Inflammation In Prostate Cancer Research Articles

The current state of inflammation-related research in prostate cancer: a bibliometric analysis and systematic review.

Prostate cancer (PCa) is the second most prevalent malignancy among men globally. The diagnosis, treatment, and prognosis of prostate cancer frequently fall short of expectations. In recent years, the connection between inflammation and prostate cancer has attracted considerable attention. However, there is a lack of bibliometric studies analyzing the research on inflammation within the domain of prostate cancer. We utilized the Web of Science Core Collection (WOSCC) as our data source to extract articles and reviews related to inflammation in prostate cancer, published up until April 12, 2024. The collected data underwent meticulous manual screening, followed by bibliometric analysis and visualization using the Biblioshiny package in R. This study encompasses an analysis of 2,786 papers focusing on inflammation-related research within the realm of prostate cancer. Recent years have seen a significant proliferation of publications in this area, with the United States and China being the foremost contributors. The most prolific author in this domain is Demarzoam, with Johns Hopkins University standing out as the most influential institution. The leading journal in disseminating these studies is PROSTATE. Keyword co-occurrence analysis reveals that 'inflammation-related biomarkers', 'inflammation index', and 'tumor immune microenvironment' represent the current research hotspots and frontiers. The findings of this bibliometric study serve to illuminate the current landscape of inflammation-related research in the field of prostate cancer, while further augmenting the discourse on inflammation-mediated cancer therapeutics. Of particular note is the potential of these discoveries to facilitate a more nuanced understanding among researchers regarding the interplay between inflammation and prostate cancer.

Involvement of Reactive Oxygen Species in Prostate Cancer and Its Disparity in African Descendants.

Reactive oxygen species (ROS) participate in almost all disorders, including cancer. Many factors, including aging, a high-fat diet, a stressful lifestyle, smoking, infection, genetic mutations, etc., lead to elevated levels of ROS. Prostate cancer, the most prevalent type of cancer in senior American men and the second leading cause of cancer mortality in American men, results from chronic oxidative stress. The doubled incident rate as well as the doubled mortality numbers of prostate cancer have persisted in African Americans in comparison with Caucasian Americans and other racial groups, indicating a prostate cancer disparity in African American men. In this review, we mainly focus on the latest findings on ROS in prostate cancer development and progression within the last five years to update our understanding in this area, as several comprehensive literature reviews addressing oxidative stress and/or inflammation in prostate cancer before 2020 are available. In addition to other known factors such as socioeconomic disadvantage, cultural mistrust of the health care system, etc. that are long-existing in the African American group, we also summarize the latest evidence that demonstrated high systemic oxidative stress and inflammation in African Americans for their potential contribution to the racial prostate cancer disparity in this population.

Inflammation in Prostate Cancer: Exploring the Promising Role of Phenolic Compounds as an Innovative Therapeutic Approach.

Prostate cancer (PCa) remains a significant global health concern, being a major cause of cancer morbidity and mortality worldwide. Furthermore, profound understanding of the disease is needed. Prostate inflammation caused by external or genetic factors is a central player in prostate carcinogenesis. However, the mechanisms underlying inflammation-driven PCa remain poorly understood. This review dissects the diagnosis methods for PCa and the pathophysiological mechanisms underlying the disease, clarifying the dynamic interplay between inflammation and leukocytes in promoting tumour development and spread. It provides updates on recent advances in elucidating and treating prostate carcinogenesis, and opens new insights for the use of bioactive compounds in PCa. Polyphenols, with their noteworthy antioxidant and anti-inflammatory properties, along with their synergistic potential when combined with conventional treatments, offer promising prospects for innovative therapeutic strategies. Evidence from the use of polyphenols and polyphenol-based nanoparticles in PCa revealed their positive effects in controlling tumour growth, proliferation, and metastasis. By consolidating the diverse features of PCa research, this review aims to contribute to increased understanding of the disease and stimulate further research into the role of polyphenols and polyphenol-based nanoparticles in its management.

Tempol differential effect on prostate cancer inflammation: In vitro and in vivo evaluation.

