Ο μεταγραφικός παράγοντας PPARγ ανήκει στην οικογένεια των πυρηνικών ορμονικών υποδοχέων και διαδραματίζει σημαντικό ρόλο στην διαδικασία της καρκινογένεσης του προστάτη, συμμετέχοντας στην κυτταρική διαφοροποίηση, στη ρύθμιση της γονιδιακής έκφρασης, στην ενεργοποίηση ή καταστολή της μεταγραφής συγκεκριμένων γονιδίων, στη ρύθμιση του κυτταρικού κύκλου, στην απόπτωση, στην αναστολή της αγγειογένεσης, στην διεισδυτική ικανότητα και στο μεταστατικό δυναμικό του αδενοκαρκινώματος του προστάτη, καθώς επίσης και στο μεταβολικό μονοπάτι του αραχιδονικού οξέος μέσω αναστολής της κυκλο-οξυγενάσης 2. O ΡΡΑRγ φαίνεται να διαθέτει αντινεοπλασματική δράση, η οποία μπορεί να χρησιμοποιηθεί τόσο στην χημειοπροφύλαξη, όσο και στην χημειοθεραπευτική αντιμετώπιση του αδενοκαρκινώματος του προστάτη. / The transcription factor PPARγ is a member of the superfamily of the nuclear hormone receptors and plays a significant role in the carcinogenesis of the prostate. PPARγ participates and controls various cellular functions, necessary for the malignant transformation of the prostatic cell, such as the cellular differentiation, the gene expression, the activation or repression of the transcription of various genes, the control of the cell cycle, the apoptosis, the inhibition of aggiogenesis, the invasive and metastatic potential of the adenocarcinoma and finally the metabolic pathway of the arachidonic acid, through inhibition of the COX-2. The antiproliferative functions of PPARγ can be used for the chemoprevention and as an adjuvant in the chemotherapeutic regimens targetting the adenocarcinoma of the prostate.

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a metalloproteinase which becomes upregulated in prostate cancer and has been implicated in processes of prostate cancer metastasis. Here, we show that MT1-MMP is minimally expressed in nonmalignant primary prostate cells, moderately expressed in DU-145 cells, and highly expressed in invasive PC-3 and PC-3N cells. Using MT1-MMP promoter reporters and mobility shift assays, we show that Sp1 regulates MT1-MMP expression in DU-145, PC-3, and PC-3N cells and in PC3-N cells using chromatin immunoprecipitation analysis and silencing RNA. Investigation of signaling pathways in these cells showed that DU-145 cells express constitutively phosphorylated extracellular stress-regulated kinase (ERK), whereas PC-3 and PC-3N cells express constitutively phosphorylated AKT/PKB and c-Jun NH2 terminal kinase (JNK). We show that MT1-MMP and Sp1 levels are decreased in PC-3 and PC-3N cells when PI-3K and JNK are inhibited, and that MT1-MMP levels are decreased in DU-145 cells when MEK is inhibited. Transient transfection of PC-3 and PC-3N cells with a dominant-negative JNK or p85, and DU-145 cells with a dominant negative ERK, reduced MT1-MMP promoter activity. We also identified the insulin-like growth factor (IGF-1R) as an upstream regulatory component of MT1-MMP in PC-3N and LNCaP cells, which express high and low levels of the enzyme, respectively. Treatment of PC-3N cells with an IGF-1R specific inhibitor decreased MT1-MMP promoter activity, RNA and protein levels. Additionally, treatment of LNCaP cells with a synthetic androgen to increase IGF-1R levels and subsequent treatment with IGF-I increased MT1-MMP promoter activity, RNA and protein levels. Analysis of MT1-MMP and IGF-1R expression in human prostate cancer tissues demonstrated that MT1-MMP expression was high in the apical cytoplasmic regions of PIN and prostate cancer and less intense in the basalateral cytoplasmic membrane regions of benign glands. IGF-1R was expressed in normal glands and highly expressed in prostate cancer. In conclusion, we have identified several novel mechanisms regulating MT1-MMP expression in prostate cancer cell lines as well as differential localization of the enzyme in human prostate cancer tissues. These results provide insight into the complex mechanisms of prostate cancer metastasis and may be useful for developing future diagnostic procedures or therapies.

