Inflammation In Prostate Cancer Research Articles

Effect of PEDF on the migration, M1 polarization, and phagocytic activity in macrophages: A new way to inhibit PCa?

e16058 Background: Macrophages have been described as one of the main inflammatory components involved in prostate cancer (PCa) development. PEDF (Pigment Epithelium-Derived Factor) is a secreted angio-inhibitor with differentiation and suggested immune-modulating activities. PEDF expression has been shown to be down-regulated in PCa compared to normal tissues. Previously, we have demonstrated that PEDF re-expression in PCa cells curbs tumor growth in vivo and prolongs the survival of tumor-bearing mice. Others have shown that PEDF increased the recruitment of tumor-cytotoxic macrophages into MatLyLu rat prostate tumors suggesting a link between PEDF and inflammation in PCa. However, PEDF modes of action on macrophages still remain unknown and need further investigation. Methods: THP-1, RAW264.7 and primary macrophages treated with PEDF, its derived active P18 peptide or ctrl were used as models. Migration was assessed using Boyden chamber and 3D PCa spheroid assays. M1/tumor-cytotoxic polarization was te...

Inflammation and prostate cancer: the role of interleukin 6 (IL‐6)

Environmental and genetic aspects are reflected in the development of prostate cancer. In this context, there is growing evidence that chronic inflammation is involved in the regulation of cellular events in prostate carcinogenesis, including disruption of the immune response and regulation of the tumour microenvironment. One of the best surrogates of chronic inflammation in prostate cancer is interleukin 6 (IL-6). Serum IL-6 levels are elevated in patients with untreated metastatic or castration-resistant prostate cancer (CRPC) and correlate negatively with tumour survival and response to chemotherapy. Via multiple signal pathways including the Janus tyrosine family kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, the extracellular signal-regulated kinase 1 and 2 (ERK1/2)-mitogen activated protein kinase (MAPK) pathway, and the phosphoinositide 3-kinase (PI3-K) pathway, IL-6 is able to promote prostate cancer cell proliferation and inhibit apoptosis in vitro and in vivo. IL-6 is associated with aggressive prostate cancer phenotype and may be involved in the metastatic process through regulation of epithelial-mesenchymal transition (EMT) and homing of cancer cells to the bone. A substantial body of evidence suggests that IL-6 plays a major role in the transition from hormone-dependent to CRPC, most notably through accessory activation of the androgen receptor. Collectively, these data have stimulated the development of agents targeting IL-6 signalling pathways. A chimeric anti-IL-6 monoclonal antibody has been tested in clinical trials, with mixed results.

The role of inflammation in prostate cancer.

In the United States and in "Westernized" countries, the prevalence of both prostate cancer and prostate inflammation is very high, indicating that the two pathologies could be causally related. Indeed, chronic inflammation is now regarded as an "enabling" characteristic of human cancer. Prostate cancer incidence is thought to be mediated in part by genetics, but also by environmental exposures, including the same exposures that may contribute to the development of prostatic inflammation. As our understanding of the role of inflammation in cancer deepens, it is increasingly apparent that "inflammation" as a whole is a complex entity that does not always play a negative role in cancer etiology. In fact, inflammation can play potentially dichotomous (both pro and antitumorigenic) roles depending on the nature and the cellular makeup of the immune response. This chapter will focus on reviewing the current state of knowledge on the role of innate and adaptive immune cells within the prostate tumor microenvironment and their seemingly complex role in prostate cancer in preventing versus promoting initiation and progression of the disease.

Expression of the CXCL12/CXCR4 and CXCL16/CXCR6 axes in cervical intraepithelial neoplasia and cervical cancer

The chemokine CXCL12 is highly expressed in gynecologic tumors and is widely known to play a biologically relevant role in tumor growth and spread. Recent evidence suggests that CXCL16, a novel chemokine, is overexpressed in inflammation-associated tumors and mediates pro-tumorigenic effects of inflammation in prostate cancer. We therefore analyzed the expression of CXCL12 and CXCL16 and their respective receptors CXCR4 and CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical cancer and further assessed their association with clinicopathologic features and outcomes. Tissue chip technology and immunohistochemistry were used to analyze the expression of CXCL12, CXCR4, CXCL16, and CXCR6 in healthy cervical tissue (21 cases), CIN (65 cases), and cervical carcinoma (60 cases). The association of protein expression with clinicopathologic features and overall survival was analyzed. These four proteins were clearly detected in membrane and cytoplasm of neoplastic epithelial cells, and their distribution and intensity of expression increased as neoplastic lesions progressed through CIN1, CIN2, and CIN3 to invasive cancer. Furthermore, the expression of CXCR4 was associated significantly with the histologic grade of cervical carcinoma, whereas the expression of CXCR6 was associated significantly with lymph node metastasis. In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly shorter overall survival than did those with low CXCR6 expression. The elevated co-expression levels of CXCL12/CXCR4 and CXCL16/CXCR6 in CIN and cervical carcinoma suggest a durative process in cervical carcinoma development. Moreover, CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer.