Tempol is a redox-cycling nitroxide that acts directly on inflammation. However, few studies have reported the use of tempol in prostate cancer (PCa). The present study investigated the effects of tempol on inflammation related to NF-κB signaling, using hormone-dependent or hormone-independent cell lines and the transgenic adenocarcinoma of the mouse prostate PCa animal model in the early and late stages of cancer progression. PC-3 and LnCaP cells were exposed to different tempol doses in vitro, and cell viability assays were performed. The optimal treatment dose was chosen for subsequent analysis using western blotting. Fiveexperimental groups were evaluated in vivo to test for tempol effects in the early (CT12 and TPL12 groups) and late stages (CT20, TPL20-I, and TLP20-II) of PCa development. The TPL groups were treated with 50 or 100 mg/kg tempol. All control groups received water as the vehicle. The ventral lobe of the prostate was collected and subjected to immunohistochemical and western blotanalysis. Tempol treatment reduced cellular proliferation in vitro and improved prostatic morphology in vivo, thereby decreasing tumor progression. Tempol reduced inflammation in preclinical models, and downregulated the initial inflammatory signaling through toll-like receptors, not always mediated by the MyD88 pathway. In addition, it upregulated iκB-α and iκB -β levels, leading to a decrease in NF-κB, TNF-α, and other inflammatory markers. Tempol also influenced cell survival markers. Tempol can be considered a beneficial therapy for PCa treatment owing to its anti-inflammatory and antiproliferative effects. Nevertheless, the action of tempol was different depending on the degree of the prostatic lesion in vivo and hormone reliance in vitro. This indicates that tempol plays a multifaceted role in the prostatic tissue environment.

A Novel Strategy to Model Age-Related Cancer for Elucidation of the Role of Th17 Inflammaging in Cancer Progression.

Cancer is a disease of aging, but most studies on cancer are in young but not aged animal models, and cancer clinical trials are rarely performed in older adults. Recognition of the connections between aging and cancer and improvement of treatment for elderly cancer patients has become one of the most critical medical issues with the global increase in the elderly population. Mouse models are essential experimental tools for understanding the molecular mechanisms of complex processes and related gene pathways of biological aging. However, few mouse models can be used to understand the role of aging in cancer development and the underlying mechanisms. One of the hallmarks of aging is chronic inflammation, often called inflammaging. This is our rationale for examining the role of aging-related inflammation in prostate cancer, a major aging malignancy. We have now developed a novel method to generate age-related cancer models in mice to better understand how age impacts cancer initiation and progression in the natural aging process. We discuss its application to elucidate some of the contributing mechanisms.

Combinatorial approaches of nanotherapeutics for inflammatory pathway targeted therapy of prostate cancer.

Prostate cancer (PC) is the most prevalent male urogenital cancer worldwide. PC patients presenting an advanced or metastatic cancer succumb to the disease, even after therapeutic interventions including radiotherapy, surgery, androgen deprivation therapy (ADT), and chemotherapy. One of the hallmarks of PC is evading immune surveillance and chronic inflammation, which is a major challenge towards designing effective therapeutic formulations against PC. Chronic inflammation in PC is often characterized by tumor microenvironment alterations, epithelial-mesenchymal transition and extracellular matrix modifications. The inflammatory events are modulated by reactive nitrogen and oxygen species, inflammatory cytokines and chemokines. Major signaling pathways in PC includes androgen receptor, PI3K and NF-κB pathways and targeting these inter-linked pathways poses a major therapeutic challenge. Notably, many conventional treatments are clinically unsuccessful, due to lack of targetability and poor bioavailability of the therapeutics, untoward toxicity and multidrug resistance. The past decade witnessed an advancement of nanotechnology as an excellent therapeutic paradigm for PC therapy. Modern nanovectorization strategies such as stimuli-responsive and active PC targeting carriers offer controlled release patterns and superior anti-cancer effects. The current review initially describes the classification, inflammatory triggers and major inflammatory pathways of PC, various PC treatment strategies and their limitations. Subsequently, recent advancement in combinatorial nanotherapeutic approaches, which target PC inflammatory pathways, and the mechanism of action are discussed. Besides, the current clinical status and prospects of PC homing nanovectorization, and major challenges to be addressed towards the advancement PC therapy are also addressed.

Abstract 784: Andrographolide altered inflammation pathways and cytokine expression in prostatecancer

