Статті в журналах: "Prostate tumour inducer"

1

Lanning, Ben, Jason Webber, Pinar Uysal-Onganer, Wen Guo Jiang, Aled Clayton, and Dafydd Alwyn Dart. "Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model." Biology 10, no. 4 (April 10, 2021): 318. http://dx.doi.org/10.3390/biology10040318.

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Skeletal metastases are the most common form of secondary tumour associated with prostate cancer (PCa). The aberrant function of bone cells neighbouring these tumours leads to the devel-opment of osteoblastic lesions. Communication between PCa cells and bone cells in bone envi-ronments governs both the formation/development of the associated lesion, and growth of the secondary tumour. Using osteoblasts as a model system, we observed that PCa cells and their conditioned medium could stimulate and increase mineralisation and osteoblasts’ differentiation. Secreted factors within PCa-conditioned medium responsible for osteoblastic changes included small extracellular vesicles (sEVs), which were sufficient to drive osteoblastogenesis. Using MiR-seq, we profiled the miRNA content of PCa sEVs, showing that miR-16-5p was highly ex-pressed. MiR-16 was subsequently higher in EV-treated 7F2 cells and a miR-16 mimic could also stimulate mineralisation. Next, using RNA-seq of extracellular vesicle (EV)-treated 7F2 cells, we observed a large degree of gene downregulation and an increased mineralisation. Ingenuity® Pathway Analysis (IPA®) revealed that miR-16-5p (and other miRs) was a likely upstream effec-tor. MiR-16-5p targets in 7F2 cells, possibly involved in osteoblastogenesis, were included for val-idation, namely AXIN2, PLSCR4, ADRB2 and DLL1. We then confirmed the targeting and dow-regulation of these genes by sEV miR-16-5p using luciferase UTR (untranslated region) reporters. Conversely, the overexpression of PLSCR4, ADRB2 and DLL1 lead to decreased osteoblastogene-sis. These results indicate that miR-16 is an inducer of osteoblastogenesis and is transmitted through prostate cancer-derived sEVs. The mechanism is a likely contributor towards the for-mation of osteoblastic lesions in metastatic PCa.

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Pascal, Laura E., Khalid Z. Masoodi, June Liu, Xiaonan Qiu, Qiong Song, Yujuan Wang, Yachen Zang, et al. "Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia." Journal of Endocrinology 235, no. 2 (November 2017): 123–36. http://dx.doi.org/10.1530/joe-17-0112.

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Elongation factor, RNA polymerase II, 2 (ELL2) is an RNA Pol II elongation factor with functional properties similar to ELL that can interact with the prostate tumor suppressor EAF2. In the prostate, ELL2 is an androgen response gene that is upregulated in benign prostatic hyperplasia (BPH). We recently showed that ELL2 loss could enhance prostate cancer cell proliferation and migration, and that ELL2 gene expression was downregulated in high Gleason score prostate cancer specimens. Here, prostate-specific deletion of ELL2 in a mouse model revealed a potential role for ELL2 as a prostate tumor suppressor in vivo. Ell2-knockout mice exhibited prostatic defects including increased epithelial proliferation, vascularity and PIN lesions similar to the previously determined prostate phenotype in Eaf2-knockout mice. Microarray analysis of prostates from Ell2-knockout and wild-type mice on a C57BL/6J background at age 3 months and qPCR validation at 17 months of age revealed a number of differentially expressed genes associated with proliferation, cellular motility and epithelial and neural differentiation. OncoPrint analysis identified combined downregulation or deletion in prostate adenocarcinoma cases from the Cancer Genome Atlas (TCGA) data portal. These results suggest that ELL2 and its pathway genes likely play an important role in the development and progression of prostate cancer.

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Abdulkadir, Sarki A., Jeffrey A. Magee, Thomas J. Peters, Zahid Kaleem, Cathy K. Naughton, Peter A. Humphrey, and Jeffrey Milbrandt. "Conditional Loss of Nkx3.1 in Adult Mice Induces Prostatic Intraepithelial Neoplasia." Molecular and Cellular Biology 22, no. 5 (March 1, 2002): 1495–503. http://dx.doi.org/10.1128/mcb.22.5.1495-1503.2002.

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ABSTRACT The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression. Disruption of the murine Nkx3.1 gene results in defects in prostate branching morphogenesis, secretions, and growth. To more closely mimic the pattern of NKX3.1 loss that occurs in human prostate tumors, we have used Cre- and loxP-mediated recombination to delete the Nkx3.1 gene in the prostates of adult transgenic mice. Conditional deletion of one or both alleles of Nkx3.1 leads to the development of preinvasive lesions that resemble PIN. The pattern of expression of several biomarkers (Ki-67, E-cadherin, and high-molecular-weight cytokeratins) in these PIN lesions resembled that observed in human cases of PIN. Furthermore, PIN foci in mice with conditional deletion of a single Nkx3.1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation.

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4

Bronte, Vincenzo, Tihana Kasic, Giorgia Gri, Keti Gallana, Giovanna Borsellino, Ilaria Marigo, Luca Battistini, et al. "Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers." Journal of Experimental Medicine 201, no. 8 (April 11, 2005): 1257–68. http://dx.doi.org/10.1084/jem.20042028.

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Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

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Song, Liankun, Vyvyan Nguyen, Shan Xu, Jana Yamak, Kia Arabzadehkaffash, Ali Fazelpour, Merci Mino, Matthew Tippin, Shuang Meng, and Xiaolin Zi. "Abstract 1: Transcriptional profiling of prostatic Skp2 knock-in mouse model and development of the associated prostate organoids for testing Skp2 targeting agents." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1. http://dx.doi.org/10.1158/1538-7445.am2022-1.

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Abstract S-phase kinase associated protein 2 (Skp2) is a promising drug target as studies have demonstrated that Skp2 is required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb), Pten, or p53 deficient mice. We, therefore, aim to establish CRISPR human Skp2 (hSkp2) knock-in in the prostates of mice to study the molecular profiling features in prostate carcinogenesis. Prostate weights increased in transgenic mice and overexpression of hSkp2 induced prostatic lesions including hyperplasia, mouse prostate intraepithelial neoplasia (mPIN), and carcinoma, which suggested the initial role of hSkp2 in early prostate carcinogenesis. RNAseq results revealed Myl3 and Ctgf as the top down-expressed and up-expressed genes respectively in hSkp2 mice prostates. Gene set enrichment analysis (GSEA) demonstrated the significant upregulations of ribosome and proteasome pathways which had similar alterations in the human prostate cancer dataset with Skp2 overexpression, suggesting the potential role of ribosome biogenesis in prostate tumorigenesis and for drug development. In addition, Skp2 organoids derived from transgenic mice prostates were being developed for convenient and efficient screening of specific Skp2 inhibitors. Flavokawain A (FKA) and Skp2 inhibitor C1 both selectively decreased the viability and altered the morphologies of hSkp2 organoids, meanwhile FKA exhibited less toxicity on wild-type organoids. Citation Format: Liankun Song, Vyvyan Nguyen, Shan Xu, Jana Yamak, Kia Arabzadehkaffash, Ali Fazelpour, Merci Mino, Matthew Tippin, Shuang Meng, Xiaolin Zi. Transcriptional profiling of prostatic Skp2 knock-in mouse model and development of the associated prostate organoids for testing Skp2 targeting agents [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 1.

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Ketteler, Julia, Andrej Panic, Henning Reis, Alina Wittka, Patrick Maier, Carsten Herskind, Ernesto Yagüe, Verena Jendrossek, and Diana Klein. "Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1." Journal of Clinical Medicine 8, no. 3 (March 12, 2019): 348. http://dx.doi.org/10.3390/jcm8030348.

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Tumour resistance to chemo- and radiotherapy, as well as molecularly targeted therapies, limits the effectiveness of current cancer treatments. We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of stromal CAV1 expression in advanced tumour stages may contribute to tumour radiotherapy resistance. Here we investigated whether fibroblast secreted anti-apoptotic proteins could induce radiation resistance of prostate cancer cells in a CAV1-dependent manner and identified TRIAP1 (TP53 Regulated Inhibitor of Apoptosis 1) as a resistance-promoting CAV1-dependent factor. TRIAP1 expression and secretion was significantly higher in CAV1-deficient fibroblasts and secreted TRIAP1 was able to induce radiation resistance of PC3 and LNCaP prostate cancer cells in vitro, as well as of PC3 prostate xenografts derived from co-implantation of PC3 cells with TRIAP1-expressing fibroblasts in vivo. Immunohistochemical analyses of irradiated PC3 xenograft tumours, as well as of human prostate tissue specimen, confirmed that the characteristic alterations in stromal-epithelial CAV1 expression were accompanied by increased TRIAP1 levels after radiation in xenograft tumours and within advanced prostate cancer tissues, potentially mediating resistance to radiation treatment. In conclusion, we have determined the role of CAV1 alterations potentially induced by the CAV1-deficient, and more reactive, stroma in radio sensitivity of prostate carcinoma at a molecular level. We suggest that blocking TRIAP1 activity and thus avoiding drug resistance may offer a promising drug development strategy for inhibiting resistance-promoting CAV1-dependent signals.

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7

Layman, Awo Akosua K., Shivam Joshi, and Sanjeev Shah. "Metastatic prostate cancer presenting as tumour-induced osteomalacia." BMJ Case Reports 12, no. 7 (July 2019): e229434. http://dx.doi.org/10.1136/bcr-2019-229434.

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Tumour-induced osteomalacia (TIO), or oncogenic osteomalacia, is a paraneoplastic syndrome marked by hypophosphataemia, renal phosphate wasting, bone pain, weakness, and fractures. The syndrome has been reported with both benign and malignant tumours including parotid gland basal cell tumours, thyroid carcinomas, colon adenocarcinomas, and prostate cancer. Often, the syndrome is marked by an insidious course during which patients present with generalised bony pain and weakness, which do not resolve until the underlying tumour is identified and treated. We present a case of a patient with Parkinson’s disease whose subacute weakness, lower extremity paresis, and renal phosphate wasting led to the synchronous diagnosis of metastatic prostate adenocarcinoma and TIO.

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8

Ene, Cosmin-Victor, Ilinca Nicolae, Bogdan Geavlete, Petrisor Geavlete, and Corina Daniela Ene. "IL-6 Signaling Link between Inflammatory Tumor Microenvironment and Prostatic Tumorigenesis." Analytical Cellular Pathology 2022 (April 12, 2022): 1–10. http://dx.doi.org/10.1155/2022/5980387.

