-78, and CXCL-16 were higher in PC3 than LNCaP. These results were confirmed by ELISA. Finally, human bone marrow mononuclear cells (HBMC) were cultured with PC3 conditioned medium. Although both recombinant human MCP-1 and IL-8 directly stimulated HBMC differentiation into osteoclast-like cells, IL-8, but not MCP-1, induced bone resorption on dentin slices with 21 days of culture in the absence of RANKL. However, the conditioned medium-induced bone resorption was inhibited by MCP-1 neutralizing antibody and was further synergistically inhibited with IL-8 antibody, indicating that MCP-1, in addition to IL-8, mediates tumor-induced osteoclastogenesis and bone resorption. MCP-1 may promote preosteoclast cell fusion, forming multinucleated tartrate-resistant acid phosphatase-positive osteoclast-like cells. This study may provide novel therapeutic targets for treatment of prostate cancer skeletal metastasis.

Lu Y. Cai Z. Galson DL. Xiao G. Liu Y. George DE. Melhem MF. Yao Z. Zhang J. Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate. 66(12):1311-8, 2006. BACKGROUND: Monocyte chemotactic protein-1 (MCP-1) plays a key role in the recruitment and activation of monocytes during inflammation. Increased MCP-1 serum levels in patients with various cancers were correlated with advanced stage. Here, we evaluated the role of MCP-1 on prostate cancer (CaP) cell proliferation and invasion. METHODS: Expression of MCP-1 in tissue specimens was analyzed by immunohistochemical staining. MCP-1 production was determined by ELISA in conditioned media collected from primary prostate epithelia (PrEC), LNCaP, C4-2B, PC3 cells, and hFOB. Cell proliferation and invasion were assayed by MTS assay and invasion chambers. RESULTS: All CaP cells, as well as hFOB, produced high amount of MCP-1 compared to PrEC cells. MCP-1 expression levels were associated with advanced pathologic stage. MCP-1 induced proliferation and invasion of CaP cells and this was abolished partially either by CCR2 antagonist or PI3 Kinase inhibitor. CONCLUSION: MCP-1 acts as a paracrine and autocrine factor for CaP growth and invasion.

McArdle PA. Mir K. Almushatat AS. Wallace AM. Underwood MA. McMillan DC. Systemic inflammatory response, prostate-specific antigen and survival in patients with metastatic prostate cancer. Urologia Internationalis. 77(2):127-9, 2006. BACKGROUND: It is increasingly recognised that, in cancer patients, disease progression is dependent on a complex interaction of the tumour and the host inflammatory response and that the systemic inflammatory response, as evidenced by an elevated C-reactive protein (CRP) concentration, may be a useful prognostic factor. MATERIALS AND METHODS: The prognostic value of CRP compared with prostate-specific antigen (PSA) was examined in 62 patients with metastatic prostate cancer receiving androgen-deprivation therapy. RESULTS: In all, 41 (66%) of patients died, 38 (61%) of their disease. On univariate survival analysis, PSA (p < 0.05) and CRP (p < 0.05) were significant predictors of cancer-specific survival. On multivariate analysis, both PSA (HR 1.96, 95% CI 1.00-3.83, p = 0.049) and CR (HR 1.97, 95% CI 0.99-3.92, p = 0.052) were independent predictors of cancer-specific survival. PSA concentrations were significantly correlated with those of CRP (r(s) = 0.46, p < 0.001). CONCLUSION: The results of the present study suggest that, in patients with metastatic prostate cancer, the presence of an elevated CRP concentration predicts poor outcome, independent of PSA.

Loberg RD. Day LL. Harwood J. Ying C. St John LN. Giles R. Neeley CK. Pienta KJ. CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia (New York). 8(7):578-86, 2006. Tumor cells in the bone interact with the microenvironment to promote tumor cell survival and proliferation, resulting in a lethal phenotype for patients with advanced prostate cancer. Monocyte chemoattractant protein 1 (CCL2) is a member of the CC chemokine family and is known to promote monocyte chemotaxis to sites of inflammation. Here we have shown that human bone marrow endothelial (HBME) cells secrete significantly higher levels of CCL2 compared to human aortic endothelial cells and human dermal microvascular endothelial cells. Furthermore, we demonstrate that CCL2 is a potent chemoattractant of prostate cancer epithelial cells, and that stimulation of PC-3 and VCaP cells resulted in a dose-dependent activation of PI3 kinase/Akt signaling pathway. Activation of the PI3 kinase/Akt pathway was found to be vital to the proliferative effects of CCL2 stimulation of both PC-3 and VCaP cells. Additionally, CCL2 stimulated the phosphorylation of p70-S6 kinase (a downstream target of Akt) and induced actin rearrangement, resulting in a dynamic morphologic change indicative of microspike formation. These data suggest that bone marrow endothelial cells are a major source of CCL2, and that an elevated secretion of CCL2 recruits prostate cancer epithelial cells to the bone microenvironment and regulates their proliferation rate.