Abstract Prostate cancer is the most diagnosed cancer in men in the USA. Andrographolide (AG) is a labdane diterpenoid compound isolated from the medicinal plant Andrographis paniculata. Previous studies in our laboratory showed that Andrographolide decreased prostate tumor size in mice, induced expression of DNA repair genes associated with double-strand break repair and altered mitochondrial function. The objective of this study is to determine the role of AG in inflammation in prostate cancer. Microarray analysis of tumors treated with Andrographolide 10 mg/kg and their vehicle were conducted. Tumors were developed using a xenograft model in which the prostates of SCID mice were injected with 22RV1, and mice were treated three times per week with Andrographolide 10 mg/kg. Tumor tissues were collected and snap frozen. Gene expression was identified and analyzed using the Affymetrix GeneChip® Human Gene 2.0 array. Using Ingenuity Pathway Analysis (IPA) we found that Andrographolide 10 mg/kg altered genes associated with inflammatory response such as ATM, DHFR, HIF-1-α, CDKAL1, DHFR, NOX1, C5, CCL4, COG6, SUPT20H, CA5B, TTC3. To determine changes of cytokine expression in PC3 prostate cancer cells treated with 25 μM Andrographolide, we used the Abcam Cytokine Antibody Array test®. PC3 prostate cancer cells treated with Andrographolide showed altered expression of cytokines such as IL-2, TNF-α, TNF-β, EGF, IGF-1, ENA-78, GM-CSF, GRO, GRO-α, I-309, and Angiogenin. These results showed that AG may alter the tumor microenvironment promoting the secretion of diverse cytokines that may inhibit tumor development. Understanding these biological pathways and networks is essential to determine possible targets of Andrographolide in prostate cancer. Citation Format: Mitzy J. Santiago Rosario, Gabriela Erazo Carde, María Sánchez Vázquez, Valerie Cardona, Magaly Martínez Ferrer. Andrographolide altered inflammation pathways and cytokine expression in prostatecancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 784.

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention.

Simple SummaryProstatitis, or the inflammation of the prostate, is frequently observed in the clinic and by research studies, but its relevance to a man’s risk of being diagnosed with prostate cancer, or to his survival after the diagnosis, is not completely understood. In this review, we summarize the current knowledge on the causes of prostate inflammation, as well as the relationship with prostate cancer, with a particular focus on aggressive, defined as a high Gleason score or clinical stage, and lethal stages of disease. We also describe the strengths and weaknesses of the various technologies used to evaluate prostate inflammation in human studies, and we consider the potential of immune therapy and lifestyle interventions to prevent lethal disease and improve outcomes for prostate cancer patients. Future research is needed to better understand the role of prostate inflammation in lethal prostate cancer, and to provide evidence to guide the development of new treatment and prevention strategies to reduce prostate inflammation and improve survival.Prostate cancer is a major cause of disease for men globally. Inflammation, an established hallmark of cancer, is frequently observed in the prostate, though its contribution to prostate cancer risks and outcomes is not fully understood. Prostate cancer is biologically and clinically heterogeneous, and there is now evidence that inflammation and immunological characteristics vary by the genomic and mutational landscape of the tumor. Moreover, it is now recognized that risk factor profiles vary between tumor subgroups, as defined by histopathological and molecular features. Here, we provide a review centered around the relationship between inflammation and prostate cancer, with a consideration of molecular tumor features and a particular focus on the advanced and lethal stages of disease. We summarize findings from epidemiological studies of the etiology and role of inflammation in prostate cancer. We discuss the pathology of prostate inflammation, and consider approaches for assessing the tumor immune microenvironment in epidemiological studies. We review emerging clinical therapies targeting immune biology within the context of prostate cancer. Finally, we consider potentially modifiable risk factors and corresponding lifestyle interventions that may affect prostate inflammation, impacting outcomes. These emerging insights will provide some hints for the development of treatment and prevention strategies for advanced and lethal prostate cancer.

C-Reactive Protein Is a Poor Marker of Baseline Inflammation in Prostate Cancer and Response to Radiotherapy or Androgen Ablation.

IntroductionC-reactive protein (CRP) is an acute-phase reactant used as a general marker for inflammation. Isolated levels have been associated with prostate cancer development, prostate-specific antigen (PSA), Gleason score, and treatment response. We seek to establish whether CRP levels reflect inflammation caused by prostate cancer by comparing levels at various points of time before, during, and after therapy.Materials and methodsA total of 209 patients had a complete blood count (CBC), PSA, and CRP taken at up to four different time points. Labs were performed up to one week prior to androgen ablation via leuprolide injection (pre-AA), up to one week prior to radiotherapy (RT) (pre-RT), within one week of RT completion (post-RT), and three months following RT completion (FU [follow-up]).ResultsSignificant relationships were found between CRP and WBC pre-AA (p-value=0.0050), pre-RT (p-value=0.0170), and post-RT (p-value=0.0113), but not at FU (p=.096). CRP had no significant relationship with PSA or lymphocytes at any time points. PSA was significantly affected by androgen ablation but lymphocytes, WBCs, and CRP were not. No CRP levels were associated with risk groups or FU-PSA. Lymphatic radiation fields significantly decreased WBCs and lymphocytes but not CRP.PSA, WBC, and lymphocytes all significantly decreased from pre-RT to post-RT, followed by a significant recovery. CRP did not significantly change during any of these periods and was not significantly related to changes in PSA, WBCs, or lymphocytes.ConclusionCRP is not a sensitive marker of the acute inflammatory effects of non-metastatic prostate cancer and treatment response with androgen ablation or radiation therapy.