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Benign prostatic hyperplasia and prostate cancer are tumoral pathologies characterized by the overexpression of inflammatory processes. The exploration of tumor microenvironment and understanding the sequential events that take place in the stromal area of the prostate could help for an early management of these pathologies. This way, it is feasible the hypothesis that normalizing the stromal environment would help to suppress or even to reverse tumor fenotype. A number of immunological and genetic factors, endocrine dysfunctions, metabolic disorders, infectious foci, nutritional deficiencies, and chemical irritants could be involved in prostate tumor development by maintaining inflammation, affecting local microcirculation, and promoting oxidative stress. Inflammatory processes activate hyperproliferative programs that ensure fibromuscular growth of the prostate and a number of extracellular changes. Acute and chronic inflammations cause accumulation of immunocompetent cells in affected prostate tissue (T cells, macrophages, mastocytes, dendritic cells, neutrophils, eosinophils, monocytes). Prostate epithelial and stromal cells, peri-prostatic fat cells, prostatic microvascular endothelial cells, and inflammatory cells produce cytokines, generating a local inflammatory environment. Interleukin-6 (IL-6) proved to be involved in the prostate tumor pathogenesis. IL-6 ability to induce pro- and anti-inflammatory responses by three mechanisms of signal transduction (classical signaling, transsignaling, cluster signaling), to interact with a diversity of target cells, to induce endocrine effects in an autocrine/paracrine manner, and the identification of an IL-6 endogenous antagonist that blocks the transmission of IL-6 mediated intracellular signals could justify current theories on the protective effects of this cytokine or by alleviating inflammatory reactions or by exacerbating tissue damage. This analysis presents recent data about the role of the inflammatory process as a determining factor in the development of benign and malign prostate tumors. The presented findings could bring improvements in the field of physiopathology, diagnosis, and treatment in patients with prostate tumors. Modulation of the expression and activity of interleukin-6 could be a mean of preventing or improving these pathologies.

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9

Sass, Stephanie N., and Sandra O. Gollnick. "Tumor-associated myeloid cells convert indolent prostate cancer to aggressive disease." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 73.21. http://dx.doi.org/10.4049/jimmunol.196.supp.73.21.

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Abstract Difficulties differentiating indolent from progressing prostate cancer (CaP) results in ineffective treatment strategies. Tumor-associated myeloid cells (TAMC) contribute to tumor progression; yet the role TAMC play in the conversion from indolent to progressing CaP is unclear. To test whether TAMC promote CaP progression we developed a murine model using two isogenic cell lines from the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. Tumorigenic C2 cells mimic progressing disease while non-tumorigenic C3 cells represent indolent disease. We report for the first time that CD11b+ TAMC isolated from C2 tumors co-injected with the non-tumorigenic C3 cells drive C3 tumor growth. In contrast, TAMC isolated from C2 tumor-bearing spleens or naïve spleens did not promote C3 tumor growth. This is the first indication that TAMC drive progression of indolent disease. Strikingly, tumor cells explanted from TAMC-induced C3 tumors were tumorigenic in the absence of additional TAMC, suggesting that TAMC induce stable changes within the C3 cells. These results have been recapitulated with the non-tumorigenic human cell line BPH-1 (benign prostatic hyperplasia). Furthermore, TAMC-induced tumor growth occurs via a TAMC secreted factor. Using a 5-day transwell system PC3M (human prostatic adenocarcinoma) TAMC were able to drive BPH-1 tumorigenesis. Future work will determine the factor secreted by TAMC and identify the molecular mechanisms responsible for tumor promotion. This work has the potential to identify critical factors responsible for the conversion of indolent to progressing disease thus laying the groundwork for novel prognostic and therapeutic strategies.

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Boutillon, Pigat, Sala, Reyes-Gomez, Moriggl, Guidotti, and Goffin. "STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice." Cancers 11, no. 7 (July 2, 2019): 929. http://dx.doi.org/10.3390/cancers11070929.

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The canonical prolactin (PRL) Signal Transducer and Activator of Transcription (STAT) 5 pathway has been suggested to contribute to human prostate tumorigenesis via an autocrine/paracrine mechanism. The probasin (Pb)-PRL transgenic mouse models this mechanism by overexpressing PRL specifically in the prostate epithelium leading to strong STAT5 activation in luminal cells. These mice exhibit hypertrophic prostates harboring various pre-neoplastic lesions that aggravate with age and accumulation of castration-resistant stem/progenitor cells. As STAT5 signaling is largely predominant over other classical PRL-triggered pathways in Pb-PRL prostates, we reasoned that Pb-Cre recombinase-driven genetic deletion of a floxed Stat5a/b locus should prevent prostate tumorigenesis in so-called Pb-PRLSTAT5 mice. Anterior and dorsal prostate lobes displayed the highest Stat5a/b deletion efficiency with no overt compensatory activation of other PRLR signaling cascade at 6 months of age; hence the development of tumor hallmarks was markedly reduced. Stat5a/b deletion also reversed the accumulation of stem/progenitor cells, indicating that STAT5 signaling regulates prostate epithelial cell hierarchy. Interestingly, ERK1/2 and AKT, but not STAT3 and androgen signaling, emerged as escape mechanisms leading to delayed tumor development in aged Pb-PRLSTAT5 mice. Unexpectedly, we found that Pb-PRL prostates spontaneously exhibited age-dependent decline of STAT5 signaling, also to the benefit of AKT and ERK1/2 signaling. As a consequence, both Pb-PRL and Pb-PRLSTAT5 mice ultimately displayed similar pathological prostate phenotypes at 18 months of age. This preclinical study provides insight on STAT5-dependent mechanisms of PRL-induced prostate tumorigenesis and alternative pathways bypassing STAT5 signaling down-regulation upon prostate neoplasia progression.

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Aldahl, Joseph, Jiaqi Mi, Ariana Pineda, Won Kyung Kim, Adam Olson, Erika Hooker, Yongfeng He та ін. "Aberrant activation of hepatocyte growth factor/MET signaling promotes β-catenin–mediated prostatic tumorigenesis". Journal of Biological Chemistry 295, № 2 (9 грудня 2019): 631–44. http://dx.doi.org/10.1074/jbc.ra119.011137.

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Co-occurrence of aberrant hepatocyte growth factor (HGF)/MET proto-oncogene receptor tyrosine kinase (MET) and Wnt/β-catenin signaling pathways has been observed in advanced and metastatic prostate cancers. This co-occurrence positively correlates with prostate cancer progression and castration-resistant prostate cancer development. However, the biological consequences of these abnormalities in these disease processes remain largely unknown. Here, we investigated the aberrant activation of HGF/MET and Wnt/β-catenin cascades in prostate tumorigenesis by using a newly generated mouse model in which both murine Met transgene and stabilized β-catenin are conditionally co-expressed in prostatic epithelial cells. These compound mice displayed accelerated prostate tumor formation and invasion compared with their littermates that expressed only stabilized β-catenin. RNA-Seq and quantitative RT-PCR analyses revealed increased expression of genes associated with tumor cell proliferation, progression, and metastasis. Moreover, Wnt signaling pathways were robustly enriched in prostate tumor samples from the compound mice. ChIP-qPCR experiments revealed increased β-catenin recruitment within the regulatory regions of the Myc gene in tumor cells of the compound mice. Interestingly, the occupancy of MET on the Myc promoter also appeared in the compound mouse tumor samples, implicating a novel role of MET in β-catenin–mediated transcription. Results from implanting prostate graft tissues derived from the compound mice and controls into HGF-transgenic mice further uncovered that HGF induces prostatic oncogenic transformation and cell growth. These results indicate a role of HGF/MET in β-catenin–mediated prostate cancer cell growth and progression and implicate a molecular mechanism whereby nuclear MET promotes aberrant Wnt/β-catenin signaling–mediated prostate tumorigenesis.

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Peak, Taylor C., Michael M. Goodman, Elena M. Fenu, and Ashok K. Hemal. "Mucinous adenocarcinoma of the prostatic urethra following a remote history of primary brachytherapy for prostate cancer." SAGE Open Medical Case Reports 8 (January 2020): 2050313X2095986. http://dx.doi.org/10.1177/2050313x20959867.

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Secondary malignancies are a known, albeit uncommon, complication of radiation for prostate cancer, either in the form of external beam radiotherapy or seed-implant brachytherapy. Of these secondary malignancies, mucinous adenocarcinoma of the prostatic urothelium is an extremely rare clinical entity that has only once been reported in the literature. We report the case of an 80-year-old gentleman who initially underwent low-dose brachytherapy for low-risk prostate cancer 18 years ago. He subsequently developed recurrent gross hematuria and obstructive voiding symptoms. He underwent cystoscopy and transurethral resection of a large tumor from within the prostate. Final pathology of the tumor revealed a mucinous adenocarcinoma. Further immunostaining revealed this is likely to have originated from the prostatic urothelium. Given his age, comorbidities, and no clear data demonstrating that aggressive extirpative surgery provides a clinical benefit, we elected to undergo surveillance. Clinicians should be aware of mucinous adenocarcinoma of the prostatic urethra as an extremely rare, radiation-induced malignancy. Once a diagnosis is made, extirpative surgery is an option for localized disease, although prognosis remains poor.

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Padilla, G. M., R. C. Yacullo, J. J. Padilla, B. Payne, and V. Petrow. "Melengestrol acetate and megestrol acetate are prostatic tumor inhibiting agents." Biochemistry and Cell Biology 68, no. 10 (October 1, 1990): 1181–88. http://dx.doi.org/10.1139/o90-175.

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We had previously reported that 6-methylene progesterone, an inhibitor of 5α-reductase, the enzyme which converts testosterone to dihydrotestosterone, markedly inhibited growth of the androgen-dependent Dunning R3327-H rat prostatic tumors. We now find that the progesterone derivatives melengestrol acetate (MGA) and megestrol acetate (MA) inhibit both the androgen-dependent (Dunning R3327-H) and the androgen-independent (Dunning R3327-AT3) prostatic tumors. Growth of the AT3 tumors was suppressed by ~53% after 9 days of daily s.c. injections with MGA at 10 mg/kg body weight. MGA also caused a 54% weight reduction of the ventral prostate and a 53% reduction of the seminal vesicles. Adrenal weights were reduced by 42%. A 24-day oral treatment with MGA (at ~15-17 mg/(kg∙day)) inhibited AT3 tumor growth by 59% and caused a weight reduction in the following tissues: prostate (46%), seminal vesicles (19%), testes (12%), and adrenals (52%). Under the same protocol, MA inhibited AT3 tumor growth by 32% and reduced the weight of the ventral prostate by 49% and the weight of the adrenals by 18%, but had no effect on the seminal vesicles and testes. The extent of the MGA-induced prostatic regression was accompanied by cytological changes similar to those effected by 6-methylene progesterone, i.e., shrinking of the acinar epithelium. The AT3 tumors in MGA-treated rats displayed a limited degree of apoptosis. Atrophy of the adrenal cortex and lowered plasma levels of corticosterone and dihydroepiandrosterone were also observed. A therapeutic role for MGA and MA against androgen-independent prostatic neoplasms in man is forecast by these observations.Key words: prostatic cancer, androgen independent, melengestrol acetate, growth inhibition, steroids.