Xu J. Lowey J. Wiklund F. Sun J. Lindmark F. Hsu FC. Dimitrov L. Chang B. Turner AR. Liu W. Adami HO. Suh E. Moore JH. Zheng SL. Isaacs WB. Trent JM. Gronberg H. The interaction of four genes in the inflammation pathway significantly predicts prostate cancer risk. Cancer Epidemiology, Biomarkers & Prevention. 14(11 Pt 1):2563-8, 2005. It is widely hypothesized that the interactions of multiple genes influence individual risk to prostate cancer. However, current efforts at identifying prostate cancer risk genes primarily rely on single-gene approaches. In an attempt to fill this gap, we carried out a study to explore the joint effect of multiple genes in the inflammation pathway on prostate cancer risk. We studied 20 genes in the Toll-like receptor signaling pathway as well as several cytokines. For each of these genes, we selected and genotyped haplotype-tagging single nucleotide polymorphisms (SNP) among 1,383 cases and 780 controls from the CAPS (CAncer Prostate in Sweden) study population. A total of 57 SNPs were included in the final analysis. A data mining method, multifactor dimensionality reduction, was used to explore the interaction effects of SNPs on prostate cancer risk. Interaction effects were assessed for all possible n SNP combinations, where n = 2, 3, or 4. For each n SNP combination, the model providing lowest prediction error among 100 cross-validations was chosen. The statistical significance levels of the best models in each n SNP combination were determined using permutation tests. A four-SNP interaction (one SNP each from IL-10, IL-1RN, TIRAP, and TLR5) had the lowest prediction error (43.28%, P = 0.019). Our ability to analyze a large number of SNPs in a large sample size is one of the first efforts in exploring the effect of high-order gene-gene interactions on prostate cancer risk, and this is an important contribution to this new and quickly evolving field.

Vela Navarrete R. Garcia Cardoso JV. Barat A. Manzarbeitia F. Lopez Farre A. BPH and inflammation: pharmacological effects of Permixon on histological and molecular inflammatory markers. Results of a double blind pilot clinical assay. European Urology. 44(5):549-55, 2003. INTRODUCTION: The role of infiltrating cells (I.C.), commonly observed in the adenoma interstitial tissue, is unknown. We tested the hypothesis that I.C. are related with BPH progression by: phenotypically characterising these cells; quantifying the expression of lymphokines and growth factors; investigating the response to Permixon (P) in a clinical study. Permixon is a lipido sterolic extract of Serenoa repens possessing pharmacological activities and widely used in the treatment of men with BPH. MATERIAL AND METHODS: A multicenter open pilot study of two parallel groups on BPH patients was carried out. They were randomized to receive either oral Permixon (P) 160 mg bid for three months or to be followed for 3 weeks without any treatment before surgery (control group C). Strict inclusion and exclusion criteria were applied to conform homogeneous groups, avoiding interferences of inflammatory drugs or others. Baseline clinical profile was almost identical in both groups in terms of age (65.7+/-5.1 vs. 67.1+/-5.8 years), IPSS (19.8+/-6.1 vs. 19.0+/-5.8), prostate volume (64.8+/-18.9 vs. 71.5+/-29.3cc), Q(max) (9.6+/-3.2 vs. 10.6+/-2.6 ml/s), and Q(L) (4.0+/-1.1 vs. 3.5+/-0.7). Surgery was ultimately performed on 29 patients (17C, 12P) by TURP or retropubic adenomectomy. Adenoma samples were routinely stained with HE and later prepared for immunohistochemical studies using CD3, CD20 and CD68 antibodies. Counting of positives cells, lymphoid aggregates and foci were done using EnVision technique and the Tech Mate processor. Cytokines, growth factors and eicosanoids were determined by Elisa kits following the manufactured recommendation. RESULTS: HISTOLOGICAL: A difference was observed in the number of lymphocytes B between C (91.4+/-44.1) and P treated (58.2+/-53.7) groups (p=0.097). BIOLOGICAL MARKERS: TNFalpha and IL-1beta were dramatically lower in the Permixon treated group. Other parameters did not show significant changes. CLINICAL: IPSS in the Permixon treated group was significantly reduced (p<0.006) from 20.0+5.9 to 14.9+3.8 after three months of treatment. COMMENTS: The BPH inflammatory hypothesis was tested in humans. Our pilot study shows a significant reduction of some inflammatory parameters in prostatic tissues of patients treated with Permixon. These biological findings justify a pharmacological effect of this drug on the inflammatory status of the adenoma. A correlation with clinical improvement was observed.