Prostatic Inflammation in Prostate Cancer: Protective Effect or Risk Factor?

The relationship between prostatic chronic inflammation (PCI) and prostate cancer (PCa) is unclear and controversial. Some authors reported that a history of chronic prostatitis may be correlated with PCa induction, while others associate chronic inflammation with less aggressive disease or consider inflammation as a possible protective factor against PCa. Four different types of prostatitis are known: bacterial acute prostatic inflammation, bacterial chronic prostatic inflammation, abacterial prostatitis/chronic pelvic pain syndrome, and asymptomatic prostatic chronic inflammation. Prostatic inflammation is underestimated during daily clinical practice, and its presence and degree often go unmentioned in the pathology report of prostate biopsies. The goal of this report is to further our understanding of how PCI influences the biology of PCa. We investigated the main pathogenetic mechanisms responsible for prostatic inflammation, including the cellular response and inflammatory mediators to describe how inflammation modifies the prostatic environment and can lead to benign or malignant prostatic diseases. We found that prostatic inflammation might have a pivotal role in the pathogenesis of prostatic diseases. Details about PCI in all prostate biopsy reports should be mandatory. This will help us better understand the prostatic microenvironment pathways involved in PCa biology, and it will allow the development of specific risk stratification and a patient-tailored therapeutic approach to prostatic diseases.

Abstract LT006: NK cells from prostate cancer patients acquire a pro-angiogenic phenotype and polarize macrophages towards a M2-like/TAM subset

Abstract Angiogenesis has been shown to play a crucial role in prostate cancer (PCa) progression in several preclinical models, in the clinic, pro-angiogenic factors have been shown to correlate with, Gleason score, metastasis and prognosis in PCa. Plasma levels of VEGF were shown to be higher in patients with metastatic PCa than those with localized disease. The natural killer (NK) cells have been found to be non cytolytic, immunosuppressed in solid cancers. Our group and others demonstrated that tumor infiltrating NK cells in lung and colorectal cancer acquire a pro-angiogenic phenotype. These cells are similar to NK cell within the decidua (dNK), and functionally support angiogenesis in a TGFb and Stat3-dependent manner. A similar subset is present in the peripheral blood of oncology patients. We characterized systemic peripheral blood NK cells (pNK) from PCa patients and their interaction with endothelial cells and macrophages. NK cell subset distribution was investigated by multicolor flow cytometry (FC) for surface antigens on peripheral blood samples PCa patients. Conditioned media (CM) of three different PCa cell lines were used to polarize the healthy donors pNK cells. CM from FACS-sorted PCa pNKs were used for functional studies of angiogenesis, on human umbilical-vein endothelial cells (HUVEC), studies for macrophage recruitment (migration assay on Boyden chambers) and polarization. Molecular studies were performed by real time PCR (qPCR) on HUCECs and macrophages exposed to CM of pNKs. Protein arrays were performed to characterize the secretome on FACS-sorted pNKs. We found that PCa pNKs acquire a pro-angiogenic/decidual-like CD56brightCD9+CD49a+CXCR4+ phenotype. The same phenotype was observed from healthy donors pNK cells exposed to CMs of three different PCa cell lines. These results were confirmed also exposing heathy-donor derived NK cells to conditioned media of 3 different prostate cancer cell lines (PC-3, DU-145, LNCaP), together with increased production of CXCL8, Angiogenin, Angiopoietin1 and reduced production of TNFa, IFNg and GranzymeA. CMs from pNK cells support the formation on capillary-like structures on HUVEC, together with increased expression of VEGF, VEGR-2, CXCL8, ICAM-1 and VCAM-1. Although in male patients, PCa NK cells resemble decidual-like ones. Finding these cells polarized in PB suggests that they could be used as non-invasive marker of inflammation in prostate cancer. Secretome analysis revealed the ability of pNK cells release pro-angiogenic factors (CLXL8, MMP-1, MMP-9; uPAR) and cytokines/chemokines involved in macrophage recruitment (CCL1, CCL2, CCL5, CCL7,CCL13, CXCL1, CXCL11) and M2-like polarization (IL-10). CMs from pNK can recruiting THP-1 monocyte and polarize THP-1 macrophage towards CD206, Arginase1, CXCL8-expressing M2-like/TAM phenotype. Our results place PCa pNK cells interaction with endothelial cells and via macrophage polarization able in supporting angiogenesis in PCa patients. Citation Format: Adriana Albini, Denisa Baci, Matteo Gallazzi, Federico Dehò, Angelo Naselli, Andrea Guernieri, Lorenzo Mortara, Douglas M. Noonan, Antonino Bruno. NK cells from prostate cancer patients acquire a pro-angiogenic phenotype and polarize macrophages towards a M2-like/TAM subset [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT006.