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Dart, D. Alwyn, Bradley Spencer-Dene, Simon C. Gamble, Jonathan Waxman, and Charlotte L. Bevan. "Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours." Endocrine-Related Cancer 16, no. 4 (December 2009): 1157–69. http://dx.doi.org/10.1677/erc-09-0028.

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Current hormonal therapies for prostate cancer are effective initially, but inevitably tumours progress to an advanced, metastatic stage, often referred to as ‘androgen independent’. However, the androgen receptor (AR) signalling pathway is still key for their growth. It is speculated that tumours escape hormonal control via reduction in corepressor proteins. Manipulating such proteins is thus a potential therapeutic strategy to halt or even reverse tumour progression. We aimed to elucidate the effects of altering levels of the AR corepressor and androgen-target protein prohibitin (PHB) on prostate tumour growth. Prostate cancer cells incorporating an integrated androgen-responsive reporter gene and stably expressing vectors to inducibly overexpress or knockdown PHB were generated and used to assess effects on androgen signalling (by real time imaging) and tumour growth both in culture and in vivo. PHB overexpression inhibited AR activity and prostate-specific antigen (PSA) expression as well as androgen-dependent growth of cells, inducing rapid accumulation in G0/G1. Conversely, reduction in PHB increased AR activity, PSA expression, androgen-mediated growth and S-phase entry. In vivo, doxycycline-induced PHB regulation resulted in marked changes in AR activity, and showed significant effects upon tumour growth. Overexpression led to tumour growth arrest and protection from hormonal starvation, whereas RNAi knockdown resulted in accelerated tumour growth, even in castrated mice. This study provides proof of principle that i) reduction in PHB promotes both androgen-dependent and ‘androgen-independent’ tumour growth, and ii) altering AR activity via increasing levels or activity of corepressors is a valid therapeutic strategy for advanced prostate cancer.

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Fujita, Kazutoshi, Takuji Hayashi, Makoto Matsushita, Motohide Uemura, and Norio Nonomura. "Obesity, Inflammation, and Prostate Cancer." Journal of Clinical Medicine 8, no. 2 (February 6, 2019): 201. http://dx.doi.org/10.3390/jcm8020201.

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The prevalence of obesity is increasing in the world, and obesity-induced disease, insulin-resistance, cardiovascular disease, and malignancies are becoming a problem. Epidemiological studies have shown that obesity is associated with advanced prostate cancer and that obese men with prostate cancer have a poorer prognosis. Obesity induces systemic inflammation via several mechanisms. High-fat diet-induced prostate cancer progresses via adipose-secretory cytokines or chemokines. Inflammatory cells play important roles in tumor progression. A high-fat diet or obesity changes the local profile of immune cells, such as myeloid-derived suppressor cells and macrophages, in prostate cancer. Tumor-associated neutrophils, B cells, and complements may promote prostate cancer in the background of obesity. Interventions to control systemic and/or local inflammation and changes in lifestyle may also be viable therapies for prostate cancer.

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Philippou, Yiannis, Hanna T. Sjoberg, Emma Murphy, Said Alyacoubi, Keaton I. Jones, Alex N. Gordon-Weeks, Su Phyu, et al. "Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model." British Journal of Cancer 123, no. 7 (July 9, 2020): 1089–100. http://dx.doi.org/10.1038/s41416-020-0956-x.

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Abstract Background Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy with radiotherapy fractions used to treat prostate cancer. We investigated tumour immune microenvironment responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, we tested whether radiotherapy-induced tumour growth delay could be enhanced with anti-PD-L1. Methods Hypofractionated radiotherapy was delivered to TRAMP-C1 and MyC-CaP flank allografts. Tumour growth delay, tumour immune microenvironment flow-cytometry, and immune gene expression were analysed. TRAMP-C1 allografts were then treated with 3 × 5 Gy ± anti-PD-L1. Results 3 × 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8+ T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post-3 × 5 Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8+, natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 × 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy. Conclusion 3 × 5 Gy hypofractionated radiotherapy can result in tumour growth delay and immune cell changes in allograft prostate cancer models. Adjuncts beyond immunomodulation may be necessary to improve the radiotherapy-induced anti-tumour response.

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Saydullaeva, Iroda, Bilge Debeleç Bütüner, and Kemal Sami Korkmaz. "Inflammatory Microenvironment-Mediated E-Cadherin Decrease Induces Migration in LNCaPs." Proceedings 2, no. 25 (December 6, 2018): 1540. http://dx.doi.org/10.3390/proceedings2251540.

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Infection and chronic inflammation contribute to about 1 in 4 of all cancer cases. Emerging evidence suggests that the host factors in the tumor microenvironment may interact with underlying inflammatory prostate cancer cells to make them aggressive. In this study, we hypothesized that soluble factors secreted by immune cells activated by inflammation can induce EMT in prostate cancer and thus promote metastasis. We identify that macrophage-secreted cytokines including TNFα act as mediators for potentiating LNCaP cell proliferation in migration assay. Hence, our data indicate a mechanistic insight of how inflammation may contribute to development of prostatic disease at an early stage through increasing cell proliferation and metastasis of LNCaP cells.

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Krolewski, John J., Shalini Singh, Kai Sha, Neha Jaiswal, Steven G. Turowski, Chunliu Pan, Laurie J. Rich, Mukund Seshadri, and Kent L. Nastiuk. "TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression." Cancers 14, no. 24 (December 7, 2022): 6020. http://dx.doi.org/10.3390/cancers14246020.

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The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. In addition to this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death, which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostates. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area, and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely by inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer microenvironment that mediates prostate cancer regression following androgen deprivation.

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Song, Kwang Hoon, Chang-Seob Seo, Won-Kyung Yang, Hyun-O. Gu, Ki-Joong Kim, and Seung-Hyung Kim. "Extracts of Phyllostachys pubescens Leaves Represses Human Steroid 5-Alpha Reductase Type 2 Promoter Activity in BHP-1 Cells and Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia in Rat Model." Nutrients 13, no. 3 (March 9, 2021): 884. http://dx.doi.org/10.3390/nu13030884.

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Benign prostatic hyperplasia (BPH) is the most common symptomatic abnormality of the human prostate characterized by uncontrolled proliferation of the prostate gland. In this study, we investigated the effect of bamboo, Phyllostachys pubescens, leaves extract (PPE) on human 5α-reductase type 2 (SRD5A2) gene promoter activity in human prostate cell lines and the protective effect of PPE on a testosterone-induced BPH rat model. PPE repressed human SRD5A2 promoter activity and its mRNA expression. The rats treated with PPE for 4 weeks showed a significantly attenuated prostate weight compared to vehicle control. PPE-treated rats also showed reduced serum dihydrotestosterone, testosterone, prostate-specific antigen, and SRD5A2 levels by testosterone injection. Quantitative real-time polymerase chain reaction showed that PPE treatment significantly decreased mRNA expression of SRD5A2, androgen receptor (AR), proliferating cell nuclear antigen (PCNA), and fibroblast growth factor 2 compared with the vehicle-treated, testosterone-injected rats in the prostate. Furthermore, PPE treatment showed reduced AR, PCNA, and tumor necrosis factor alpha expression in the prostate via immunohistofluorescence staining. In conclusion, oral administration of PPE prevented and inhibited the development and progression of enlarged prostate lesions in testosterone-induced animal models through various anti-proliferative and anti-inflammatory pharmacological effects and induced suppression of SRD5A2 gene expression.

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Ardura, Juan A., Luis Álvarez-Carrión, Irene Gutiérrez-Rojas, Peter A. Friedman, Arancha R. Gortázar та Verónica Alonso. "MINDIN secretion by prostate tumors induces premetastatic changes in bone via β-catenin". Endocrine-Related Cancer 27, № 7 (липень 2020): 441–56. http://dx.doi.org/10.1530/erc-20-0116.

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Bone metastases are common in advanced prostate cancer patients, but mechanisms by which specific pro-metastatic skeletal niches are formed before tumor cell homing are unclear. We aimed to analyze the effects of proteins secreted by primary prostate tumors on the bone microenvironment before the settlement and propagation of metastases. Here, using an in vivo pre-metastatic prostate cancer model based on the implantation of prostate adenocarcinoma TRAMP-C1 cells in immunocompetent C57BL/6 mice, we identify MINDIN as a prostate tumor secreted protein that induces bone microstructural and bone remodeling gene expression changes before tumor cell homing. Associated with these changes, increased tumor cell adhesion to the endosteum ex vivo and to osteoblasts in vitro was observed. Furthermore, MINDIN promoted osteoblast proliferation and mineralization and monocyte expression of osteoclast markers. β-catenin signaling pathway revealed to mediate MINDIN actions on osteoblast gene expression but failed to affect MINDIN-induced adhesion to prostate tumor cells or monocyte differentiation to osteoclasts. Our study evidences that MINDIN secretion by primary prostate tumors creates a favorable bone environment for tumor cell homing before metastatic spread.

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Pakula, Hubert, Ryan Carelli, Nicolo Fanelli, Madhavi Jere, Caitlin Unkenholz, Mohamed Omar, Caroline Ribeiro Fidalgo, et al. "Abstract 3816: Functional atlas of prostate mesenchyme." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3816. http://dx.doi.org/10.1158/1538-7445.am2022-3816.

