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Sample records for prostate tumor formation

  1. S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells

    International Nuclear Information System (INIS)

    Amaral, Camila L.; Freitas, Lidia B.; Tamura, Rodrigo E.; Tavares, Mariana R.; Pavan, Isadora C. B.; Bajgelman, Marcio C.; Simabuco, Fernando M.

    2016-01-01

    The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms–p70-S6K1, p85-S6K1 and p54-S6K2–in prostate cancer, as well as their potential as therapeutic targets. In this study we performed S6K knockdown and overexpression and investigated its role in prostate cancer cell proliferation, colony formation, viability, migration and resistance to docetaxel treatment. In addition, we measured tumor growth in Nude mice injected with PC3 cells overexpressing S6K isoforms and tested the efficacy of a new available S6K1 inhibitor in vitro. S6Ks overexpression enhanced PC3-luc cell line viability, migration, resistance to docetaxel and tumor formation in Nude mice. Only S6K2 knockdown rendered prostate cancer cells more sensitive to docetaxel. S6K1 inhibitor PF-4708671 was particularly effective for reducing migration and proliferation of PC3 cell line. These findings demonstrate that S6Ks play an important role in prostate cancer progression, enhancing cell viability, migration and chemotherapy resistance, and place both S6K1 and S6K2 as a potential targets in advanced prostate cancer. We also provide evidence that S6K1 inhibitor PF-4708671 may be considered as a potential drug for prostate cancer treatment. The online version of this article (doi:10.1186/s12885-016-2629-y) contains supplementary material, which is available to authorized users

  2. Inhibitory Effect of a γ-Tocopherol-Rich Mixture of Tocopherols on the Formation and Growth of LNCaP Prostate Tumors in Immunodeficient Mice

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    Zheng, Xi, E-mail: xizheng@rci.rutgers.edu [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Cui, Xiao-Xing [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Khor, Tin Oo; Huang, Ying [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); DiPaola, Robert S; Goodin, Susan [Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Lee, Mao-Jung [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Yang, Chung S [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Kong, Ah-Ng [Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Allan H, Conney [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States)

    2011-09-28

    In the present study, we determined the effects of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on the growth and apoptosis of cultured human prostate cancer LNCaP cells. We also determined the effects of dietary γ-TmT on the formation and growth of LNCaP tumors in immunodeficient mice. In the in vitro study, we found that the activity of γ-TmT was stronger than α-tocopherol for inhibiting the growth and stimulating apoptosis in LNCaP cells. In the animal study, treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT inhibited the formation and growth of LNCaP xenograft tumors in a dose-dependent manner. Mechanistic studies showed that γ-TmT administration inhibited proliferation as reflected by decreased mitosis and stimulated apoptosis as reflected by increased caspase-3 (active form) expression in LNCaP tumors. In addition, dietary administration of γ-TmT increased the levels of α-, γ- and δ- tocopherol in plasma, and increased levels of γ- and δ- tocopherol were also observed in the prostate and in tumors. The present study demonstrated that γ-TmT had strong anticancer activity both in vitro and in vivo. Additional studies are needed to determine the potential preventive effect of γ-TmT for prostate cancer in humans.

  3. Inhibitory Effect of a γ-Tocopherol-Rich Mixture of Tocopherols on the Formation and Growth of LNCaP Prostate Tumors in Immunodeficient Mice

    International Nuclear Information System (INIS)

    Zheng, Xi; Cui, Xiao-Xing; Khor, Tin Oo; Huang, Ying; DiPaola, Robert S; Goodin, Susan; Lee, Mao-Jung; Yang, Chung S; Kong, Ah-Ng; Allan H, Conney

    2011-01-01

    In the present study, we determined the effects of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on the growth and apoptosis of cultured human prostate cancer LNCaP cells. We also determined the effects of dietary γ-TmT on the formation and growth of LNCaP tumors in immunodeficient mice. In the in vitro study, we found that the activity of γ-TmT was stronger than α-tocopherol for inhibiting the growth and stimulating apoptosis in LNCaP cells. In the animal study, treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT inhibited the formation and growth of LNCaP xenograft tumors in a dose-dependent manner. Mechanistic studies showed that γ-TmT administration inhibited proliferation as reflected by decreased mitosis and stimulated apoptosis as reflected by increased caspase-3 (active form) expression in LNCaP tumors. In addition, dietary administration of γ-TmT increased the levels of α-, γ- and δ- tocopherol in plasma, and increased levels of γ- and δ- tocopherol were also observed in the prostate and in tumors. The present study demonstrated that γ-TmT had strong anticancer activity both in vitro and in vivo. Additional studies are needed to determine the potential preventive effect of γ-TmT for prostate cancer in humans

  4. Trimethoxy-resveratrol and piceatannol administered orally suppress and inhibit tumor formation and growth in prostate cancer xenografts

    Science.gov (United States)

    Resveratrol (Res) is recognized as a promising cancer chemoprevention dietary polyphenol with antioxidative, anti-inflammatory and anticancer properties. However, the role of its analogues in prostate cancer (PCa) chemoprevention is still unknown. METHODS. We synthesized natural and synthetic anal...