C-Reactive Protein is a Poor Marker of Baseline Inflammation in Prostate Cancer and Response to Radiotherapy or Androgen Ablation

C-Reactive Protein (CRP) is an acute phase reactant used as a general marker for inflammation. There is some evidence that elevated levels are associated with increased risk of prostate cancer development, PSA, Gleason score, and decreased response to chemotherapy and radiotherapy (RT). Available literature largely focuses on pre-therapeutic levels as a prognostic marker. We seek to establish whether CRP levels reflect inflammation caused by prostate cancer before and in response to RT with or without prior androgen ablation (AA). This study included 209 patients who had a CBC, PSA, and CRP taken at up to four different time points. Labs were performed prior to AA via leuprolide injection (pre-AA), up to one week prior to RT (pre-RT), during the final week of RT (post-RT), and 3 months following RT completion (FU). Prior to RT, 33% of patients had received prior prostatectomy and 50.7% had received AA. Radiation fields included pelvic lymph nodes in 82% of patients. For comparisons at each time point, CRP had a significant relationship with WBCs pre-AA (p-value = 0.0050), pre-RT (p-value = 0.0170), and post-RT (p-value = 0.0113), but not at FU (p = .096). CRP had no significant relationship with PSA at any time points. For those who did or did not receive AA, pre-RT mean PSA was significantly lower (2.3 vs 5.4, p-value = 0.0072) while CRP was not. Pre-AA, pre-RT, and post-RT CRP levels were not significantly related to FU-PSA. No CRP levels were associated with risk groups. Only PSA significantly changed from pre-AA to pre-RT (p-value<0.0001). PSA, WBCs, and lymphocytes significantly decreased from pre-RT to post-RT, with significant recovery from post-RT to FU (p-value<0.0001 for all six comparisons), though still with overall significant change from pre-RT to FU (p-value = 0.0054, p-value<0.0001, p-value<0.0001, respectively). CRP did not significantly change during any period, nor significantly relate to changes in WBCs or PSA. There was a significant difference between the treated vs. untreated lymph node groups in post-RT lymphocytes (p-value<0.0001), FU-lymphocytes (p-value<0.0001), post-RT-WBCs (p-value = 0.0004), and FU-WBCs (p-value = 0.0141). CRP was not significantly different between these groups. Our results demonstrate a lack of clinical utility for CRP as a marker of the inflammatory effects of prostate cancer. It has no correlation with PSA levels or trends, before or after radiation therapy, with or without androgen ablation. It does not change with significant PSA decrease after androgen ablation and corresponding decrease in cancer activity. It does not change at the end of radiation therapy despite significant changes in lymphocytes and WBCs. It does not change with 3-month follow-up to correspond with either significant recovery of lymphocytes and WBCs or a decrease of radiation-induced inflammation.

Inflammation as a Driver of Prostate Cancer Metastasis and Therapeutic Resistance.