Abstract 584: Vitamin D suppresses pro-inflammatory cytokines and microRNAs in 3D prostatic co-cultures

Abstract MiRNAs are involved in the progression and regulation of inflammation and the immune response in cancer. Understanding the interplay between miRNAs and inflammation in the prostate may be beneficial for the treatment or prevention of prostate cancer (PCa) with anti-inflammatory agents such as vitamin D. We previously found that vitamin D effectively blocked inflammatory cytokine signaling and secretion in primary cultures of normal prostatic epithelial cells. Because inflammatory signaling relies on the crosstalk between epithelial, stromal, and immune cells, our new studies use a human prostate 3-dimensional co-culture model of primary human prostatic epithelial (PrE) cells and stromal (PrS) cells. Single PrE cells seeded in matrigel were grown into spheroid structures termed prostaspheres (PS). Simulating an inflammatory trigger from immune cells with TNF-α and IL-1α (T+I), we found a prolonged inflammatory response in our co-cultures that persisted beyond 24 hours as compared to the transient response in monolayer cultures. IL-6 expression increased and persisted beyond 24 hours after T+I exposure in both the PrS and PS-PrE cells. However, only in the PS-PrE cells did vitamin D blocked IL-6 expression. Cytokine array profiling revealed that vitamin D decreased expression of many T+I-induced cytokine genes, including TNF, IL-1A, IL-8, CCL7. CCL5, and CXCL10. MicroRNAs are also mediators of inflammation. A miRNA microarray demonstrated that miR-146a, -155, and -223, and other miRNAs were altered by cytokine stimulation in co-culture. MiR-146a is a known mediator of inflammation and vitamin D significantly reduced T+I-stimulated miR-146a expression in both PS-PrE and PrS cells. These data demonstrate that vitamin D is involved in the regulation of inflammation at both the mRNA and the miRNA level in a novel 3D prostasphere co-culture model. As miR-146a is found to be down-regulated in PCa, further studies will determine the role of T+I and/or vitamin D in co-cultures of PS-PrE (normal) and PS-PrECa (Cancer) on miR-146a to further understand vitamin D's inflammatory role in cancer. Our model provides a more in vivo-like method to study inflammation in PCa. We will fully validate these in vitro results in laser-capture-microdissected patient tissue from a vitamin D clinical trial, in which patients were supplemented with 400-40,000 IU/day of vitamin D3 prior to radical prostatectomy. Our results should shed light on the complex inflammatory signaling pathways in the prostate and provide further evidence for anti-inflammatory benefits of vitamin D supplementation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 584. doi:1538-7445.AM2012-584

Abstract A37: Low-density protein array reveals inflammation associated serum-autoantibody profile in prostate cancer.