For cancer cells to initiate cell migration and progress to metastasize, epithelial genes must be silenced and the expression of mesenchymal genes must be upregulated. During prostate carcinogenesis, E-cadherin expression is downregulated through multiple mechanisms, the majority of which combine to silence E-cadherin expression through transcriptional regulation at the level of the E-cadherin promoter. Recently it has been discovered that there is transcriptional upregulation of the mesenchymal cadherin, N-cadherin during prostate cancer metastasis. Although N-cadherin expression can be detected in human prostate cancer and in prostate carcinoma cell lines, the mechanisms controlling the transcriptional regulation of N-cadherin in cancer are uncharacterized. This body of work offers the first evidence for the mechanisms controlling the transcriptional upregulation of N-cadherin expression in prostate carcinoma. We utilized anchorage independent culture to induce downregulation of N-cadherin expression, and then analyzed the necessary events for N-cadherin upregulation when cells attached to Fibronetin (FN). In order to determine the functional regions of the N-cadherin proximal promoter that were involved in the upregulation of N-cadherin expression, we cloned regions of the human N-cadherin 5’ proximal promoter, and regions of the first intron of the N-cadherin gene into a luciferase reporter vector. It was determined that the bHLH transcription factor Twist1 controlled the upregulation of N-cadherin transcription in PC-3 cells, through β1 integrin dependent nuclear localization of Twist1. A cis-element located in the first intron of the N-cadherin gene was shown to be necessary for Twist1 mediated effects on the N-cadherin promoter. We then determined the requirements for cell-type specific expression of the N-cadherin promoter. It was determined that an additional cis-element located in the first intron of the N-cadherin gene was necessary to repress N-cadherin promoter activity in cells lacking N-cadherin. Through deletion analysis of the N-cadherin promoter luciferase construct, a DNA binding site for the transcription factor FoxP1 was discovered. FoxP1 binds to the repressive cis-element in vitro, and mutation of the FoxP1 DNA binding site eliminated cell-type specific activity of the N-cadherin promoter. Therefore, we have documented that the aberrant expression of N-cadherin in prostate carcinoma involves alterations in both positive and negative transcriptional regulators.

Aim: The aims of this essay were first to see if there were any factors that could have an inpact on participating in supportive care groups and activities after a prostatic cancer diagnosis. The second aim was to examine what kind of support the patients would chose.   Methods: Data was collected with a survey handed out to the prostate cancer patients visiting the urologist reception at the hospital in Uppsala, during two weeks in the fall of 2011.   Main Results: Men show very little interest in participating in supportive care groups and activities. When asked to chose which kind of support they could consider, individual sessions and group sessions were the most common choice.   Conclusion: Men diagnosed with prostate cancer chose not to participate in supportive care. Further studies are required to determine what may be the reason to that. / Syfte: Syftet med detta arbete var att se om olika faktorer kunde påverka deltagande i stödverksamhet efter att patienten fått diagnosen prostatacancer, samt vilken form av psykosocialt stöd patienterna föredrar.    Metod: Metoden som använts var en enkätstudie med både kvantitativ ansats, som delades ut under hösten 2011 till prostatacancerpatienter på urologmottagningen, Akademiska sjukhuset.   Huvudresultat: Män anger att de inte är intresserade av att delta i stödverksamhet efter diagnos och eventuell behandling. Vid behov ansåg de att enskilda eller gruppsamtal var mest relevanta som stödverksamheter. Informanterna ansåg att rehabilitering med samtal och yoga hade minst relevans.   Slutsats: Män som drabbats av prostatacancer väljer att inte delta i stödverksamhet. Behov finns därför av att utföra mer studier för att klargöra orsakerna till detta.