Simple SummaryProstate cancer is the most common malignancy in men, with a high mortality rate when disease progresses to metastasis and therapeutic resistance. Evidence implicates inflammation as a driver of prostate cancer risk and has a significant impact on processes in the tumor microenvironment that facilitate progression to advanced therapeutically resistant disease. In this review, we discuss the sources of inflammation in the prostate, the functional contribution of the critical inflammatory effectors to prostate cancer initiation and metastatic progression, and the therapeutic challenges that they impose on treatment of advanced disease and overcoming therapeutic resistance. Full understanding of the role of inflammation in prostate cancer progression to advanced metastatic disease and tumor relapse will aid in the development of personalized predictive biomarkers and therapy to reduce the burden and mortality in prostate cancer patients.Prostate cancer is the most common malignancy among men, and progression to metastasis and the emergence of therapeutically resistant disease confers a high mortality rate. Growing evidence implicates inflammation as a driver of prostate cancer development and progression, resulting in increased cancer risk for prostate cancer. Population-based studies revealed that the use of antinflammatory drugs led to a 23% risk reduction prostate cancer occurrence, a negative association that was stronger in men who specifically used COX-2 inhibitors. Furthermore, patients that were taking aspirin had a 21% reduction in prostate cancer risk, and further, long-term users of daily low dose aspirin had a 29% prostate cancer risk reduction as compared to the controls. Environmental exposure to bacterial and viral infections, exposure to mutagenic agents, and genetic variations predispose the prostate gland to inflammation, with a coordinated elevated expression of inflammatory cytokines (IL-6, TGF-β). It is the dynamics within the tumor microenvironment that empower these cytokines to promote survival and growth of the primary tumor and facilitate disease progression by navigating the immunoregulatory network, phenotypic epithelial-mesenchymal transition (EMT), angiogenesis, anoikis resistance, and metastasis. In this review, we discuss the sources of inflammation in the prostate, the functional contribution of the critical inflammatory effectors to prostate cancer initiation and metastatic progression, and the therapeutic challenges that they impose on treatment of advanced disease and overcoming therapeutic resistance. Growing mechanistic evidence supports the significance of inflammation in localized prostate cancer, and the systemic impact of the process within the tumor microenvironment on disease progression to advanced therapeutically-resistant prostate cancer. Rigorous exploitation of the role of inflammation in prostate cancer progression to metastasis and therapeutic resistance will empower the development of precise biomarker signatures and effective targeted therapeutics to reduce the clinical burden and lethal disease in the future.

Increased inflammatory potential of diet is associated with increased odds of prostate cancer in Argentinian men.

Various aspects of diet, including specific food items and nutrients, have been shown to modulate inflammation and have been implicated in the etiology of prostate cancer (PrCA). No study examining the role of diet-associated inflammation in PrCA has been conducted in Latin America. We examined the association between the Dietary Inflammatory Index (DII®) and PrCA in a population-based case-control study in Córdoba, Argentina. A total of 153 incident cases of PrCA and 309 controls frequency matched on sex, age (± 5years), and place of residence were recruited from 2008 to 2015. The DII was developed to determine the inflammatory potential of individuals' diets and was computed from a validated food frequency questionnaire using nutrient data from diet only. Multi-level logistic regression models were fit to evaluate the association between DII scores and PrCA, adjusting for age, body mass index, energy intake, and occupational exposure as first-level covariates and family history of prostate cancer as the second-level variable. Odds ratios were estimated in all subject and stratified by BMI (< 30 vs. ≥ 30kg/m2). Men in the most pro-inflammatory group (tertile 3) had 50% higher odds of having PrCA compared to men in the most anti-inflammatory group (tertile 1) (ORtertile3 vs. tertile1 1.50; 95% CI 1.24-1.80). The odds of prostate cancer were higher in obese men (n = 109, ORtertile3 vs. tertile1 1.81; 95% CI 1.45-2.27), while no association was found among non-obese men (n = 375, ORtertile3 vs. tertile1 0.93; 95% CI 0.25-3.51). A pro-inflammatory diet, reflected by higher DII scores, was positively associated with PrCA occurrence. Based on these results and those from other studies, steps should be taken to promote a diet rich in anti-inflammatory foods, in order to reduce risk of PrCA and other chronic diseases. Future studies should explore this association in a prospective setting.

Abstract 58: Age-related elevated Th17 immune response contributes to prostate carcinogenesis