Abstract Background: Chronic prostatic inflammation of the prostate is one of the main reasons for false positive serum PSA tests in prostate cancer screening. In addition there is accumulating evidence that an inflammatory microenvironment may support the development of malignancy and the progression to metastatic disease. Easy accessible and non-invasive indicators for prostate inflammation would be very helpful for a biopsy decision after an elevated PSA test result. However, at present, the histological examination of prostate biopsies remains the only way for identification of prostatic inflammation. The finding that cancer is immunogenic and that patients are able to elicit and potentially amplify an immune response against their tumor antigens suggests that autoantibodies serve as non-invasive serum biomarkers for prostate cancer diagnosis. Consequently, autoantibodies may also be capable of detecting differential disease progression grades -e.g. inflammatory states- enabling a more specific and individualized treatment in cancer therapy. In the present study, we aimed to find new non-invasive biomarkers for the diagnosis of prostatic inflammation in prostate cancer. Methods: Seventy prostate cancer tissue samples derived from radical prostatectomy were classified into two groups (high/low inflammation) according to the amount of tissue infiltrating lymphocytes. Clinical parameters including PSA, fPSA, GSC, prostate weight, prostate volume, tumor size, age and CRP were controlled for equal distribution amongst the two groups. The corresponding blood serum samples were analyzed using a low density protein array (microarray) containing 4012 prostate cancer associated and inflammation related recombinant proteins. Statistical comparison of the serum autoantibody profile in the two groups was used to identify differentially expressed biomarkers. Finally, specificity of candidate autoantibody markers was validated by immunohistochemical detection of corresponding autoantigens in prostate tissue. Results: Autoantibodies against 165 antigens were found to be differentially expressed in the high compared to the low inflammation group. 30 out of these proteins have recently been identified to be associated with prostate cancer. The identified autoantibody profile discriminated between prostate cancer patients bearing high or low inflammation in prostate tissue with a ROC curve AUC of 0.71. Out of the top ranked autoantibodies, three candidate proteins were selected due to their differential expression and significant up-regulation in serum samples of the high inflammation group: SPAST (Spastin), STX18 (Syntaxin 18) and SPOP (speckle-type POZ protein). Immunohistochemical analysis showed that targets of all three autoantibody candidates are expressed in epithelial prostate cells. Remarkably, the highest staining intensity was detected in tissue infiltrating lymphocytes in both high and low inflammation samples. Conclusion: The presented data evaluates the possible use of serum autoantibody markers as non-invasive indicators for the diagnosis of chronic inflammation in prostate cancer. The polyclonal immune response to aberrant proteins in heterogeneous diseases such as cancer and autoimmunity favors the development of autoantibody markers with potential specificities to detect disease subtypes and disease progression grades. We provide evidence for an inflammation specific antibody profile and verify the expression of three biomarker candidates in prostate tissue. Citation Format: Bettina Schlick, Petra Massoner, Angelika Luecking, Christof Saifarth, Georg Schaefer, Klaus Marquart, Peter Amersdorfer, Peter Schulz-Knappe, Helmut Klocker. Low-density protein array reveals inflammation associated serum-autoantibody profile in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A37.

Abstract C226: CSF1R-mediated inhibition of alternatively activated macrophages to augment androgen receptor blockade therapy.

Abstract There is growing evidence for the role of inflammation in prostate cancer (PCa) progression, although the precise role of inflammation in the context of androgen ablation therapy remains unclear. Various reports demonstrate that androgen deprivation results in an increased inflammatory response in PCa and also suggest a potential role of inflammatory cells, such as macrophages and B-cells, in the acquisition of castration-resistant prostate cancer (CRPC). New PCa therapeutics have emerged showing great promise in clinical trials, such as the second generation androgen receptor (AR) antagonist MDV3100 (MDV). MDV has been shown to be more potent and effective in delaying tumor progression in CRPC patients compared to the commonly used first generation antagonist bicalutamide. However, acquired resistance to MDV has begun to emerge in preclinical models. A great deal of attention has been focused on the tumor-cell instrinsic AR bypass as the key mechanism of therapeutic resistance or failure. Few studies have explored the possible roles of tumor microenvironment in modulating therapeutic response. We and others have shown that tumor-associated macrophages (TAMs) can modulate PCa progression and therapeutic resistance. The recruitment of macrophages to and their functions in the tumor is recognized to be critically dependent on the macrophage colony-stimulating factor-1 (M-CSF-1, CSF-1), signaling through its receptor, CSF1R. Exploiting this fact, we used a selective CSF1R inhibitor, GW2580, to block TAMs influx and showed that they contribute to PCa progression and therapeutic resistance. In this current study, we observed a high level of TAMs infiltrating the CSF-1-expressing Myc-CaP murine prostate tumors. Additionally, MDV treatment further increased the level of CSF-1 expressed in tumors, further boosting the infiltration of TAMs which was reversed by GW2580. We have also observed increased expression of matrix-remodeling and pro-angiogenic factors, MMP-9 and VEGF-A in macrophages treated with conditioned media from MDV-treated Myc-CaP cells in vitro and in MDV-treated Myc-CaP tumors in vivo. These results lead us to hypothesize that blocking the CSF-1/CSF1R axis in combination with MDV anti-AR therapy, could result in synergistic anti-tumor effects. Indeed our preliminary studies indicate the combined therapies achieve slightly more effective tumor growth suppression than either of the single therapies. Our data suggest that infiltrating TAMs are alternatively activated (M2-skewed), which have been demonstrated to promote tumor growth and metastasis in many cancers. Our results suggest that TAMs in the prostatic microenvironment contribute to PCa progression and therapeutic resistance. The rational combined targeted therapy pursued here holds promise to improve the long term-efficacy of new PCa therapeutics such as MDV, and ultimately increase overall survival of prostate cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C226.