As the most frequently diagnosed cancer in North American men, prostate cancer can progress to the androgen independent stage after initial response to androgen ablation therapy. The molecular mechanisms involved in the hormonal progression of prostate cancer are not completely understood. Here, we analyze changes in the transcriptome of prostate cancer cells at different stages of progression to reveal potential mechanisms. Applying Affymetrix GeneChip technology, we identified the transcriptomes in response to stimulation of androgen and PKA pathways in human prostate cancer cells. In addition to PSA, other common target genes were identified. Genes differentially expressed in response to androgen and stimulation of the PKA pathway in vitro were also differentially expressed during hormonal progression in vivo. Upon androgen stimulation, androgen receptor binds to a functional androgen response element within the promoter region of SESN1, a p53 targeted gene, and represses its expression. The expression of SESN1 was induced by castration in LNCaP xenografts, but the expression was eventually suppressed again in the androgen independent stage of prostate cancer. Knockdown of SESN1 promoted the proliferation of prostate cancer cells. Expression patterns of androgen-regulated genes in androgen independent tumours were revealed to be more similar to that from before castration than to the tumors under androgen ablation. The β-catenin, a potent coactivator of the androgen receptor, and Wnt pathway was deregulated in androgen-independent tumours. There was increased nuclear colocalization and interaction of androgen receptor and β-catenin with hormonal progression of prostate cancer. This study provides insight into hormonal effects on prostate cancer and possible pathways involved in the development of androgen independent disease, as well as potential therapeutic targets.

The mechanism by which prostate cancer progresses from androgen dependence (AD) to androgen independence/castration resistance (AI/CR) is currently a major focus of prostate cancer-related research. Prostate cancers that progress to a state of AI/CR are typically resistant to most standard types of treatments. Due to its primary role in driving normal prostate cell growth and proliferation, the androgen receptor (AR) is believed to play a key role in progression. Coregulators, or any proteins which may either enhance or abrogate AR activity, are considered to be one of the potential mechanisms by which AR function may become impaired. Cyclin G-associated kinase (GAK) was initially identified as a potential coregulator of AR in a Tup 1 repressed transactivation system. A LNCaP cDNA library was screened for proteins which interacted with the NH2-terminus of AR. GAK was isolated from three independent library clones using two different AR baits (AR 1-549 and AR 1-646). This interaction was confirmed via GST pulldown and coimmunoprecipitation experiments, and preliminary luciferase assays suggested that GAK activates AR in a hormone dependent manner. In this study, my objectives were to validate GAK’s role as a coregulator of AR and to determine if overexpressing GAK affects progression to AI. In vitro luciferase assays whereby GAK was either overexpressed or knocked down in both LNCaP and PC3 cells did not significantly affect AR activity. Xenograft experiments utilizing a doxycycline (DOX) inducible lentiviral LNCaP-GAK overexpressing stable cell line demonstrated that while GAK may not play a significant role in modulating AR activity, it may adopt a more subtle role enhancing tumour take and tumour volume growth rate in vivo. While these results could not confirm GAK to be a direct coregulator of AR, it is entirely possible that GAK may influence prostate cancer progression, albeit indirectly. Recent publications report a growing amount of evidence suggesting GAK’s involvement in the critical cellular process of clathrin coated vesicle endocytosis, the dysregulation of which could potentially indirectly affect AR regulated genes.