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Abstract Prostate cancer has a heterogeneous prognosis, and genetic alterations alone do not fully explain clinical behavior. We previously characterized the stroma of localized human prostates by Laser Capture Microdissection, and found that stroma was substantially different in prostates with and without tumor. Furthermore, a stromal gene signature reflecting bone remodeling was upregulated in high compared to low Gleason grade cases. To determine how stromal cells contribute to carcinogenesis and progression we study whether specific genetic alterations in the epithelium induce unique stromal changes. To do this, we utilized Genetically Engineered Mouse Models (GEMMs) representing common prostate cancer mutations and compared these to their wild-type conterparts: the Tmprss2-ERG fusion knock-in murine model induces histological alterations in the stroma in the absence of an epithelial phenotype; the Pten deletion mouse model (PtenKO) results in prostate intraepithelial neoplasia (PIN) but not invasive cancer; the Hi-Myc GEMM, leads to PIN and subsequently invasion; and the Pb4-Cre +/-;Pten f/f; LSL-MYCN +/+; Rb1 f/f (MNRPDKO) mouse model that leads to neuroendocrine prostate cancer (NEPC). We generated a comprehensive single-cell transcriptomic atlas of the mouse prostate cancer mesenchyme in these models. Using deep generative modeling followed by graph-based clustering and gene regulatory network inference, six (6) distinct subsets of fibroblasts and two (2) subsets of smooth muscle cells (myofibroblasts and pericytes) were identified. Notably, some subsets were common across all GEMMs and WT mice, while others aligned with specific genotypes. Moreover, we found a variable pattern of positive and negative Ar expressing cells between genotypes. Analysis by CellphoneDB of mesenchymal-epithelial communications revealed the complex cross-talk between mutated epithelial cells and the tumor microenvironment. Multiplex immunofluorescence phenotyping of mesenchymal cell confirmed the cluster subtypes by both expression and spatial location. Finally, stromal transcripts defining mesenchymal cluster subtypes associated with Tmprss2-ERG were conserved between mouse and human genotypes.This study lays the groundwork for understanding and ultimately targeting stromal-epithelial interactions in prostate cancer. Citation Format: Hubert Pakula, Ryan Carelli, Nicolo Fanelli, Madhavi Jere, Caitlin Unkenholz, Mohamed Omar, Caroline Ribeiro- Fidalgo, Filippo Pederzoli, Cory Abate-Shen, David S. Rickman, Brian Robinson, Luigi Marchionni, Massimo Loda. Functional atlas of prostate mesenchyme [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 3816.

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Schipper, R. G., J. C. Romijn, V. M. J. I. Cuijpers, and A. A. J. Verhofstad. "Polyamines and prostatic cancer." Biochemical Society Transactions 31, no. 2 (April 1, 2003): 375–80. http://dx.doi.org/10.1042/bst0310375.

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The importance of polyamines in prostatic growth and differentiation has prompted studies to evaluate the clinical relevance of the ornithine decarboxylase/polyamine system in prostatic cancer. These studies show that differences in biological behaviour of prostatic (cancer) cells are associated with changes in polyamine levels and/or the activity of their metabolic enzymes. Faulty antizyme regulation of polyamine homoeostasis may play an important role in the growth and progression of prostatic carcinoma. Treatment of human prostate carcinoma cells with inhibitors of polyamine metabolic enzymes or polyamine analogues induces cell growth arrest or (apoptotic) cell death. Our recent in vitro studies using conformationally restricted polyamine analogues show that these compounds inhibit cell growth, probably by inducing antizyme-mediated degradation of ornithine decarboxylase. Sensitivity of human prostate cancer cells for these compounds was increased in the absence of androgens. These results suggest that these analogues might have chemotherapeutic potential in case prostatic cancer has become androgen-independent. Pilot data in an in vivo model show that these analogues have effects on tumour cell proliferation, vascularity, blood perfusion and tissue hypoxia. Overall, these studies show that polyamines may serve as important biomarkers of prostatic malignancy and provide a promising target for chemotherapy of prostatic cancer.

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Miyauchi, Toshiya, Masahiro Takahashi, Koji Mitsuzuka, Yuriko Saiki, Teppei Okubo, Paula M. Vertino, Akiteru Goto, Yoichi Arai, Akira Horii, and Shinichi Fukushige. "Aberrant Hypermethylation-Mediated Suppression of PYCARD Is Extremely Frequent in Prostate Cancer with Gleason Score ≥ 7." Disease Markers 2021 (February 4, 2021): 1–13. http://dx.doi.org/10.1155/2021/8858905.

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Epigenetic gene silencing by aberrant DNA methylation leads to loss of key cellular pathways in tumorigenesis. In order to analyze the effects of DNA methylation on prostate cancer, we established LNCaP-derived human prostate cancer cells that can pharmacologically induce global reactivation of hypermethylated genes by the methyl-CpG targeted transcriptional activation (MeTA) method. The MeTA suppressed the growth of LNCaP-derived cells and induced apoptosis. Microarray analysis indicated that PYCARD (PYD and CARD domain containing) encoding an apoptosis-inducing factor was upregulated by 65-fold or more after treatment with MeTA. We analyzed DNA methylation statuses using 50 microdissected primary prostate cancer tissues and found an extremely high frequency of tumor-specific promoter hypermethylation of PYCARD (90%, 45/50). Moreover, DNA methylation status was significantly associated with Gleason score ( P = 0.0063 ); the frequency of tumor-specific hypermethylation was 96% (44/46) in tumors with Gleason score ≥ 7 , whereas that in tumors with Gleason score 6 was 25% (1/4). Immunohistochemical analyses using these 50 cases indicated that only 8% (4/50) of cancerous tissues expressed PYCARD, whereas 80% (40/50) of corresponding normal prostate epithelial and/or basal cells expressed PYCARD. In addition, there was no relationship between PYCARD immunostaining and the Gleason score in cancerous tissue and surrounding normal tissue. Inducible expression of PYCARD inhibited cell proliferation by induction of apoptosis. These results suggest that aberrant methylation of PYCARD is a distinctive feature of prostate cancers with Gleason score ≥ 7 and may play an important role in escaping from apoptosis in prostatic tumorigenesis.

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Kim, Kwang-Youn, Un-Jung Yun, Seung-Hee Yeom, Sang-Chan Kim, Hu-Jang Lee, Soon-Cheol Ahn, Kwang-Il Park, and Young-Woo Kim. "Inhibition of Autophagy Promotes Hemistepsin A-Induced Apoptosis via Reactive Oxygen Species-Mediated AMPK-Dependent Signaling in Human Prostate Cancer Cells." Biomolecules 11, no. 12 (December 1, 2021): 1806. http://dx.doi.org/10.3390/biom11121806.

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Chemotherapy is an essential strategy for cancer treatment. On the other hand, consistent exposure to chemotherapeutic drugs induces chemo-resistance in cancer cells through a variety of mechanisms. Therefore, it is important to develop a new drug inhibiting chemo-resistance. Although hemistepsin A (HsA) is known to have anti-tumor effects, the molecular mechanisms of HsA-mediated cell death are unclear. Accordingly, this study examined whether HsA could induce apoptosis in aggressive prostate cancer cells, along with its underlying mechanism. Using HsA on two prostate cancer cell lines, PC-3 and LNCaP cells, the cell analysis and in vivo xenograft model were assayed. In this study, HsA induced apoptosis and autophagy in PC-3 cells. HsA-mediated ROS production attenuated HsA-induced apoptosis and autophagy after treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, autophagy inhibition by 3-MA or CQ is involved in accelerating the apoptosis induced by HsA. Furthermore, we showed the anti-tumor effects of HsA in mice, as assessed by the reduced growth of the xenografted tumors. In conclusion, HsA induced apoptosis and ROS generation, which were blocked by protective autophagy signaling.

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Song, Kyung, Hui Wang, Tracy L. Krebs, Bingcheng Wang, Thomas J. Kelley та David Danielpour. "DHT Selectively Reverses Smad3-Mediated/TGF-β-Induced Responses through Transcriptional Down-Regulation of Smad3 in Prostate Epithelial Cells". Molecular Endocrinology 24, № 10 (1 жовтня 2010): 2019–29. http://dx.doi.org/10.1210/me.2010-0165.

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Abstract Androgens suppress TGF-β responses in the prostate through mechanisms that are not fully explored. We have recently reported that 5α-dihydrotestosterone (DHT) suppresses the ability of TGF-β to inhibit proliferation and induce apoptosis of prostatic epithelial cells and provided evidence that such suppression was fueled by transcriptional down-regulation of TGF-β receptor II (ΤβRII). We now show that androgen receptor (AR) activated by DHT suppresses the TGF-β-induced phosphorylation of Sma- and Mad-related protein (Smad)3 in LNCaP cells overexpressing TβRII under the control of a cytomegalovirus promoter, which is not regulated by DHT, suggesting that transcriptional repression of TβRII alone does not fully account for the impact of DHT on TGF-β responses. Instead, we demonstrate that such suppression occurs through loss of total Smad3, resulting from transcriptional suppression of Smad3. We provide evidence that DHT down-regulates the promoter activity of Smad3 in various prostate cancer cell lines, including NRP-154+AR, DU145+AR, LNCaP, and VCaP, at least partly through androgen-dependent inactivation of Sp1. Moreover, we show that overexpression of Smad3 reverses the ability of DHT to protect against TGF-β-induced apoptosis in NRP-154+AR, supporting our model that loss of Smad3 by DHT is involved in the protection against TGF-β-induced apoptosis. Together, these findings suggest that deregulated/enhanced expression and activation of AR in prostate carcinomas may intercept the tumor suppressor function of TGF-β through transcriptional suppression of Smad3, thereby providing new mechanistic insight into the development of castration-resistant prostate cancer.

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Yan, Lisa, Diane Da Silva, Shreya Kanodia, Andrew Gray, and W. Martin Kast. "LIGHT expression in prostate cancer inhibits tumor growth and induces prostate antigen-specific immunity (156.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 156.2. http://dx.doi.org/10.4049/jimmunol.186.supp.156.2.

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Abstract An immunosuppressive tumor microenvironment has always been a hurdle for successful immunotherapy even in the presence of induced tumor-specific T cells. Regulatory T cells (Tregs) appear to be key regulators in local immune suppression. LIGHT, a ligand for lymphotoxin-β receptor (LTβR), is predominantly expressed on activated immune cells, signaling via LTβR is required for the formation of organized lymphoid tissues. Forced expression of LIGHT recruits naive T cells into tumors and is capable of establishing tumor specific immunity. However this has never been tested in prostate cancer models where tolerance to self-antigen likely exists. Here we test the hypothesis that forced expression of LIGHT in prostate tumors induces prostate cancer-specific immunity and results in tumor regression by altering the suppressive activity of Tregs and consequently enhancing a more persistent proinflammatory microenvironment. Our data show that intratumoral expression of LIGHT via adenovirus delivery in TRAMP-C2 tumor challenged mice develop de novo CD8+ IFNγ-secreting prostate antigen-specific T cells and display increased survival compared to control treated mice. LIGHT-treated mice also display an increase in ratio of tumor infiltrating lymphocytes to Tregs as well as decrease in Treg suppression activity. Our data suggest that LIGHT treatment can alter the microenvironment such that natural and vaccine-induced prostate tumor antigen specific T cells mediate tumor regression.