Abstract Prostate cancer is associated with advanced age, but how age contributes to prostate cancer remains unknown. Aging is characterized by a chronic, low-grade systemic inflammation, so called “inflamm-aging”. Data supporting the role of inflammation in prostate cancer comes from a variety of fields, thus, inflamm-aging represents a strong candidate to connect age and prostate cancer. Recent studies have shown that T helper (Th) 17 immune responses are elevated in aging humans and mice. However, the contribution of age-related elevated Th17 immune responses to prostate cancer remains unclear. The aim of this study was to investigate the role of Th17 immune responses in the aging process in prostate carcinogenesis. Initial investigation of mouse prostate tissues from wild-type C57BL/6J mice showed that aged (&amp;gt;80-week-old) mouse prostates had significantly increased inflammatory cell infiltration, increased protein and mRNA levels of pro-inflammatory mediators and Th17 cytokines and activated NF-κB and ERK1/2 signaling compared to young (12-20-week-old) mouse prostates. To gain a mechanistic understanding of how the Th17 immune response promotes prostate carcinogenesis in the aging process, we isolated splenic T cells from young and aged mice. Naïve CD4+ T cells isolated from the young and aged mice were differentiated in Th17 polarization conditions. Th0 cells were cultured in the absence of cytokines to serve as control. Four days later cells were re-stimulated with anti-CD3 and CD28 with PMA and ionomycin in the presence of brefeldin A for 6 hours, then the cells were washed and re-cultured in serum free media for 24 hours. Cells were then collected and used for flow cytometry or qPCR. Conditioned media from both young and aged Th0 and Th17 cultures were collected and used in subsequent experiments. Results indicated that Th17 cells, Th17 cytokines and Th17/Treg ratio were significantly increased in aged mice compared to young mice. The human prostate cancer cell lines (LNCaP, DU-145 and PC3) and mouse prostate cancer cell line (PTEN-CaP8) was cultured in their suitable medium as in our previous study. These cell lines were treated with the above mentioned conditioned media (Th0 and Th17) for 48 and 72 hours and harvested for subsequent experiments. When human and mouse prostate cancer cell lines were exposed to the aged Th17 conditioned media, cell proliferation, migration and invasion were significantly increased, and the pro-inflammatory NF-κB pathway in PCa cell lines was activated compared to cells exposed to young ones. In summary, these results collectively indicate that Th17 immune responses are elevated in mice in the aging process, and this age-related elevated Th17 immune responses may play an important role in prostate carcinogenesis. This work was supported by the NIH-National Institute of General Medical Sciences COBRE (2P20GM103629-06, PI: SMJ; Pilot Project PI: QZ). Citation Format: Qiuyang Zhang, Sen Liu, Zongbing You, Brian G. Rowan, S M. Jazwinski, Alun R. Wang, Leann Myers. Age-related elevated Th17 immune response contributes to prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 58.

IL-15 regulates migration, invasion, angiogenesis and genes associated with lipid metabolism and inflammation in prostate cancer.

Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer. In the United States it is second leading cause of cancer related deaths in men. PCa is often treated via radical prostatectomy (RP). However, 15–30% of the patients develop biochemical recurrence (i.e. increased serum prostate specific antigen (PSA) levels). Interleukin-15 (IL-15) is a secreted cytokine found over expressed in patients with recurrence-free survival after RP. In our study, we aim to determine the role of IL-15 in PCa using in vitro and in vivo models, and gene expression analysis. PC3 (androgen-independent) and 22RV1 (androgen-dependent) cell lines were treated with IL-15 at 0.0013 ng/mL and 0.1 ng/mL. Tumor growth was evaluated using an orthotopic xenograft model. The anterior prostate lobes of SCID mice were injected with 250,000 22RV1 cells and IL-15 was administered bi-weekly with intraperitoneal (IP) injections during 4 weeks. Tumor tissue was collected for immunohistochemical and gene expression analysis. To study changes in gene expression, we looked at “Tumor Metastasis” and “PI3K pathway” using commercially available PCR arrays. In addition, we employed a microarray approach using the Affymetrix Hugene 2.0 ST array chip followed by analysis with Ingenuity Pathways Analysis (IPA) software. In vitro studies showed that IL-15 decreased PCa cell motility at both concentrations. In vivo studies showed that IL-15 increased neutrophil infiltration, and the expression of adiponectin, desmin and alpha smooth muscle actin (α-sma) in the tumor tissue. Angiogenesis analysis, using CD31 immunohistochemistry, showed that IL-15 decreased the number of blood vessels. Gene expression analysis identified Cancer, Cell Death, Immune Response and Lipid Metabolism as the major diseases and functions altered in tumors treated with IL-15. This suggests that IL-15 causes inflammation and changes in stroma that can promote decreased tumor cell proliferation.

Signalling pathways associated with IL-6 production and epithelial-mesenchymal transition induction in prostate epithelial cells stimulated with Trichomonas vaginalis.

Trichomonas vaginalis (Tv) has been found in patient tissue of benign prostatic hyperplasia (BPH), and suggested to cause chronic prostatitis. IL-6 is known as one of the important factors of chronic inflammation in prostate cancer. Patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) had higher levels of IL-6 in seminal plasma. Furthermore, inflammatory conditions induced by pathogen infections have been shown to promote epithelial-mesenchymal transition (EMT). Here, we investigated the signals involved in IL-6 production by human prostate epithelial cells (PECs) stimulated with Tv and examined whether Tv induces EMT in PECs. We found that PECs stimulated with Tv increased the production of IL-6, as well as the expression of TLR2, TLR4, MAPKs (p38, JNK, ERK), NF-κB and JAK2/STAT3, and levels of ROS. Inhibition of TLR2 or TLR4 reduced IL-6 production as well as expression of these other factors, and agents inhibiting ROS, MAPKs, NF-κB and JAK reduced IL-6 production. However, when PECs were stimulated with Tv, transcripts of mesenchymal cell markers increased, and epithelial cell markers decreased. In addition, the induction of EMT was suppressed by inhibitors of JAK or NF-κB. These findings are the first evidence that Tv infection of prostate epithelial cells may induce EMT.