Numerous studies have demonstrated that tumour cells have the ability to alter immune function to create an immune suppressed environment. This allows tumour cells to escape immune surveillance and consequently the tumour can progress. Dendritic and T cells have critical roles in immune activation and tolerance and are thus major targets of tumour-mediated immune suppression. Understanding the mechanism(s) by which tumour cells modulate the immune system will facilitate the development of immune system-based therapies for cancer treatments. In this study we sought to determine the nature of, and cellular and molecular mechanisms underlying, changes in immune status during tumour progression using mouse models of prostate cancer. Detailed analysis of the immunological status in a mouse prostate dysplasia model (12T-7slow) revealed that immune suppression accompanied tumour progression. We found that T cells isolated from tumour-bearing hosts were hypo-responsive to antigen stimulation. Furthermore, we demonstrated that CD4+CD25+ regulatory T cells were responsible, at least in part, for this alteration. Anti-CD25 antibody treatment reduced, but did not prevent, tumour growth in either a transplanted prostate tumour model or a spontaneously developing prostate tumour model. In addition, an altered dendritic cell phenotype and an elevated frequency of CD4+CD25+ regulatory T cells were observed within the tumour mass. Similar alterations were observed in the prostate-specific Pten knockout mice which develop advanced prostate adenocarcinoma. Interestingly, evidence of immune activation, such as an increased frequency of activated T cells, was detected in the tumour microenvironment in both mouse prostate tumour models. To identify factors that may play critical roles in the altered immune cell phenotype observed in the tumour microenvironment, a global gene expression profiling analysis was carried out to evaluate the changes in immune-related gene expression patterns. This analysis provided additional evidence for the co-existence of immune suppression and immune activation. Moreover, subsequent analyses suggested that one differentially expressed transcript, interferon regulatory factor 7, and its target genes might be involved in modulating immune cells and/or tumour progression. Taken together, these studies have important implications for designing specific and effective anti-tumour immune therapy strategies that involve manipulation of tumour cells, dendritic cells and regulatory T cells.

Prostate cancer is the most commonly diagnosed cancer in Canadian males, and is the third most common cause of cancer related deaths with decreasing mortality in men. Previous studies have suggested that an increased risk of prostate cancer among men may be associated with rural environment. The etiology of prostate cancer is not precisely known among men in rural Saskatchewan. We investigated the prevalence of prostate cancer and the putative relationship between rural exposures (occupational i.e. farming and environmental), personal smoking history, family history of cancer and prostate cancer. A baseline mail out survey was conducted in 2010-2011 of 11,982 households located in four geographic regions (South West, South East, North West, and North East) of Saskatchewan, Canada. Completed questionnaires were obtained from 4,624 households (8,261 individuals). The questionnaires collected information on individual (demographic factors, exposure to pesticides including insecticides, herbicides and fungicides) and contextual (household characteristics such as income, smoking) determinants from a rural population. In total 2,938 males (114 prostate cancer cases) were included for this analysis who were older than 45 years. Logistic regression analysis was used to analyze the relationship between independent variables and prostate cancer. Among prostate cancer cases, 46% of men lived on farms of rural Saskatchewan. The age standardized prevalence of prostate cancer was 3.32% (3.81% (n=52) and 2.95% (n=61) among farm and non-farm resident men). Farming job and farming duration did not have a statistically significant association with prostate cancer. A trend was observed for men who had work place exposure to insecticides and fungicides collectively and radiation to have an increased risk in comparison to men without these exposures. Personal smoking history, history of smoking pack years and family history of cancer modified the relationship between residence and prostate cancer. Age of an individual (≥ 65 years) was the strongest and most consistent risk factor of prostate cancer. Other factors such as marital status, household income adequacy, history of cardiovascular disease may also be associated with prostate cancer. The results may help research professionals by directing the focus of their research towards rural population examining prostate cancer.