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Messex, Justin K., Crystal J. Byrd, Mikalah U. Thomas, and Geou-Yarh Liou. "Macrophages Cytokine Spp1 Increases Growth of Prostate Intraepithelial Neoplasia to Promote Prostate Tumor Progression." International Journal of Molecular Sciences 23, no. 8 (April 12, 2022): 4247. http://dx.doi.org/10.3390/ijms23084247.

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Prostate cancer development and progression are associated with increased infiltrating macrophages. Prostate cancer is derived from prostatic intraepithelial neoplasia (PIN) lesions. However, the effects macrophages have on PIN progression remain unclear. Here, we showed that the recruited macrophages adjacent to PIN expressed M2 macrophage markers. In addition, high levels of Spp1 transcripts, also known as osteopontin, were identified in these macrophages. Extraneously added Spp1 accelerated PIN cell proliferation through activation of Akt and JNK in a 3D culture setting. We also showed that PIN cells expressed CD44, integrin αv, integrin β1, and integrin β3, all of which have been previously reported as receptors for Spp1. Finally, blockade of Akt and JNK activation through their specific inhibitor completely abolished macrophage Spp1-induced cell proliferation of PIN. Hence, our data revealed Spp1 as another macrophage cytokine/growth factor and its mediated mechanism to upregulate PIN cell growth, thus promoting prostate cancer development.

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Kawahara, Takashi, Yuki Teramoto, Yi Li, Hitoshi Ishiguro, Jennifer Gordetsky, Zhiming Yang, and Hiroshi Miyamoto. "Impact of Vasectomy on the Development and Progression of Prostate Cancer: Preclinical Evidence." Cancers 12, no. 8 (August 15, 2020): 2295. http://dx.doi.org/10.3390/cancers12082295.

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Some observational studies have implied a link between vasectomy and an elevated risk of prostate cancer. We investigated the impact of vasectomy on prostate cancer outgrowth, mainly using preclinical models. Neoplastic changes in the prostate were compared in transgenic TRAMP mice that underwent vasectomy vs. sham surgery performed at 4 weeks of age. One of the molecules identified by DNA microarray (i.e., ZKSCAN3) was then assessed in radical prostatectomy specimens and human prostate cancer lines. At 24 weeks, gross tumor (p = 0.089) and poorly differentiated adenocarcinoma (p = 0.036) occurred more often in vasectomized mice. Vasectomy significantly induced ZKSCAN3 expression in prostate tissues from C57BL/6 mice and prostate cancers from TRAMP mice. Immunohistochemistry showed increased ZKSCAN3 expression in adenocarcinoma vs. prostatic intraepithelial neoplasia (PIN), PIN vs. non-neoplastic prostate, Grade Group ≥3 vs. ≤2 tumors, pT3 vs. pT2 tumors, pN1 vs. pN0 tumors, and prostate cancer from patients with a history of vasectomy. Additionally, strong (2+/3+) ZKSCAN3 expression (p = 0.002), as an independent prognosticator, or vasectomy (p = 0.072) was associated with the risk of tumor recurrence. In prostate cancer lines, ZKSCAN3 silencing resulted in significant decreases in cell proliferation/migration/invasion. These findings suggest that there might be an association between vasectomy and the development and progression of prostate cancer, with up-regulation of ZKSCAN3 expression as a potential underlying mechanism.

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Maggiolini, M., AG Recchia, A. Carpino, A. Vivacqua, G. Fasanella, V. Rago, V. Pezzi, PA Briand, D. Picard, and S. Ando. "Oestrogen receptor beta is required for androgen-stimulated proliferation of LNCaP prostate cancer cells." Journal of Molecular Endocrinology 32, no. 3 (June 1, 2004): 777–91. http://dx.doi.org/10.1677/jme.0.0320777.

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The role of oestrogens in the development of prostate cancer is poorly understood. However, a large body of evidence has suggested that oestrogenic hormones may be involved in prostatic malignancy. The localization of oestrogen receptor beta (ERbeta) in the secretory epithelium of the human prostate has raised the intriguing possibility that the action of oestrogen could be mediated, at least in part, by this receptor during the process of carcinogenesis. Hence, specific interference with oestrogen-activated and ERbeta-mediated transcriptional activity could open new issues in the endocrine manipulation of prostate tumours. In the present study, we provide new insights into the role of ERbeta in the context of an androgen-responsive prostate cancer cell line such as LNCaP, which was used as a model system together with steroid receptor negative HeLa cells. ERbeta and the mutated androgen receptor (AR) T877A did not discriminate between oestrogen- or androgen-induced transactivation, whereas ERbeta and AR transcriptional activity were inhibited only by the respective hormone antagonists ICI 182,780 and casodex. Furthermore, the nuclear localization of ERbeta evaluated by immunocytochemistry confirmed the promiscuous response to hormones in addition to the specific inhibitory action of antagonists. Interestingly, ICI 182,780 and an ERbeta antisense expression vector repressed the growth effects of both 17beta-oestradiol and 5alpha-dihydrotestosterone, suggesting that ERbeta has a key role in the proliferation induced by these steroids in LNCaP prostate cancer cells. Thus our findings implicate ERbeta as a potential target for the treatment of prostate tumours.

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Kumar, Sanjay, Shalie Malik, Udai P. Singh, Selvarangan Ponnazhagan, Karyn Scissum-Gunn, Upender Manne, and Manoj K. Mishra. "PD-1 expression on Foxp3+ Treg cells modulates CD8+ T cell function in prostatic tumor microenvironment." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 155.11. http://dx.doi.org/10.4049/jimmunol.198.supp.155.11.

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Abstract Regulatory T (Treg) cells act as terminators of T cell immune response during prostate cancer progression and development. However, their role and immunosuppressive mechanism(s) in context to programmed death 1 (PD-1) is not completely understood. The present investigation is aimed to determine the role of PD-1 on Treg cells and their impact on CD8+ T cell function in prostatic tumor microenvironment using transgenic adenocarcinoma of the mouse prostate (TRAMP) cells (TRAMP C1, C2 and C3) as a model system. To execute the above aim, tumor induction studies were performed. Briefly, the C57BL/6 mice were administered with serial log concentrations of TRAMP (C1-3) cells. Interestingly, the TRAMP-C3 cells do not form tumor, however, TRAMP-C1 and TRAMP-C2 cells do form tumor. After tumor development, mice were sacrificed by cervical dislocation; tumor, lung, spleen, and draining lymph nodes were harvested when the tumor size reached approximately 20mm. Single cell suspensions were prepared from different organs, cells were then stained with specific antibodies, and flow analyzed for the expression of different immune markers. Our preliminary findings demonstrated that PD-1 expression on Foxp3+ Treg cells displayed greater suppressive capacity against CD8+ T cell function in tumor, lung, spleen, and draining lymph node when compared to the control. More importantly, Foxp3+ Treg(high) PD-1(high) interaction with PDL-1 induced immunosuppression by blocking CD8+ T cells function in prostatic tumor microenvironment. In conclusion, Foxp3+ Treg(high), PD-1(high), and CD8+(low) T cells may enhance tumor progression; thus, targeting the PD-1 on Treg cells may be a possible therapy to treat prostate cancer.

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Yu, Xiaoqin, Ran Chen, Fei Wang, Weihua Liu, Wenjing Zhang, Maolei Gong, Han Wu, et al. "Pattern recognition receptor-initiated innate immune responses in mouse prostatic epithelial cells." Biology of Reproduction 105, no. 1 (April 23, 2021): 113–27. http://dx.doi.org/10.1093/biolre/ioab076.

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Abstract Three major pathogenic states of the prostate, including benign prostatic hyperplasia, prostate cancer, and prostatitis, are related to the local inflammation. However, the mechanisms underlying the initiation of prostate inflammation remain largely unknown. Given that the innate immune responses of the tissue-specific cells to microbial infection or autoantigens contribute to local inflammation, this study focused on pattern recognition receptor (PRR)-initiated innate immune responses in mouse prostatic epithelial cells (PECs). Primary mouse PECs abundantly expressed Toll-like receptor 3 (TLR3), TLR4, TLR5, melanoma differentiation-associated protein 5 (MDA5), and IFN-inducible protein 16 (p204 in mouse). These PRRs can be activated by their respective ligands: lipopolysaccharide (LPS) and flagellin of Gram-negative bacteria for TLR4 and TLR5, polyinosinic-polycytidylic acid (poly(I:C)) for TLR3 and MDA5, and herpes simplex virus DNA analog (HSV60) for p204. LPS and flagellin predominantly induced the expression of inflammatory cytokines, including tumor necrosis factor alpha (TNFA), interleukin 6 (IL6), chemokines monocyte chemoattractant protein-1 (MCP1), and C-X-C motif chemokine 10 (CXCL10). Poly(I:C) and HSV60 predominantly induced the expression of type 1 interferons (IFNA and IFNB) and antiviral proteins: Mx GTPase 1, 2′,5′-oligoadenylate synthetase 1, and IFN-stimulated gene 15. The replication of mumps virus in PECs was inhibited by type 1 IFN signaling. These findings provide insights into the mechanisms underlying innate immune response in the prostate.

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Bok, Robert, Jessie Lee, Renuka Sriram, Kayvan Keshari, Subramaniam Sukumar, Saeed Daneshmandi, David Korenchan, et al. "The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized 13C MRSI." Cancers 11, no. 2 (February 22, 2019): 257. http://dx.doi.org/10.3390/cancers11020257.