  5. Circulating Tumor Cells in Prostate Cancer

    International Nuclear Information System (INIS)

    Hu, Brian; Rochefort, Holly; Goldkorn, Amir

    2013-01-01

    Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management

  6. Acute bacterial prostatitis and abscess formation.

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    Lee, Dong Sup; Choe, Hyun-Sop; Kim, Hee Youn; Kim, Sun Wook; Bae, Sang Rak; Yoon, Byung Il; Lee, Seung-Ju

    2016-07-07

    The purpose of this study was to identify risk factors for abscess formation in acute bacterial prostatitis, and to compare treatment outcomes between abscess group and non-abscess group. This is a multicenter, retrospective cohort study. All patients suspected of having an acute prostatic infection underwent computed tomography or transrectal ultrasonography to discriminate acute prostatic abscesses from acute prostatitis without abscess formation. A total of 31 prostate abscesses were reviewed among 142 patients with acute prostatitis. Univariate analysis revealed that symptom duration, diabetes mellitus and voiding disturbance were predisposing factors for abscess formation in acute prostatitis. However, diabetes mellitus was not related to prostate abscess in multivariate analysis. Patients with abscesses 20 mm who underwent transurethral resection had a shorter duration of antibiotic treatment than did those who did not have surgery. Regardless of surgical treatment, both the length of hospital stay and antibiotic treatment were longer in patients with prostatic abscesses than they were in those without abscesses. However, the incidence of septic shock was not different between the two groups. A wide spectrum of microorganisms was responsible for prostate abscesses. In contrast, Escherichia coli was the predominant organism responsible for acute prostatitis without abscess. Imaging studies should be considered when patients with acute prostatitis have delayed treatment and signs of voiding disturbance. Early diagnosis is beneficial because prostatic abscesses require prolonged treatment protocols, or even require surgical drainage. Surgical drainage procedures such as transurethral resection of the prostate were not necessary in all patients with prostate abscesses. However, surgical intervention may have potential merits that reduce the antibiotic exposure period and enhance voiding function in patients with prostatic abscess.

  7. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation

    NARCIS (Netherlands)

    Hamid, A.R.; Verhaegh, G.W.C.T.; Smit, F.P.; RIjt-van de Westerlo, C.; Armandari, I.; Brandt, A.; Sweep, F.C.; Sedelaar, J.P.M.; Schalken, J.A.

    2015-01-01

    PURPOSE: Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are

  8. Tumor clone dynamics in lethal prostate cancer.

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    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; S de Bono, Johann; Demichelis, Francesca; Attard, Gerhardt

    2014-09-17

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. Copyright © 2014, American Association for the Advancement of Science.

  9. Characterization of Heterogeneous Prostate Tumors in Targeted Pten Knockout Mice.

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    Hanneke Korsten

    Full Text Available Previously, we generated a preclinical mouse prostate tumor model based on PSA-Cre driven inactivation of Pten. In this model homogeneous hyperplastic prostates (4-5m developed at older age (>10m into tumors. Here, we describe the molecular and histological characterization of the tumors in order to better understand the processes that are associated with prostate tumorigenesis in this targeted mouse Pten knockout model. The morphologies of the tumors that developed were very heterogeneous. Different histopathological growth patterns could be identified, including intraductal carcinoma (IDC, adenocarcinoma and undifferentiated carcinoma, all strongly positive for the epithelial cell marker Cytokeratin (CK, and carcinosarcomas, which were negative for CK. IDC pattern was already detected in prostates of 7-8 month old mice, indicating that it could be a precursor stage. At more than 10 months IDC and carcinosarcoma were most frequently observed. Gene expression profiling discriminated essentially two molecular subtypes, denoted tumor class 1 (TC1 and tumor class 2 (TC2. TC1 tumors were characterized by high expression of epithelial markers like Cytokeratin 8 and E-Cadherin whereas TC2 tumors showed high expression of mesenchyme/stroma markers such as Snail and Fibronectin. These molecular subtypes corresponded with histological growth patterns: where TC1 tumors mainly represented adenocarcinoma/intraductal carcinoma, in TC2 tumors carcinosarcoma was the dominant growth pattern. Further molecular characterization of the prostate tumors revealed an increased expression of genes associated with the inflammatory response. Moreover, functional markers for senescence, proliferation, angiogenesis and apoptosis were higher expressed in tumors compared to hyperplasia. The highest expression of proliferation and angiogenesis markers was detected in TC2 tumors. Our data clearly showed that in the genetically well-defined PSA-Cre;Pten-loxP/loxP prostate tumor

  10. Prostatic Adenocarcinoma with Concurrent Sertoli Cell Tumor in a Dog

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    Gill, C. W.