Antigen-specific immunity and tumor inflammation after vaccination with BPX-101, a drug-activated dendritic cell vaccine for metastatic castration-resistant prostate cancer (mCRPC).

176 Background: We report evidence of antigen-specific immunity and severe prostate cancer inflammation and necrosis after vaccination in patients enrolled in a phase I-IIa clinical trial of BPX-101, a drug-activated DC vaccine for mCRPC. Methods: Twelve men with progressive, mCRPC were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and activating agent AP1903. BPX-101, which targets prostate-specific membrane antigen (PSMA), was administered intradermally every 2 weeks for 6 doses, followed 24 hours after each dose by infusion of AP1903 (0.4 mg/kg). Injection site skin biopsies were performed after the fourth vaccination. T cells cultured from the skin biopsy ex vivo were stimulated with PSMA protein or control antigens, and were analyzed using Luminex microspheres for 30 inflammatory cytokines/chemokines. One patient (#1007) with an intact prostate developed lower urinary tract bleeding after the fifth vaccination and underwent a transurethral resection of bleeding prostate cancer tissue. Paraffin-embedded blocks were stained for hematoxylin and eosin (H&E). Immunohistochemical stains for CD3, CD4, CD8 and CD34 were also performed. Results: Of 5 subjects with evaluable injection site biopsy results, all exhibited PSMA-specific immunity (3 TH1-biased and 2 TH2- biased). Subject 1007's injection site biopsy demonstrated a significant >10-fold increase in IFN-gamma and IL-2 after stimulation by PSMA, compared to stimulation by ovalbumin, consistent with induction of a strong PSMA-specific CTL or TH1-biased immune response. H&E stained resected prostate tissue demonstrated Gleason 8 (4+4) prostate adenocarcinoma exhibiting a severe inflammatory response, consisting of infiltrating plasma cells and CD4+ and CD8+ T cells. Large areas of necrosis were seen adjacent to inflamed prostate cancer tissue. Conclusions: Vaccination with BPX-101 followed by AP1903 can induce a strong, PSMA-specific immune response. Furthermore, evidence of severe prostate cancer-specific inflammation and necrosis, associated with a strong PSMA-specific immune response has been observed after multiple doses of BPX-101. [Table: see text]

Innate and adaptive inflammation in prostate cancer

Innate and adaptive inflammation in prostate cancer

COX-2 Expression Might Be an Important Prognostic Marker in Prostate Cancer

The etiologic role of inflammation in prostate cancer is an area of active investigation. Cyclooxygenase (COX)-2 plays a major part in the inflammatory

High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy

Objectives. To assess the prognostic value of prostatic stromal inflammation in surgically treated localized prostate carcinoma for biochemical recurrence-free survival. Methods. Stromal prostatic inflammation grading was studied in 161 patients who underwent radical prostatectomy for prostate cancer without involvement of the lymph nodes and who did not receive preoperative or postoperative radiotherapy or hormonal therapy until recurrence occurred. Inflammation was graded as high-grade inflammation if confluence of inflammatory cell infiltrate and/or glandular epithelium disruption associated with interstitial inflammatory infiltrate were present and as low-grade inflammation otherwise. Each specimen was graded separately first in the stroma surrounding nonmalignant glands and second in the stroma surrounding malignant glands. Biochemical recurrence based on serum prostate-specific antigen (PSA) level was defined as two successive PSA measurements greater than 1 ng/mL. Results. Malignant tissue was significantly less involved in high-grade inflammation than benign adjacent tissue (9.3% and 19.9%, respectively; P <0.01). In a univariate Kaplan-Meier analysis, the 5-year recurrence-free survival rate for patients with high-grade and low-grade classified prostates was 61.0% and 66.7% in benign tissue and 27.0% and 65.3% in malignant tissue, respectively, with a significant difference between grades only in malignant tissue ( P <0.02). In a multivariate analysis controlling for Gleason grade, preoperative serum PSA, pathologic stage, and inflammation grade in malignant tissue, the latter factor remained significantly predictive of biochemical recurrence ( P = 0.03). Conclusions. Patients with high-grade inflammation surrounding malignant glands in radical prostatectomy specimens had significantly more postoperative biochemical recurrence than patients with low-grade inflammation.