Darbo tikslas. Atsitiktinės atrankos perspektyviniame klinkiniame tyrime nustatyti ir palyginti lokalaus priešinės liaukos vėžio įprastai frakcionuoto (CFRT) ir hipofrakcionuoto (HFRT) išorinio trimačio konforminio spindulinio gydymo sukeliamas ūmines spindulines reakcijas, gydymo efektyvumą, bei lėtines spindulines reakcijas. Tyrimo medžiaga ir metodai. CFRT taikyta 44 pacientams, švitinta prostata ir sėklinių pūslelių pagrindas 37 frakcijos po 2,0 Gy iki suminės 74 Gy dozės. HFRT taikyta 47 pacientams, toks pat taikinys švitintas 13 frakcijų po 3,0 Gy ir 4 frakcijos po 4,5 Gy iki suminės 57 Gy dozės. Pacientai stebėti mažiausiai 2 metus. Rezultatai. Ūminių 2 laipsnio šlapimo pūslės spindulinių reakcijų buvo statistiškai reikšmingai mažiau HFRT pacientų grupėje. Visų tiesiosios žarnos ūminių spindulinių reakcijų trukmė buvo mažesnė HFRT grupėje . Lėtinių šlapimo pūslės ir tiesiosios žarnos spindulinių reakcijų dažnumas pacientų grupėse nesiskyrė. Biocheminio atsako į gydymą dydis ir greitis pacientų grupėse per 2 metų stebėjimo laiką nesiskyrė. Išvados. Taikytas hipofrakcionuotas išorinis lokalaus prostatos vėžio spindulinis gydymas yra saugus, tačiau atokiam šio gydymo metodo efektyvumui nustatyti reikalingas ilgesnis pacientų stebėjimo laikas. / The aim of the study. To investigate and compare toxicity and efficacy of conventionally fractionated (CFRT) vs. hypofractionated (HFRT) three dimensional conformal external beam radiotherapy for localized prostate carcinoma within prospective randomized study. Matherial and Methods. Forty-four patients in the CFRT treatment arm were irradiated with 74 Gy in 37 fractions (2 Gy per fraction), and 47 in the HFRT arm were treated with 57 Gy, given in 13 fractions of 3 Gy plus 4 fractions of 4.5 Gy. The clinical target volume includes the prostate and a base of seminal vesicles. A minimum follow-up was 2 years. Results. The only grade 2 genitourinary acute toxicity proportion was significantly lower in the HFRT arm. The median duration of overall gastrointestinal acute toxicity was significantly shorter with HFRT. There were no statistically significant differences in the late toxicity rates, biochemical tumor response rates and time to the response between study arms during 2 year follow-up. Conclusions. The investigated hypofractionated 3DCRT for localized prostate carcinoma found to be safe, but extended follow-up is needed to justify the efficacy of our fractionation schedule in the long term.

Objectives: Men who receive androgen deprivation therapy (ADT) for prostate cancer (PCa) are at risk of several adverse effects that can be detrimental to both their physical and mental health. Common adverse effects include weight gain, muscle wasting, cardiovascular morbidity, fatigue and impaired quality of life (QOL). This study tested whether a combined aerobic and resistance exercise program can alleviate some of these symptoms in men receiving ADT. Design: Men with PCa, aged 50-80 years, receiving ADT were recruited to participate in this prospective randomized controlled trial. Subjects were assigned to a usual care group (UCG) or an exercise intervention group (EIG). The EIG completed a 16 week combined aerobic and resistance exercise program. Outcomes measures were assessed at baseline, 16 weeks, and 24 weeks and included: cardio-respiratory fitness; muscle strength and endurance; body composition; and reports of QOL, fatigue, mood, partner relations, and exercise behaviour. Results: Fifteen men were recruited to this study, but two participants in the EIG did not finish the study leaving the EIG with an n = 6 and the UCG with an n = 7. The exercise program did not lead to changes in weight, BMI or body fat. There was a small, close to significant, increase in muscle mass in the EIG over the intervention period (p = 0.052). This is encouraging as it demonstrates that exercise can counteract the catabolic effects of ADT. Interestingly, cardio-respiratory fitness improved over the course of the study for both groups. Muscular fitness, however, improved only for the EIG. There was a significant difference in chest press strength (p = 0.041) and leg press strength was bordering significance (p = 0.058). Unexpectedly, QOL declined for both groups during the intervention (p = 0.029). Participants in both groups also reported increased levels of fatigue from baseline to 24 weeks, although these changes were not significant (p = 0.586). Mood worsened over the study period for both groups from baseline to 16 weeks, but this increase in anxiety and depression was reduced at the follow-up period. These changes, too, were not significant (p = 0.364). Reports of partner relationships trended towards lower scores from baseline to 16 weeks. The men’s report in both groups and the women’s report in the EIG improved at the 24 week mark, but women in the UCG experienced further decline. Surprisingly, participants in both groups reported increases in exercise behaviour from baseline to 24 weeks. This could account for the lack of difference found in many of the measures. The power of this study was 0.22. Conclusion: Although this was a small study, it showed that a combined aerobic and resistance exercise program can have some positive benefits for men with PCa who are receiving ADT. Larger trials are needed to further examine the role of exercise in ameliorating the side effects of ADT, particularly in the areas of mood and partner relationships.