    1981-01-01

    A case of metastatic prostatic adenocarcinoma with concurrent Sertoli cell tumor is presented in an old, miniature Schnauzer dog. The prostatic neoplasm was highly anaplastic and had metastasized widely. Clinical signs were compatible with increased estrogen production. It is interesting to note that the prostatic carcinoma, usually considered to be androgen dependent, developed and metastasized, despite the presence of apparently increased estrogen levels. ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 5.Figure 6. PMID:7340923

  11. Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

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    2017-12-01

    is associated with androgen receptor (AR). We detected Oct4 protein expression in prostate cancer cells as well as in tumor tissue specimens...unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Identification of genes driving prostate carcinogenesis will lead to new cancer treatment. The human...a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due to the gene expression of POU5F1B

  12. Molecular differences in transition zone and peripheral zone prostate tumors

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    Sinnott, Jennifer A.; Rider, Jennifer R.; Carlsson, Jessica; Gerke, Travis; Tyekucheva, Svitlana; Penney, Kathryn L.; Sesso, Howard D.; Loda, Massimo; Fall, Katja; Stampfer, Meir J.; Mucci, Lorelei A.; Pawitan, Yudi; Andersson, Sven-Olof; Andrén, Ove

    2015-01-01

    Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20–30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P zones. Zone of origin may be important to consider in prostate tumor biomarker research. PMID:25870172

  13. Identification and Reconstruction of Prostate Tumor-Suppressing Exosomes for Therapeutic Applications

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    2016-03-01

    to the altered contents of exosomes , those from prostate cancer cells (tumor exosomes ) no longer have tumor suppressive functions. If this... cancer . To develop this concept, exosomes will be isolated from normal prostate epithelial cells by differential centrifugations or affinity...purifications and evaluated for tumor suppressing activities against various prostate cancer cells (Aim 1). Then the components of the tumor suppressing exosomes

  14. Transcriptome sequencing in prostate cancer identifies inter-tumor heterogeneity

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    Janet Mendonca

    2015-06-01

    Full Text Available Given the dearth of gene mutations in prostate cancer, [1] ,[2] it is likely that genomic rearrangements play a significant role in the evolution of prostate cancer. However, in the search for recurrent genomic alterations, "private alterations" have received less attention. Such alterations may provide insights into the evolution, behavior, and clinical outcome of an individual tumor. In a recent report in "Genome Biology" Wyatt et al. [3] defines unique alterations in a cohort of high-risk prostate cancer patient with a lethal phenotype. Utilizing a transcriptome sequencing approach they observe high inter-tumor heterogeneity; however, the genes altered distill into three distinct cancer-relevant pathways. Their analysis reveals the presence of several non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression.

  15. Naked DNA Immunization for Prevention of Prostate Cancer in a Dunning Rat Prostate Tumor Model

    National Research Council Canada - National Science Library

    Mincheff, Milcho

    2003-01-01

    ...: H-PSMA-T, R-"PSMA"-T, H-PSA, H-PSA-T, H-PAP-T and R"PSMA"-S. Preliminary studies using the Copenhagen rat tumor prostate model showed uniform tumor development in rats that were injected subcutaneously with 100 000 AT3B-lPSMA,PSA cells...

  16. On complex preparation for radiotherapy of prostatic tumor patients

    International Nuclear Information System (INIS)

    Tkachev, S.I.

    1980-01-01

    An experience with the treatment of 62 patients with prostatic gland tumor has contributed to the elaboration of some approaches to the utilization of modern diagnostic facilities in order to define the spread of neoplastic process and select therapeutic tactics. A sequence of methods to be used has been described, including clinical and X-ray, radioisotope and ultrasonic methods of examination. The matter of particular attention is a newly developed method of the prostatic gland cranio-caudal size determination. The latter together with ultrasonic data enable one to detect the size of the tumor and select an adequate physico-technical regime of irradiation for each individual patient

  17. Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

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    Chua, Chee Wai; Epsi, Nusrat J; Leung, Eva Y; Xuan, Shouhong; Lei, Ming; Li, Bo I; Bergren, Sarah K; Hibshoosh, Hanina; Mitrofanova, Antonina

    2018-01-01

    Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer. PMID:29334357

  18. BMI-1 targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer

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    Yusuff, Shamila; Davis, Stephani; Flaherty, Kathleen; Huselid, Eric; Patrizii, Michele; Jones, Daniel; Cao, Liangxian; Sydorenko, Nadiya; Moon, Young-Choon; Zhong, Hua; Medina, Daniel J.; Kerrigan, John; Stein, Mark N.; Kim, Isaac Y.; Davis, Thomas W.; DiPaola, Robert S.; Bertino, Joseph R.; Sabaawy, Hatem E.

    2016-01-01

    Purpose Current prostate cancer (PCa) management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy-resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. Experimental design We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient derived prostate cancer cells and xenograft models to characterize the effects of pharmacological inhibitors of BMI-1. Results We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacological inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor (AR)-directed therapies, without toxic effects on normal tissues. Conclusions Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective PCa treatment. PMID:27307599

  19. Tumor-Associated Antigens for Specific Immunotherapy of Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kiessling, Andrea [Biologics Safety and Disposition, Preclinical Safety, Translational Sciences, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Werk Klybeck, Klybeckstraße 141, Basel CH-4057 (Switzerland); Wehner, Rebekka [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Füssel, Susanne [Department of Urology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Bachmann, Michael [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Wirth, Manfred P. [Department of Urology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Schmitz, Marc, E-mail: marc.schmitz@tu-dresden.de [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany)

