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      Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

      review-article
      1 , 2 ,   1 , 2 , *
      Cells
      MDPI
      prostate, cancer, androgen, castration, inflammation, NF-κB, cytokines, protein kinase C, signaling, clinical

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          Abstract

          Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West. The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities. NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy. Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge. Here, we review the role of inflammation and its link with androgen signaling in prostate cancer. We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling. Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described. A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patients.

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          Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.

          J R Vane (1971)
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            Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients.

            The prognosis of prostate cancer is mainly determined by the presence or absence of metastases. Nevertheless, the metastatic pathways in prostate cancer are not entirely understood. Among 19,316 routine autopsies performed from 1967 to 1995 on men older than 40 years of age, the reports from those 1,589 (8.2%) with prostate cancer were analyzed. Hematogeneous metastases were present in 35% of 1,589 patients with prostate cancer, with most frequent involvement being bone (90%), lung (46%), liver (25%), pleura (21%), and adrenals (13%). Several lines of evidence suggested the existence of a backward metastatic pathway through veins from the prostate to the spine in addition to classical hematogeneous tumor spread via the vena cava. First, there was an inverse relationship between spine and lung metastases, suggesting that metastasis to the spine is independent of lung metastasis. Second, the maximum frequency of spine involvement occurred in smaller tumors (4 to 6 cm) as compared with the maximum spread to lung (6 to 8 cm) and liver (>8 cm), suggesting that spine metastases precede lung and liver metastases in many prostate cancers. Third, there was a gradual decrease in spine involvement from the lumbar to the cervical level (97% v 38%), which is consistent with a subsequent upward metastatic spread along spinal veins after initial lumbar metastasis. The results of this study show that bone, lung, and liver are the most frequent sites of distant prostate cancer metastases. Besides the cava-type of metastasis through lung passage, there are strong arguments for the existence and clinical significance of a backward venous spread to the spine, which is likely to occur early in the metastatic process.
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              Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer.

              Although systemic androgen deprivation prolongs life in advanced prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a castration-resistant prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most androgen-regulated genes are reactivated despite castrate levels of serum androgens. Recent evidence indicates that intraprostatic levels of androgens remain moderately high following systemic androgen deprivation therapy, whereas the androgen receptor (AR) remains functional, and silencing the AR expression following castration suppresses tumor growth and blocks the expression of genes known to be regulated by androgens. From these observations, we hypothesized that CRPC progression is not independent of androgen-driven activity and that androgens may be synthesized de novo in CRPC tumors leading to AR activation. Using the LNCaP xenograft model, we showed that tumor androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all enzymes necessary for androgen synthesis are expressed in prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that tumor explants isolated from CRPC progression are capable of de novo conversion of [(14)C]acetic acid to dihydrotestosterone and uptake of [(3)H]progesterone allows detection of the production of six other steroids upstream of dihydrotestosterone. This evidence suggests that de novo androgen synthesis may be a driving mechanism leading to CRPC progression following castration.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                29 August 2018
                September 2018
                : 7
                : 9
                : 122
                Affiliations
                [1 ]VIB-UGent Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, 9052 Ghent, Belgium
                [2 ]Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
                Author notes
                [* ]Correspondence: rudi.beyaert@ 123456irc.vib-ugent.be ; Tel.: +32-9-3313770
                Author information
                https://orcid.org/0000-0003-2664-3357
                https://orcid.org/0000-0002-5704-582X
                Article
                cells-07-00122
                10.3390/cells7090122
                6162478
                30158439
                810f233f-3384-4e9d-9dd6-a3c3aa2cce70
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 July 2018
                : 27 August 2018
                Categories
                Review

                prostate,cancer,androgen,castration,inflammation,nf-κb,cytokines,protein kinase c,signaling,clinical

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