From Inflammation to Prostate Cancer: The Role of Inflammasomes.

Inflammation-associated studies entice specific attention due to inflammation's role in multiple stages of prostate cancer development. However, mechanistic regulation of inflammation inciting prostate cancer remains largely uncharacterized. A focused class of inflammatory regulators known as inflammasomes has recently gained attention in cancer development. Inflammasomes are a multiprotein complex that drives a cascade of proinflammatory cytokines regulating various cellular activities. Inflammasomes activation is linked with infection, stress, or danger signals, which are common events within the prostate gland. In this study, we review the potential of inflammasomes in understanding the role of inflammation in prostate cancer.

Prevalence and Characteristics of Inflammation in Prostate Cancer

Background: The presence of lymphocytic inflammatory aggregates (LIAs) is a common finding in submitted prostate tissue and frequently not mentioned. Recent studies linked prostate cancer (PCa) to chronic inflammation of prostate and exposure to sexually transmitted diseases, and suggested that viruses may play a role in development of PCa. Another study demonstrated that pathogenesis of prostatic neoplasia (in the PhIP treated rat prostate) proceeds …

Abstract 3359: PEDF modulatory action on macrophages: A new way to curb prostate cancer development

Abstract Macrophages have been described as one of the main inflammatory components involved in prostate cancer (PCa) initiation, progression, and metastasis. PEDF (Pigment Epithelium-Derived Factor) is an anti-angiogenic factor with differentiation activities and was recently suggested as an immune-modulating factor. PEDF expression has been shown to be down-regulated in PCa compared to normal tissues. In previous studies we have demonstrated that PEDF re-expression in PCa cells curbs tumor growth in vivo and significantly prolongs the survival of tumor-bearing mice. Others have shown that PEDF expression increased the recruitment of tumor-cytotoxic macrophages into orthotopic MatLyLu rat prostate tumors suggesting a link between PEDF and inflammation in PCa. While PEDF's role in inflammation has been suggested, the precise modes of action of PEDF on macrophages still remain unknown and necessitate further investigation. Our preliminary data have showed that PEDF stimulates the migration of monocytes/macrophages using in vitro chemotaxis boyden chamber assay and towards tumor 3D spheroids. We showed that PEDF expression levels positively correlate with macrophage density in human prostate. In both cell lines and prostate specimens, we have demonstrated that PEDF directly induces the polarization of macrophages and bone marrow derived macrophages (BMDMs) towards a M1/tumor-cytotoxic pathway. As a result of their differentiation, we have found that PEDF stimulates the phagocytosis of tumor cells, which suggest another mechanism by which PCa growth is halted. We are currently investigating the molecular mechanisms by which PEDF induces migration, differentiation and phagocytic activity in macrophages. PEDF mechanisms are being investigated by expression levels of PEDF receptors (ATP5B, PNPLA2, LRP6) in macrophage cell lines and BMDMs. So far we have been identified ATP5B and PNPLA2 as the two main receptors expressed in both cell types. While all three receptors in cell lines increased, only ATP5B and PNPLA2 receptors increased in BMDMs in response to PEDF. To map the functional region involved in PEDF's inflammatory action, we are investigating the PEDF-derivative synthetic 18-mer peptide (residues 39-57). P18 has been shown to block endothelial cell chemotaxis and induces apoptosis in vitro, and to be more effective than its parental 34-mer peptide (residues 24-57) in blocking growth and angiogenesis in PCa. We were able to demonstrate that macrophages treated with P18 in comparison to PEDF, show a higher efficacy for macrophages differentiation. Using confocal microscopy we demonstrated a larger rate of phagocytosis of PCa cells by macrophages than compared to PEDF. The results of our study are of importance as they suggest that macrophages may play a key role in PEDF anti-tumor effects. A better understanding of PEDF may lead to further development of PEDF-based anticancer therapy or improvement of alternatives to chemotherapy for PCa. Citation Format: Dalia Martinez-Marin, Thomas Nelius, Olga Volpert, Stephanie Filleur. PEDF modulatory action on macrophages: A new way to curb prostate cancer development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3359. doi:10.1158/1538-7445.AM2015-3359