    2012-02-22

    Prostate cancer (PCa) is the most common noncutaneous cancer diagnosis and the second leading cause of cancer-related deaths among men in the United States. Effective treatment modalities for advanced metastatic PCa are limited. Immunotherapeutic strategies based on T cells and antibodies represent interesting approaches to prevent progression from localized to advanced PCa and to improve survival outcomes for patients with advanced disease. CD8{sup +} cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4{sup +} T cells augment the antigen-presenting capacity of dendritic cells and promote the expansion of tumor-reactive CTLs. Antibodies mediate their antitumor effects via antibody-dependent cellular cytotoxicity, activation of the complement system, improving the uptake of coated tumor cells by phagocytes, and the functional interference of biological pathways essential for tumor growth. Consequently, several tumor-associated antigens (TAAs) have been identified that represent promising targets for T cell- or antibody-based immunotherapy. These TAAs comprise proteins preferentially expressed in normal and malignant prostate tissues and molecules which are not predominantly restricted to the prostate, but are overexpressed in various tumor entities including PCa. Clinical trials provide evidence that specific immunotherapeutic strategies using such TAAs represent safe and feasible concepts for the induction of immunological and clinical responses in PCa patients. However, further improvement of the current approaches is required which may be achieved by combining T cell- and/or antibody-based strategies with radio-, hormone-, chemo- or antiangiogenic therapy.

  20. Quantification of tumor extension in prostate biopsies: importance in the identification of confined tumors

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    Leite Kátia R.M.

    2003-01-01

    Full Text Available OBJECTIVE: To assess the importance of quantifying the adenocarcinoma in prostate biopsies when determining the tumor's final stage in patients who undergo radical prostatectomy. To identify the best methodology for obtaining such data. PATIENTS AND METHODS: Prostate biopsies from 132 patients were examined, with determination of Gleason histological grade and tumor volume in number of involved fragments, tumor extent of the fragment mostly affected by the tumor and the total percentage of tumor in the specimen. Theses parameters were statistically correlated with the neoplasia's final stage following the evaluation of radical prostatectomy specimens. RESULTS: An average of 12 and a median of 14 biopsy fragments were evaluated per patient. In the univariate analysis the Gleason histological grade, the largest tumor extent in one fragment and the total percentage of tumor in the specimen were correlated with tumor stage of the surgical specimen. In the multivariate analysis, the Gleason histological grade and the total percentage of tumor were strongly correlated with the neoplasia's final stage. The risk of the tumor not being confined was 3 for Gleason 7 tumors and 10.6 for Gleason 8 tumors or above. In cases where the tumor involved more than 60% of the specimen, the risk of non-confined disease was 4.4 times. Among 19 patients with unfavorable histological parameters, Gleason > 7 and extension greater than 60% the tumor final stage was pT3 in 95%. CONCLUSION: When associated to the Gleason histological grade, tumor quantification in prostate biopsies is an important factor for determining organ-confined disease, and among the methods, total percentage of tumor is the most informative one. Such data should be included in the pathological report and must be incorporated in future nomograms.

  1. Hedgehog pathway activity in the LADY prostate tumor model

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    Kasper Susan

    2007-03-01

    Full Text Available Abstract Background Robust Hedgehog (Hh signaling has been implicated as a common feature of human prostate cancer and an important stimulus of tumor growth. The role of Hh signaling has been studied in several xenograft tumor models, however, the role of Hh in tumor development in a transgenic prostate cancer model has never been examined. Results We analyzed expression of Hh pathway components and conserved Hh target genes along with progenitor cell markers and selected markers of epithelial differentiation during tumor development in the LADY transgenic mouse model. Tumor development was associated with a selective increase in Ihh expression. In contrast Shh expression was decreased. Expression of the Hh target Patched (Ptc was significantly decreased while Gli1 expression was not significantly altered. A survey of other relevant genes revealed significant increases in expression of Notch-1 and Nestin together with decreased expression of HNF3a/FoxA1, NPDC-1 and probasin. Conclusion Our study shows no evidence for a generalized increase in Hh signaling during tumor development in the LADY mouse. It does reveal a selective increase in Ihh expression that is associated with increased expression of progenitor cell markers and decreased expression of terminal differentiation markers. These data suggest that Ihh expression may be a feature of a progenitor cell population that is involved in tumor development.

  2. Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes.

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    Yan, Lisa; Da Silva, Diane M; Verma, Bhavna; Gray, Andrew; Brand, Heike E; Skeate, Joseph G; Porras, Tania B; Kanodia, Shreya; Kast, W Martin

    2015-02-15

    LIGHT, a ligand for lymphotoxin-β receptor (LTβR) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LTβR signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LTβR has been previously shown to activate immune cells and result in tumor regression in a virally-induced tumor model, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration toward an anti-tumoral milieu, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors. Real Time PCR was used to evaluate expression of forced LIGHT and other immunoregulatory genes in prostate tumors samples. For in vivo studies, adenovirus encoding murine LIGHT was injected intratumorally into TRAMP-C2 prostate cancer cell tumor bearing mice. Chemokine and cytokine concentrations were determined by multiplex ELISA. Flow cytometry was used to phenotype tumor infiltrating lymphocytes and expression of LIGHT on the tumor cell surface. Tumor-specific lymphocytes were quantified via ELISpot assay. Treg induction and Treg suppression assays determined Treg functionality after LIGHT treatment. LIGHT in combination with a therapeutic vaccine, PSCA TriVax, reduced tumor burden. LIGHT expression peaked within 48 hr of infection, recruited effector T cells that recognized mouse prostate stem cell antigen (PSCA) into the tumor microenvironment, and inhibited infiltration of Tregs. Tregs isolated from tumor draining lymph nodes had impaired suppressive capability after LIGHT treatment. Forced LIGHT treatment combined with PSCA TriVax therapeutic vaccination delays prostate cancer progression in mice by recruiting effector T lymphocytes to the tumor and inhibiting Treg mediated