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This study applied a dual-agent, 13C-pyruvate and 13C-urea, hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) 1H magnetic resonance imaging (MRI) approach in the transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate changes in tumor perfusion and lactate metabolism during prostate cancer development, progression and metastases, and after lactate dehydrogenase-A (LDHA) knock-out. An increased Warburg effect, as measured by an elevated hyperpolarized (HP) Lactate/Pyruvate (Lac/Pyr) ratio, and associated Ldha expression and LDH activity were significantly higher in high- versus low-grade TRAMP tumors and normal prostates. The hypoxic tumor microenvironment in high-grade tumors, as measured by significantly decreased HP 13C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased Hif1α and then Ldha expression. Increased lactate induced Mct4 expression and an acidic tumor microenvironment that provided a potential mechanism for the observed high rate of lymph node (86%) and liver (33%) metastases. The Ldha knockdown in the triple-transgenic mouse model of prostate cancer resulted in a significant reduction in HP Lac/Pyr, which preceded a reduction in tumor volume or apparent water diffusion coefficient (ADC). The Ldha gene knockdown significantly reduced primary tumor growth and reduced lymph node and visceral metastases. These data suggested a metabolic transformation from low- to high-grade prostate cancer including an increased Warburg effect, decreased perfusion, and increased metastatic potential. Moreover, these data suggested that LDH activity and lactate are required for tumor progression. The lactate metabolism changes during prostate cancer provided the motivation for applying hyperpolarized 13C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response.

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Maitland, Norman J. "Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced?" Cancers 13, no. 2 (January 17, 2021): 327. http://dx.doi.org/10.3390/cancers13020327.

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Анотація:

Increasingly sophisticated therapies for chemical castration dominate first-line treatments for locally advanced prostate cancer. However, androgen deprivation therapy (ADT) offers little prospect of a cure, as resistant tumors emerge rather rapidly, normally within 30 months. Cells have multiple mechanisms of resistance to even the most sophisticated drug regimes, and both tumor cell heterogeneity in prostate cancer and the multiple salvage pathways result in castration-resistant disease related genetically to the original hormone-naive cancer. The timing and mechanisms of cell death after ADT for prostate cancer are not well understood, and off-target effects after long-term ADT due to functional extra-prostatic expression of the androgen receptor protein are now increasingly being recorded. Our knowledge of how these widely used treatments fail at a biological level in patients is deficient. In this review, I will discuss whether there are pre-existing drug-resistant cells in a tumor mass, or whether resistance is induced/selected by the ADT. Equally, what is the cell of origin of this resistance, and does it differ from the treatment-naïve tumor cells by differentiation or dedifferentiation? Conflicting evidence also emerges from studies in the range of biological systems and species employed to answer this key question. It is only by improving our understanding of this aspect of treatment and not simply devising another new means of androgen inhibition that we can improve patient outcomes.

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Wallner, K., J. Roy, and L. Harrison. "Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma." Journal of Clinical Oncology 14, no. 2 (February 1996): 449–53. http://dx.doi.org/10.1200/jco.1996.14.2.449.

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PURPOSE To quantify disease progression and morbidity following computer tomography (CT)-based transperineal iodine 125 prostate implantation. METHODS Ninety-two patients with clinical stage T1 or T2, Gleason score 2 to 7/10, prostatic carcinoma had outpatient, CT-based transperineal 125I prostate implantation and were monitored for 1 to 7 years (median, 3). The prescribed minimum radiation dose was 140 to 160 Gy. Lymph node dissection and postimplantation prostatic biopsies were not routinely performed. RESULTS In 46% of patients, radiation-related urinary symptoms were substantial enough at 1 month following implantation to require medication. Radiation-related urinary symptoms gradually resolved. Two years after implantation, 14% of patients had persistent urinary symptoms of Radiation Therapy Oncology Group (RTOG) > or = grade 2. Eight percent of patients underwent a transurethral resection of the prostate (TURP) within 2 years of implantation. Five patients developed radiation-induced rectal ulcerations. Of 56 patients who were sexually potent preimplantation, 86% retained potency at 3 years. Twenty-five patients had biochemical disease progression. The overall actuarial freedom from biochemical failure rate at 4 years following implantation was 63%. In Cox proportional hazards multivariate analysis, the strongest predictor of failure was prostate-specific antigen (PSA) level less than or greater than 10 ng/mL (P = .005), followed by Gleason score (2 to 4 v 5 to 7, P = .08) and stage (T1 v T2, P = .09). CONCLUSION The 5-year biochemical freedom-from-progression rates following transperineal 125I implantation are comparable with those achieved with prostatectomy. The morbidity has decreased with increased physician experience.

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Youlin, Kuang, He Weiyang, Liang Simin та Gou Xin. "Prostaglandin E2 Inhibits Prostate Cancer Progression by Countervailing Tumor Microenvironment-Induced Impairment of Dendritic Cell Migration through LXRα/CCR7 Pathway". Journal of Immunology Research 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/5808962.

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Migration and homing of dendritic cells (DCs) to lymphoid organs are quite crucial for T cell-induced immune response against tumor. However, tumor microenvironment can make some tumor cells escape immune response by impairing DC migration. Prostaglandin E2 (PGE2) plays important roles in initiating and terminating inflammatory responses. In this study, we investigated whether PGE2 could inhibit murine prostate cancer progression by countervailing tumor microenvironment-induced impairment of dendritic cell migration. We found that murine prostate cancer cell line RM-1-conditioned medium impaired chemotactic movement of marrow-derived DCs and splenic cDCs toward CC chemokine receptor-7 (CCR7) ligand CCL19 in vitro and migration to draining lymph gland in vivo. Meanwhile, it also induced LXRα activation and CCR7 inhibition on maturing DCs. However, the treatment of PGE2 rescued this impairment of DC migration with upregulation of CCR7 and inhibition of LXRα. Further, it was observed that PGE2 also increased MMP9 expression and activated Notch1 signaling on DCs. In RM-1-bearing mouse model, PGE2 treatment was identified to inhibit tumor growth and induce more tumor-infiltrating T cells and CD11c dendritic cells in tumor sites. Therefore, our findings may demonstrate a new perspective for therapeutic interventions on prostate cancer immunoescape.

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Josson, Sajni, Starlette Sharp, Shian-Ying Sung, Peter A. S. Johnstone, Ritu Aneja, Ruoxiang Wang, Murali Gururajan, Timothy Turner, Leland W. K. Chung, and Clayton Yates. "Tumor-Stromal Interactions Influence Radiation Sensitivity in Epithelial- versus Mesenchymal-Like Prostate Cancer Cells." Journal of Oncology 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/232831.

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HS-27a human bone stromal cells, in 2D or 3D coultures, induced cellular plasticity in human prostate cancerARCaPEandARCaPMcells in an EMT model. CoculturedARCaPEorARCaPMcells with HS-27a, developed increased colony forming capacity and growth advantage, withARCaPEexhibiting the most significant increases in presence of bone or prostate stroma cells. Prostate (Pt-N or Pt-C) or bone (HS-27a) stromal cells induced significant resistance to radiation treatment inARCaPEcells compared toARCaPMcells. However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in bothARCaPE- andARCaPM-cocultured cells. Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin. These cell adhesion molecules such as E-cadherin and integrin alpha v in cancer cells induce cell survival signals and mediate resistance to cancer treatments such as radiation.

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Stenberg, Vilde Yuli, Roy Hartvig Larsen, Li-Wei Ma, Qian Peng, Petras Juzenas, Øyvind Sverre Bruland, and Asta Juzeniene. "Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer." International Journal of Molecular Sciences 22, no. 9 (May 1, 2021): 4815. http://dx.doi.org/10.3390/ijms22094815.

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Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of 212Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of 212Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of 212Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of 212Pb-NG001.

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Vignozzi, Linda, Ilaria Cellai, Raffaella Santi, Letizia Lombardelli, Annamaria Morelli, Paolo Comeglio, Sandra Filippi, et al. "Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells." Journal of Endocrinology 214, no. 1 (May 4, 2012): 31–43. http://dx.doi.org/10.1530/joe-12-0142.

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Progression of benign prostatic hyperplasia (BPH) involves chronic inflammation and immune dysregulation. Preclinical studies have demonstrated that prostate inflammation and tissue remodeling are exacerbated by hypogonadism and prevented by testosterone supplementation. We now investigated whether, in humans, hypogonadism was associated with more severe BPH inflammation and the in vitro effect of the selective androgen receptor agonist dihydrotestosterone (DHT) on cultures of stromal cells derived from BPH patients (hBPH). Histological analysis of inflammatory infiltrates in prostatectomy specimens from a cohort of BPH patients and correlation with serum testosterone level was performed. Even after adjusting for confounding factors, hypogonadism was associated with a fivefold increased risk of intraprostatic inflammation, which was also more severe than that observed in eugonadal BPH patients. Triggering hBPH cells by inflammatory stimuli (tumor necrosis factor α, lipopolysaccharide, or CD4+T cells) induced abundant secretion of inflammatory/growth factors (interleukin 6 (IL6), IL8, and basic fibroblast growth factor (bFGF)). Co-culture of CD4+T cells with hBPH cells induced secretion of Th1 inducer (IL12), Th1-recruiting chemokine (interferon γ inducible protein 10, IP10), and Th2 (IL9)- and Th17 (IL17)-specific cytokines. Pretreatment with DHT inhibited NF-κB activation and suppressed secretion of several inflammatory/growth factors, with the most pronounced effects on IL8, IL6, and bFGF. Reduced inflammatory cytokine production by testosterone cells, an increase in IL10, and a significant reduction of testosterone cells proliferation suggested that DHT exerted a broad antiinflammatory effect on testosterone cells. In conclusion, our data demonstrate that DHT exerts an immune regulatory role on human prostatic stromal cells, inhibiting their potential to actively induce and/or sustain autoimmune and inflammatory responses.

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S. Mohammed, Ebtehal, Wafa F. Al-Taie, Intesar T. Numan, and Saad A. Hussain. "Changes in Serum Levels of Tumor Necrosis Factor-Alpha and Antioxidant status in Different Stages of Malignant Prostate Cancer Patients in Iraq." Iraqi Journal of Pharmaceutical Sciences ( P-ISSN 1683 - 3597 E-ISSN 2521 - 3512) 21, no. 1 (March 28, 2017): 56–60. http://dx.doi.org/10.31351/vol21iss1pp56-60.

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Chronic inflammation can induce proliferative events and posttranslational DNA modifications in prostate tissue through oxidative stress. The present study was designed to evaluate the changes in serum levels of TNF-Î±, malomdialdehyde (MDA) and total antioxidant status (TAS) patients with different stages of malignant prostatic cancer (PCa) and benign prostatic hyperplasia (BPH). One hundred males (age range of 58-72 years) with different stages of malignant PCa were recruited from the Radiotherapy and Nuclear Medicine Teaching Hospital in Baghdad during the period from September 2010 to April 2011. The patients were categorized according to the 4 disease stages (I, II, III, and IV); 25 patients with benign prostatic hyperplasia (BPH) and 25 normal healthy subjects were considered as comparator groups. Blood samples were taken from all subjects for analysis of TNF-Î± TAS and MDA levels. The results showed significant differences between the four stages of PCa patients in all parameters; however, highly significant difference was observed in stage IV compared to control and BPH patients. In conclusion, TNF-Î± and total antioxidant status could be utilized for marking the advanced stages of malignant PCa. Key words: Malignant Prostate cancer, Inflammation, TNF-Î±, Oxidative stress

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Esmat, Amr Y., Fawzia M. Refaie, Mohamed H. Shaheen, and Mahmoud M. Said. "Chemoprevention of Prostate Carcinogenesis by DFMO and/or Finasteride Treatment in Male Wistar Rats." Tumori Journal 88, no. 6 (November 2002): 513–21. http://dx.doi.org/10.1177/030089160208800616.