  3. Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

    National Research Council Canada - National Science Library

    Pasquale, Elena B

    2007-01-01

    Mutations have been recently identified in the EphB2 receptor gene in prostate cancer suggesting that EphB2, a member of the large Eph receptor tyrosine kinase family, is a tumor suppressor in prostate cancer...

  4. Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

    National Research Council Canada - National Science Library

    Pasquale, Elena B

    2006-01-01

    Mutations have been recently identified in the EphB2 receptor gene in prostate cancer suggesting that EphB2, a member of the large Eph receptor tyrosine kinase family, is a tumor suppressor in prostate cancer...

  5. The Effect of Tumor-Prostate Ratio on Biochemical Recurrence after Radical Prostatectomy

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    Sung Yong Cho

    2016-08-01

    Full Text Available Purpose: Prostate tumor volume calculated after surgery using pathologic tissue has been shown to be an independent risk factor for biochemical recurrence. Nonetheless, prostate size varies among individuals, regardless of the presence or absence of cancer. We assumed to be lower margin positive rate in the surgical operation, when the prostate volume is larger and the tumor lesion is same. Thus, we defined the tumor-prostate ratio in the ratio of tumor volume to prostate volume. In order to compensate the prostate tumor volume, the effect of tumor-prostate ratio on biochemical recurrence was examined. Materials and Methods: This study included 251 patients who underwent open retropubic radical prostatectomy for prostate cancer in a single hospital. We analyzed the effects of tumor volume and tumor-prostate ratio, as well as the effects of known risk factors for biochemical recurrence, on the duration of disease-free survival. Results: In the univariate analysis, the risk factors that significantly impacted disease-free survival time were found to be a prostate-specific antigen level ≥10 ng/mL, a tumor volume ≥5 mL, tumor-prostate ratio ≥10%, tumor capsular invasion, lymph node invasion, positive surgical margins, and seminal vesicle invasion. In the multivariate analysis performed to evaluate the risk factors found to be significant in the univariate analysis, positive surgical margins (hazard ratio=3.066 and a tumor density ≥10% (hazard ratio=1.991 were shown to be significant risk factors for biochemical recurrence. Conclusions: Tumor-prostate ratio, rather than tumor volume, should be regarded as a significant risk factor for biochemical recurrence.

  6. Molecular imaging of tumor blood vessels in prostate cancer.

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    Tilki, Derya; Seitz, Michael; Singer, Bernhard B; Irmak, Ster; Stief, Christian G; Reich, Oliver; Ergün, Süleyman

    2009-05-01

    In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of tumor vascular remodelling. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not necessarily result in the reduction of tumor diameter. The basis for the molecular imaging of tumor blood vessels is the remodelling of the tumor vessels under anti-angiogenic therapy which obviously occurs at an early stage and seems to be a convincing parameter. Beside the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodelling of the micro tumor vessels. New imaging approaches combining specific molecular markers for tumor vessels with the different imaging techniques are needed to overcome this issue as exemplarily discussed for prostate cancer in this review. Molecular contrast agents targeting the vasculature will allow clinicians the visualization of vascular remodelling processes taking place under anti-angiogenic therapy and improve tumor diagnosis and follow-up.

  7. Apoptosis and Tumor Progressionin Prostate Cancer

    National Research Council Canada - National Science Library

    Tenniswood, Martin P

    2005-01-01

    ... (as measured by BrdU incorporation) and apoptosis as measured by TUNEL staining. We have standardized an efficient methodologies for isolating cells from primary tumors expressing REP by fluorescence activated cell sorting (FACS...

  8. Tumor-specific RNA interference targeting Pokemon suppresses tumor growth and induces apoptosis in prostate cancer.

    Science.gov (United States)

    Li, Yining; Xu, Shuxiong; Wang, Xiangwei; Shi, Hua; Sun, Zhaolin; Yang, Zhao

    2013-02-01

    To explore the exact mechanism of Pokemon in prostate cancer. Pokemon is a member of the POK family of transcriptional repressors. Its main function is suppression of the p14ARF (alternate reading frame) tumor suppressor gene. Although Pokemon expression has been found to be increased in various types of lymphoma, the exact mechanism of the gene in prostate cancer is not clear. In the present study, prostate cancer cells were transfected with the specific short hairpin ribonucleic acid (RNA) expression vector targeting Pokemon. The expression of Pokemon messenger RNA and its protein was detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cell growth and cell apoptosis were also examined using the methyl thiazolyl tetrazolium assay and flow cytometry. The results demonstrated that specific RNA interference (RNAi) could decrease the expression levels of Pokemon gene messenger RNA and protein in prostate cancer cells. In addition, that specific RNAi significantly inhibited the cell proliferation and increased the apoptotic rate. In vivo experiments showed that specific RNAi inhibited the tumorigenicity of prostate cancer cells and significantly suppressed tumor growth. Therefore, an RNAi-targeted Pokemon gene strategy could be a potential approach to prostate cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor

    International Nuclear Information System (INIS)

    Bourke, Vincent A.; Zhao Dawen; Gilio, Joseph; Chang, C.-H.; Jiang Lan; Hahn, Eric W.; Mason, Ralph P.

    2007-01-01

    Purpose: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. Methods and Materials: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by 19 F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. Results: Large tumors (>3.0 cm 3 ) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO 2 ) than their smaller counterparts ( 3 ). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO 2 , and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO 2 > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. Conclusions: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy

  10. Osteopontin is a tumor autoantigen in prostate cancer patients

    Science.gov (United States)

    TILLI, TATIANA M.; SILVA, ELOÍSIO A.; MATOS, LÍVIA C.; FAGET, DOUGLAS V.; DIAS, BIANCA F.P.; VASCONCELOS, JULIANA S.P.; YOKOSAKI, YASUYUKI; GIMBA, ETEL R.P.

    2011-01-01

    Anti-tumor antibodies act as biomarkers for the early diagnosis of prostate cancer (PCa). Osteopontin (OPN) is overexpressed in PCa cells and contributes to the progression of the disease. This study aimed to evaluate whether OPN evokes a humoral immune response in PCa patients and whether the reactivity levels of anti-OPN antibodies may be used to better differentiate PCa from benign and healthy donor plasma samples. Plasma samples from biopsy-proven PCa patients (29), benign prostate hyperplasia (BPH) (18) and control healthy donors (HD) (30) were tested by immunoblots using the recombinant human OPN. The frequency of anti-OPN antibodies was significantly higher in PCa (66%) plasma samples as compared to BPH (33%) and HD controls (10%). Anti-OPN antibodies were detected in a high proportion of plasma samples from patients with a Gleason score of less than 6 (57%), prostate-specific antigen levels lower than 10 ng/ml (67%) and pT2 organ-confined disease (70%), suggesting that anti-OPN antibodies may be used as an early serum marker for PCa. To the best of our knowledge, this is the first description of OPN as a tumor autoantigen and one of the most reactive individual autoantigens described thus far. These data support the inclusion of OPN in a multiplex of tumor antigens in order to perform antibody profiling in PCa as well as in other malignancies overexpressing OPN. PMID:22870138

  11. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    Science.gov (United States)

    2016-10-01

    cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression...impact of pharmacological inhibition of Cxcl5 and Cxcr2 on MDSCs using the transwell migration assay 26 . First, anti-Cxcl5 neutralizing antibody...and MRI . (B) Generation of the CPPSML chimera model. (C) Fluorescence microscopy and H&E image of snap frozen prostate tumor from chimera showing that

  12. Perioperative Search for Circulating Tumor Cells in Patients Undergoing Prostate Brachytherapy for Clinically Nonmetastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Hideyasu Tsumura

    2017-01-01

    Full Text Available Despite the absence of local prostate cancer recurrence, some patients develop distant metastases after prostate brachytherapy. We evaluate whether prostate brachytherapy procedures have a potential risk for hematogenous spillage of prostate cancer cells. Fifty-nine patients who were undergoing high-dose-rate (HDR or low-dose-rate (LDR brachytherapy participated in this prospective study. Thirty patients with high-risk or locally advanced cancer were treated with HDR brachytherapy after neoadjuvant androgen deprivation therapy (ADT. Twenty-nine patients with clinically localized cancer were treated with LDR brachytherapy without neoadjuvant ADT. Samples of peripheral blood were drawn in the operating room before insertion of needles (preoperative and again immediately after the surgical manipulation (intraoperative. Blood samples of 7.5 mL were analyzed for circulating tumor cells (CTCs using the CellSearch System. While no preoperative samples showed CTCs (0%, they were detected in intraoperative samples in 7 of the 59 patients (11.8%; preoperative vs. intraoperative, p = 0.012. Positive CTC status did not correlate with perioperative variables, including prostate-specific antigen (PSA at diagnosis, use of neoadjuvant ADT, type of brachytherapy, Gleason score, and biopsy positive core rate. We detected CTCs from samples immediately after the surgical manipulation. Further study is needed to evaluate whether those CTCs actually can survive and proliferate at distant sites.

  13. Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation.

    Science.gov (United States)

    Araujo, John C; Poblenz, Ann; Corn, Paul; Parikh, Nila U; Starbuck, Michael W; Thompson, Jerry T; Lee, Francis; Logothetis, Christopher J; Darnay, Bryant G

    2009-11-01

    Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases.

  14. FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer.

    Science.gov (United States)

    Davidsson, Sabina; Andren, Ove; Ohlson, Anna-Lena; Carlsson, Jessica; Andersson, Swen-Olof; Giunchi, Francesca; Rider, Jennifer R; Fiorentino, Michelangelo

    2018-01-01

    The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (T regs ). In the present study we evaluated the prevalence of T reg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer. Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4 + T regs and CD8 + T regs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of T regs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area. In men with prostate cancer, similarly high numbers of stromal CD4 + T regs were identified in PAH and tumor, but CD4 + T regs were less common in PIN. Greater numbers of epithelial CD4+ T regs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4 + T regs in the normal prostatic tissue counterpart. Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4 + T regs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established. © 2017 The Authors. The Prostate Published by Wiley Periodicals Inc.