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In the present study the chemopreventive activities of DFMO, the irreversible inhibitor of ornithine decarboxylase, and finasteride, the inhibitor of prostatic 5a-reductase, against the development of chemically induced prostate adenocarcinoma by methylnitrosourea/testosterone propionate in male Wistar rats were investigated. According to histological examination, oral administration of DFMO and finasteride, either alone or combined, for two months to MNU/TP-inoculated rats reduced the tumor incidence to 11.11%, 10% and 10%, respectively, compared to tumored controls (64.3%). DFMO and/or finasteride treatment resulted in significant reductions in the wet weight of the prostate gland and seminal vesicles and its ratio relative to the total body weight, as well as the levels of prostate total protein, DNA, RNA and DNA/RNA ratio, compared to tumored controls. However, the effect of the combined treatment was of no statistical significance compared to single DFMO or finasteride treatment, as demonstrated by the non-significant differences between the mean values of most of the studied parameters. The tumor chemopreventive activity and the prostate growth inhibitory effect of DFMO and finasteride were due to suppression of prostate polyamine synthesis. ANOVA test revealed that the relative weight of the prostate as well as blood and tissue polyamine levels could be used as significant endpoint biomarkers for DFMO and finasteride as cancer chemopreventive agents.

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Rowles III, Joe, Matthew Wallig, Kimberly Selting, Timothy Fan, Rita Miller, William O'Brien Jr., and John Erdman Jr. "Can Tomato Powder Reduce Radiation-Induced Effects in a Murine Model of Prostate Cancer?" Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 348. http://dx.doi.org/10.1093/cdn/nzaa044_047.

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Abstract Objectives Tomatoes contain carotenoids and other potent antioxidants that may protect the surrounding tissue from the detrimental effects of external beam radiation therapy, while reducing rates of prostate carcinogenesis. The objective of this study was to determine whether dietary lyophilized tomato paste (TP) alters early inflammatory and oxidative events following a single dose of radiation and leads to a more successful therapeutic outcome. Methods Male Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice (n = 76) were provided a powdered AIN-93 G diet (Control) or a modified AIN-93 G diet containing 10% TP (w/w) at 4 weeks of age. Mice were monitored by ultrasound for in vivo tumor detection and 3-D volumetric measurement biweekly. Once tumors reached a volume of 1000 mm3, the caudal half of the mouse was irradiated with 7.5 gy (Rad, n = 18–19 per diet) or 0 gy (sham, n = 16–20 per diet) with a Cobalt-60 source. Mice were euthanized 24 hours after radiation or sham treatment. Antioxidants (carotenoids and α-tocopherol) were measured by high performance liquid chromatography (HPLC) in the serum, tumor, prostate, and liver. Sections of tumor, liver, kidneys, bladder, lymph, bladder and intestines were stained by hematoxylin and eosin (H&E) and cleaved-caspase 3 were assessed for radiation-induced changes and apoptosis. Inflammatory markers (C-reactive protein, IL-6, IL-17A, TNFα, IFNγ, and IL-10) were measured in serum, liver, prostate, tumor, and epididymal adipose tissues by ELISA. Results This study is the first to explore the effects of TP on the tumor microenvironment following irradiation. Initial results suggest that TP consumption does not alter circulating or tissue (liver and prostate) concentrations of inflammatory markers (C-reactive protein, TNFα, IFNγ, IL-6, IL-17, or IL-10). We hypothesize that TP-Rad will maintain similar levels of circulating concentrations of antioxidants (carotenoids and α-tocopherol) compared to sham-treated mice. Additionally, we hypothesize that TP will reduce markers of cell damage in surrounding tissues. Conclusions This study will provide important preclinical data to inform future clinical trials evaluating approaches to lessen extra-prostatic damage from radiation therapy and thus improve therapeutic outcomes. Funding Sources This work was supported by USDA NIFA ILLU-971–334.

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Renzulli, J. F., G. Dooner, C. Owens, G. Colvin, M. Dooner, M. Del Tatto, L. Goldstein, and P. Quesenberry. "Microvesicular-mediated gene transfer of prostate tumor markers." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e16076-e16076. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16076.

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e16076 Background: Microvesicles have been a subject of research for many years. Recent work has focused on the potential for cancer vaccines via microvesicles. It has also been demonstrated that various cell-specific phenotypes can be transferred from one cell type to another through microvesicle transfer. Studies in our laboratory have demonstrated that co-culture of murine lung tissue with marrow cells across a cell impermeable membrane can induce elevations in lung-specific mRNA expression in human donor marrow stem cells. Our objective is to determine whether there is transfer of genetic or transcriptional factors via microvesicles from human prostate cancer cells to fresh human marrow cells. Methods: Fresh prostate tissue was harvested from surgical specimens following radical retropubic prostatectomy. Samples were histologically confirmed to contain prostatic adenocarcinoma. Co-cultures were established using a transwell system in which 0.05–0.100 grams of prostate tissue was minced and co-cultured with 1–3 million normal, human donor marrow cells for 2–7 days. Marrow not co-cultured with tumorserved as a control. Target cells were collected and total RNA was analyzed for prostate-specific gene expression byReal Time RT-PCR. Fold differences in expression of the genes were analyzed, using TaqMan®, gene assays (Applied Biosystems) and were expressed in relation to the marrow control. Results: We have observed significant increases in gene expression in marrow cells co-cultured with prostate tumor cells (Gleason grades 6–9). Variable increases in expression were seen in 3 patient samples, as high as 7-fold for ERG, greater than 10-fold for ACPP and greater than 100-fold for STEAP, PART, TMPRSS2, PSCA and ETV1. Conclusions: These studies demonstrate that prostate specific genes are present in fresh human marrow cells after co-culture with tumor tissue. This establishes a base to begin evaluating the significance of microvesicle-mediated genetic transfer, mechanisms of transfer and therapeutic options for blocking or manipulating such transfer to influence the disease process. No significant financial relationships to disclose.

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Shukla, Vaibhav, Ashish Tyagi, Venkatesh Kolluru, Uttara Saran, Balaji Chandrasekaran, Murali K. Ankem, and Chendil Damodaran. "Abstract 2999: Activation of NFKB is responsible for defective autophagy in cadmium-induced transformation of prostate cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2999. http://dx.doi.org/10.1158/1538-7445.am2022-2999.

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Abstract Background: Evidence from the epidemiological, laboratory and clinical studies suggest that chronic exposure to cadmium (Cd) leads to the development and progression of prostate cancer (CaP). Previously, we reported defective autophagy due to upregulation of Placenta Specific 8 (Plac8) (a phagosome and lysosome fusion regulator) is responsible for Cd-induced transformation of normal prostate epithelial cells. This study mechanistically dissects the upstream signaling that regulates Plac8 function, which drives defective autophagy during Cd-induced transformation. Methods: To examine the molecular interaction between NFκB and Plac8, we developed NFκB/Plac8 overexpression and knockdown in normal prostate epithelial cells (RWPE-1) and cadmium transformed prostate epithelial cells lines (CTPE). In addition, we performed phenotypic, and molecular analysis including promoter-based studies, western blot, and in vivo analysis to determine the interaction between Plac8 and p65 in Cd-exposed prostate epithelial cells. Results: Our results confirmed that overexpression of Plac8 in normal prostate epithelial cells mimics Cd-transformed prostate cells (CTPE) and induces defective autophagy by regulating autophagy-related genes (ATGs) and an enhanced autophagic flux. Conversely, either NFκB or Plac8 knockdown in CTPE cells abrogates autophagy signaling. Further, Cd-exposure failed to induce defective autophagy signaling in transformed cells. Silencing p65 either by genetically or pharmacological inhibitors downregulated Plac8 expression and its survival function in CTPE cells. Hence, we investigated the interaction between NFκB and Plac8 by promoter-based analysis. We found NFκB binding site in the Plac8 promoter, and mutating NFκB binding sites in the Plac8 promoter showed a decline in luciferase activity confirming our hypothesis that NFκB activation is necessary for Plac8 activation and autophagy signaling in CTPE cells. Finally, we confirmed that silencing Plac8 significantly inhibited the tumor growth of CTPE cells compared to vehicle control. Our ongoing studies on xenotransplanted stably knockdown of p65 in CTPE cells may confirm that NFκB activation is responsible for Plac8 function and tumor growth in mice models. Conclusion: In conclusion, our results suggest that NFκB transcriptionally regulates Plac8 function, which drives pro-survival autophagy signaling in Cd-transformed prostate epithelial cells. Citation Format: Vaibhav Shukla, Ashish Tyagi, Venkatesh Kolluru, Uttara Saran, Balaji Chandrasekaran, Murali K. Ankem, Chendil Damodaran. Activation of NFKB is responsible for defective autophagy in cadmium-induced transformation of prostate cells [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 2999.

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Zhang, Denglu, Kailin Li, Chao Sun, Guangshang Cao, Yuanfu Qi, Zhaomin Lin, Yanxia Guo, et al. "Anti-Cancer Effects of Paris Polyphylla Ethanol Extract by Inducing Cancer Cell Apoptosis and Cycle Arrest in Prostate Cancer Cells." Current Urology 11, no. 3 (2017): 144–50. http://dx.doi.org/10.1159/000447209.