  15. Rapid ex vivo imaging of PAIII prostate to bone tumor with SWIFT-MRI.

    Science.gov (United States)

    Luhach, Ihor; Idiyatullin, Djaudat; Lynch, Conor C; Corum, Curt; Martinez, Gary V; Garwood, Michael; Gillies, Robert J

    2014-09-01

    The limiting factor for MRI of skeletal/mineralized tissue is fast transverse relaxation. A recent advancement in MRI technology, SWIFT (Sweep Imaging with Fourier Transform), is emerging as a new approach to overcome this difficulty. Among other techniques like UTE, ZTE, and WASPI, the application of SWIFT technology has the strong potential to impact preclinical and clinical imaging, particularly in the context of primary or metastatic bone cancers because it has the added advantage of imaging water in mineralized tissues of bone allowing MRI images to be obtained of tissues previously visible only with modalities such as computed tomography (CT). The goal of the current study is to examine the feasibility of SWIFT for the assessment of the prostate cancer induced changes in bone formation (osteogenesis) and destruction (osteolysis) in ex vivo specimens. A luciferase expressing prostate cancer cell line (PAIII) or saline control was inoculated directly into the tibia of 6-week-old immunocompromised male mice. Tumor growth was assessed weekly for 3 weeks before euthanasia and dissection of the tumor bearing and sham tibias. The ex vivo mouse tibia specimens were imaged with a 9.4 Tesla (T) and 7T MRI systems. SWIFT images are compared with traditional gradient-echo and spin-echo MRI images as well as CT and histological sections. SWIFT images with nominal resolution of 78 μm are obtained with the tumor and different bone structures identified. Prostate cancer induced changes in the bone microstructure are visible in SWIFT images, which is supported by spin-echo, high resolution CT and histological analysis. SWIFT MRI is capable of high-quality high-resolution ex vivo imaging of bone tumor and surrounding bone and soft tissues. Furthermore, SWIFT MRI shows promise for in vivo bone tumor imaging, with the added benefits of nonexposure to ionizing radiation, quietness, and speed. Copyright © 2013 Wiley Periodicals, Inc.

  16. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: fyang@bcm.edu...W81XWH-13-1-0163 " Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer " Introduction AR signaling

  17. ERF is a Potential ERK Modulated Tumor Suppressor in Prostate Cancer

    Science.gov (United States)

    2016-10-01

    6/27/2016 - 6/27/2019 1.20 calendar Prostate Cancer Foundation (formerly CaP CURE) $ 75,000 Epigenetic ...AWARD NUMBER: W81XWH-15-1-0277 TITLE: ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer PRINCIPAL INVESTIGATOR: Dr. Rohit...4. TITLE AND SUBTITLE ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0277

  18. Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor

    Energy Technology Data Exchange (ETDEWEB)

    Bourke, Vincent A [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Dawen, Zhao [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Gilio, Joseph [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Chang, C -H [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Lan, Jiang [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Hahn, Eric W [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Mason, Ralph P [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States)

    2007-03-15

    Purpose: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. Methods and Materials: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by {sup 19}F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. Results: Large tumors (>3.0 cm{sup 3}) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO{sub 2}) than their smaller counterparts (<1.5 cm{sup 3}). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO{sub 2}, and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO{sub 2} > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. Conclusions: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy.

  19. Solitary Fibrous Tumor of the Prostate: Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Laurence Moureau-Zabotto

    2012-01-01

    Full Text Available Solitary fibrous tumor (SFT, usually described in the pleura, is exceedingly rare in the prostate. We report a 60-year-old man with prostatic SFT revealed by obstructive urinary symptoms, and detected by ultrasonography. Computed tomography (CT and magnetic resonance imaging suggested a prostatic origin. CT-guided tumor biopsy diagnosed a SFT. A cystoprostatectomy was performed. Pathologic examination showed a 15-cm tumor arising from the prostate and showing histological criteria suggestive of aggressiveness. The surgical resection margins were tumor-free. The patient was then regularly monitored and is still alive in complete remission, 28 months after surgery. In conclusion, we report a new exceptional case of prostatic SFT. We review the literature and discuss the challenging issues of misdiagnosis, prognosis and treatment.

  20. Solitary fibrous tumor of the prostate: case report and review of the literature.

    Science.gov (United States)

    Moureau-Zabotto, Laurence; Chetaille, Bruno; Bladou, Franck; Dauvergne, Pierre-Yves; Marcy, Myriam; Perrot, Delphine; Guiramand, Jérôme; Sarran, Anthony; Bertucci, François

    2012-01-01

    Solitary fibrous tumor (SFT), usually described in the pleura, is exceedingly rare in the prostate. We report a 60-year-old man with prostatic SFT revealed by obstructive urinary symptoms, and detected by ultrasonography. Computed tomography (CT) and magnetic resonance imaging suggested a prostatic origin. CT-guided tumor biopsy diagnosed a SFT. A cystoprostatectomy was performed. Pathologic examination showed a 15-cm tumor arising from the prostate and showing histological criteria suggestive of aggressiveness. The surgical resection margins were tumor-free. The patient was then regularly monitored and is still alive in complete remission, 28 months after surgery. In conclusion, we report a new exceptional case of prostatic SFT. We review the literature and discuss the challenging issues of misdiagnosis, prognosis and treatment.