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Objective: To evaluate the potential anti-prostate cancer effects of Paris polyphylla ethanol extract (PPEE) and its underlying mechanisms. Materials and Methods: The anti-proliferation activity of PPEE was tested on PC3 and DU145 cells using Cell Counting Kit-8 assay. The pro-apoptotic and cell cycle arrest effects of PPEE were confirmed by flow cytometry. Apoptosis of prostate cancer cells was induced by PPEE through endogenous and exogenous pathways. A mouse xenograft model was used to examine its anti-prostate cancer effects in vivo. Results: We found that the IC50 of PPEE on PC3 cells was 3.98 µg/ml and the IC50 of PPEE on DU145 cells was 8 µg/ml. PPEE induced prostate cancer cell apoptosis in a concentration dependent manner, through endogenous and exogenous pathways. PPEE induced PC3 cell cycle arrest in G0/G1 and G2/M phases, while in DU145cell it induced cell arrest in the G0/G1 phase. PPEE inhibited the growth of prostate cancer cells in vivo. Conclusion: PPEE could inhibit prostate cancer growth in vitro and in vivo, induce apoptosis of prostate cancer cells, and cause cell cycle arrest, which laid the foundation for further research on the anti-tumor mechanism of PPEE.

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Yeewa, Ranchana, Aya Naiki-Ito, Taku Naiki, Hiroyuki Kato, Shugo Suzuki, Teera Chewonarin, and Satoru Takahashi. "Hexane Insoluble Fraction from Purple Rice Extract Retards Carcinogenesis and Castration-Resistant Cancer Growth of Prostate Through Suppression of Androgen Receptor Mediated Cell Proliferation and Metabolism." Nutrients 12, no. 2 (February 20, 2020): 558. http://dx.doi.org/10.3390/nu12020558.

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Prostate cancer and castration-resistant prostate cancer (CRPC) remain major health challenges in men. In this study, the inhibitory effects of a hexane insoluble fraction from a purple rice ethanolic extract (PRE-HIF) on prostate carcinogenesis and CRPC were investigated both in vivo and in vitro. In the Transgenic Rat for Adenocarcinoma of Prostate (TRAP) model, 1% PRE-HIF mixed diet-fed rats showed a significantly higher percentage of low-grade prostatic intraepithelial neoplasia and obvious reduction in the incidence of adenocarcinoma in the lateral lobes of the prostate. Additionally, 1% PRE-HIF supplied diet significantly suppressed the tumor growth in a rat CRPC xenograft model of PCai1 cells. In LNCaP and PCai1 cells, PRE-HIF treatment suppressed cell proliferation and induced G0/G1 cell-cycle arrest. Furthermore, androgen receptor (AR), cyclin D1, cdk4, and fatty acid synthase expression were down-regulated while attenuation of p38 mitogen-activated protein kinase, and AMP-activated protein kinase α activation occurred in PRE-HIF treated prostate cancer cells, rat prostate tissues, and CRPC tumors. Due to consistent results with PRE-HIF in PCai1 cells, cyanidin-3-glucoside was characterized as the active compound. Altogether, we surmise that PRE-HIF blocks the development of prostate cancer and CRPC through the inhibition of cell proliferation and metabolic pathways.

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Li, Juan, Baotong Zhang, Mingcheng Liu, Xing Fu, Xinpei Ci, Jun A, Changying Fu, et al. "KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells." Cancers 12, no. 3 (March 21, 2020): 748. http://dx.doi.org/10.3390/cancers12030748.

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Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.

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Goris Gbenou, Maximilien C. "The influence of obesity in patients with prostate cancer - Review of the literature." Functional Foods in Health and Disease 3, no. 4 (April 29, 2013): 80. http://dx.doi.org/10.31989/ffhd.v3i4.63.

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Recent studies have demonstrated an association between higher body mass index and increased aggressiveness in prostate cancer. The present narrative review, based on a search of Medline® and Embase® databases from October 1982 to October 2012, explores the relationship between higher body mass index and localized prostate cancer. In particular, the current epidemiological and mechanistic evidence for interactions between obesity and prostate cancer are discussed. Obesity is associated with alterations in androgen levels, decreased sex hormone binding globulin and increased estrogen levels, insulin resistance, hyperglycemia, alterations in plasma lipoprotein levels particularly raised triglycerides and reduced high density lipoprotein, decreased levels of adiponectin, and increased levels of circulating insulin-growth factor- 1, leptin and dietary saturated fats. Obese men have more aggressive prostate cancer with a greater percentage prostate involvement, increased tumor volume and higher-grade disease, enlarged prostates, high prostate-specific antigen levels, increased risk of having positive margins and recurrence. Moreover, there is strong evidence of the beneficial effects of functional foods for the treatment of obesity. Additionally, an increasing number of studies support that obesity-induced inflammation plays an important role in the development of obesity-related pathologies. Despite, the beneficial role of nutriment in prostate cancer control, the use of functional foods in prostate cancer is not recommended for lack of large epidemiological studies. This data supports the hypothesis that obese men have more aggressive prostate cancers and that the obesity is a modifiable risk factor of prostate cancer. Key Words: prostate cancer, metabolic syndrome, obesity, high BMI, risk factor, diet, functional foods.

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Rocha-Rodrigues, Sílvia, Andreia Matos, José Afonso, Miguel Mendes-Ferreira, Eduardo Abade, Eduardo Teixeira, Bruno Silva, Eugenia Murawska-Ciałowicz, Maria José Oliveira, and Ricardo Ribeiro. "Skeletal Muscle–Adipose Tissue–Tumor Axis: Molecular Mechanisms Linking Exercise Training in Prostate Cancer." International Journal of Molecular Sciences 22, no. 9 (April 25, 2021): 4469. http://dx.doi.org/10.3390/ijms22094469.

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Increased visceral adiposity may influence the development of prostate cancer (PCa) aggressive tumors and cancer mortality. White adipose tissue (WAT), usually referred to as periprostatic adipose tissue (PPAT), surrounds the prostatic gland and has emerged as a potential mediator of the tumor microenvironment. Exercise training (ET) induces several adaptations in both skeletal muscle and WAT. Some of these effects are mediated by ET-induced synthesis and secretion of several proteins, known as myo- and adipokines. Together, myokines and adipokines may act in an endocrine-like manner to favor communication between skeletal muscle and WAT, as they may work together to improve whole-body metabolic health. This crosstalk may constitute a potential mechanism by which ET exerts its beneficial role in the prevention and treatment of PCa-related disorders; however, this has not yet been explored. Therefore, we reviewed the current evidence on the effects of skeletal muscle–WAT–tumor crosstalk in PCa, and the potential mediators of this process to provide a better understanding of underlying ET-related mechanisms in cancer.

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Kehwar, Than S., Heather A. Jones, M. Saiful Huq, and Ryan P. Smith. "Changes in radiobiological parameters in 131Cs permanent prostate implants." Journal of Radiotherapy in Practice 12, no. 1 (March 2013): 66–79. http://dx.doi.org/10.1017/s146039691200009x.

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AbstractIn prostate permanent implants using 131Cs seeds, the prostatic edema developed during the implantation procedure, increases the separation between the seeds. This leads to a decrease in the prostate coverage and thus causes an edema induced dose reduction, which results in an increase in tumour cell surviving fraction (SF) with a corresponding decrease in tumour control probability (TCP). To investigate the impact of edema on the SF and the TCP, the expression of the SF of the linear quadratic (LQ) model was extended to account for the effects of edema using the exponential nature of edema resolution and the dose delivered to the edematous prostate. The SF and the TCP for edematous prostate implants were calculated for 31 patients who underwent real time 131Cs permanent seed implantation. The dose delivered to the edematous prostate was calculated to compute the SF and the TCP for these patients for edema half lives (EHL) ranging from 4 days to 34 days and for edemas of magnitudes (M0) varying from 5 to 60% of the actual prostate volume.A reduction in the dose delivered to the edematous prostate was found with the increase of EHL and edema magnitude which results in an increase of the SF, and corresponding decrease in the TCP. The dose reductions in 131Cs implants varied from 1.1% (for EHL = 4 days and M0 = 5%) to 32.3% (for EHL = 34 days and M0 = 60%). These are higher than the dose reduction in 125I implants, which vary from 0.3% (for EHL = 4 days and M0 = 5%) to 17.5% (for EHL = 34 days and M0 = 60%). As edema half life increased from 4 days to 34 days and edema magnitude increased from 5 to 60% the SF increased by 4.57 log, and the TCP decreased by 0.80. Compensation of edema induced increase in the SF and decrease in the TCP in 131Cs seed implants should be carefully done by redefining seed positions with the guidance of post-needle plans. The presented model in this study can be used to estimate the SF or the TCP for pre plan or real time permanent prostate implants using day 0 post-implant CT images.

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Landriscina, M., C. Bagalà, A. Piscazzi, M. Quirino, N. Maiorano, G. Schinzari, A. Fabiano, A. Cassano, and C. Barone. "Nevirapine restores hormone sensitivity in undifferentiated androgen-refractory prostate carcinoma cells." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13149. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13149.

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13149 Background: The majority of prostate carcinomas are hormone-dependent tumors and androgen deprivation is the mainstay of therapy for advanced prostate cancer. However, androgen deprivation is ineffective on intermediate androgen-independent cells that are responsible for the hormone-refractory prostate cancer progression. Furthermore, other signaling pathways - i.e. EGF - can provide additional molecular mechanisms contributing to androgen-independent tumor progression. Reverse transcriptase (RT) inhibitors represent differentiating agents able to induce a reprogramming of gene expression in several human tumor cell models. Indeed, nevirapine and efavirenz, two widely used RT inhibitors, block the activity of endogenous RT, a gene highly expressed in tumor cells. Methods: We evaluated the ability of nevirapine to antagonize tumor growth and induce hormone sensitivity in androgen-independent human prostate tumor PC-3 cells either in vitro or in vivo. Results: Nevirapine induced the expression of several molecular markers of an androgen-dependent phenotype, such androgen receptor (AR), PSA and K18 and a reduced expression of K5, a marker of the intermediate-cell phenotype. Indeed, nevirapine enhanced the ability of prostate tumor cells to up-regulate AR in response to dihidrotestosterone. Moreover, the pharmacological inhibition of RT resulted in a significant reprogramming of gene expression, characterized by down-regulation of the notch family receptors, the EGFR1, the VEGF receptor KDR, the FGF family receptors, as well as the angiogenic factors VEGF and FGF1. Interestingly, this exocrine differentiated phenotype correlated with a reversible inhibition of cell proliferation and migration in response to nevirapine. Furthermore, the treatment of mice xenografts of prostate carcinoma cells with efavirenz and nevirapine resulted in the inhibition of tumor growth and in a reduced tumorigenic potential of cells. Conclusions: These findings suggest that RT inhibition is able to convert the androgen-independent intermediate-cell phenotype into an androgen-dependent exocrine luminal phenotype and support the need for clinical trials to test the ability of RT inhibitors and LH-RH analogs in androgen-independent prostate tumors. No significant financial relationships to disclose.

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