  1. BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone

    Science.gov (United States)

    2013-07-01

    of NDRG1 is correlated with tumor progression and poor prog- nosis in patients with esophageal squamous cell carcinoma. Dis. Esophagus . 19:454–458...Dormancy of Prostatic Tumor Stem Cell in Bone PRINCIPAL INVESTIGATOR: Fei Xing, Ph.D...BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone 5b. GRANT NUMBER W81XWH-10-1-0666 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Fei

  2. Extratumoral Heme Oxygenase-1 (HO-1 Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.

    Directory of Open Access Journals (Sweden)

    Sofia Halin Bergström

    Full Text Available Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1. To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

  3. Skeletal metastases of carcinomas of prostate in dependence on tumor size and tumor differentiation

    International Nuclear Information System (INIS)

    Krause, U.

    1981-01-01

    153 patients with carcinoma of the prostate underwent holebody skeletal scintiscanning. It resulted that the tendency to the development of skeletal metastases increases with increasing dedifferentiation of the tumor. Also the tumor size correlated with the metastase identification. The tumor dedifferentiation also increased with the tumor size. The findings proved that the early diagnosis of a carcinoma of the prostate is a necessary prerequisite, because a radical total removal can only be curative when any metastases are absent. The comparative evaluation of the diagnostic methods proved the superiority of the nuclear medical examination. In 68% of the cases the roentgenologic examination led to correctly positive results. This investigation showed with 98% a high diagnostic specificity and therefore it should be applied in addition to scintiscanning in order to obtain supplementary information. The alkaline and the acid phosphatase offering an almost identical informative value resulted to be not useful for establishing an early diagnosis of skeletal metastases. It was found that the determination of the blood sedimentation rate and of the lactate dehydrogenase do also not render possible the early diagnosis of skeletal metastases. (orig./MG) [de

  4. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

    Science.gov (United States)

    Bonkhoff, Helmut

    2018-01-01

    The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

  5. Carcinoid tumor of the verumontanum (colliculus seminalis of the prostatic urethra with a coexisting prostatic adenocarcinoma: a case report

    Directory of Open Access Journals (Sweden)

    Werahera Priya N

    2010-01-01

    Full Text Available Abstract Introduction Urethral carcinoid tumors are very rare tumors with only four cases described in the literature. Case presentation We present the case of a 61-year-old man with a primary carcinoid tumor of the verumontanum (colliculis seminalis portion of the prostatic urethra with a coexisting prostatic adenocarcinoma. In addition to whole mount hematoxylin and eosin staining, special immunoperoxidase staining specific for chromogranin A, neuron specific enolase, synaptophysin, pan-cytokeratin and PSA, and a special combined staining for racemase (α-methyl CoA antigen and p63 antigen were performed. A review of the literature is included. A single focus of invasive prostatic adenocarcinoma was identified in the periphery of the mid-left, posterior quadrant of the prostate. Approximately 17 mm from this adenocarcinoma, within the verumontanum of the prostatic urethra, there was a 3 mm maximal dimension carcinoid tumor. Conclusion Based on different histological features and antigenic profiles, we concluded that the two tumors were distinct.

  6. Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progressioan

    International Nuclear Information System (INIS)

    Dozmorov, Mikhail G; Lin, Hsueh-Kung; Azzarello, Joseph T; Wren, Jonathan D; Fung, Kar-Ming; Yang, Qing; Davis, Jeffrey S; Hurst, Robert E; Culkin, Daniel J; Penning, Trevor M

    2010-01-01

    Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR1C enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we propose a novel pathological function of AKR1C3 in tumor angiogenesis and its potential role in promoting PCa progression. To recapitulate elevated AKR1C3 expression in cancerous prostate, the human PCa PC-3 cell line was stably transfected with an AKR1C3 expression construct to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analysis were performed to identify AKR1C3-mediated pathways of activation and their potential biological consequences in PC-3 cells. Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and an in vitro Matrigel angiogenesis assays were applied to validate the pro-angiogenic activity of PC3-AKR1C3 transfectants identified by bioinformatics analysis. Microarray and bioinformatics analysis suggested that overexpression of AKR1C3 in PC-3 cells modulates estrogen and androgen metabolism, activates insulin-like growth factor (IGF)-1 and Akt signaling pathways, as well as promotes tumor angiogenesis and aggressiveness. Levels of IGF-1 receptor (IGF-1R) and Akt activation as well as vascular endothelial growth factor (VEGF) expression and secretion were significantly elevated in PC3-AKR1C3 transfectants in comparison to PC3-mock transfectants. PC3-AKR1C3 transfectants also promoted endothelial cell (EC) tube formation on Matrigel as compared to the AKR1C3-negative parental PC-3 cells and PC3-mock transfectants. Pre-treatment of PC3-AKR1C3 transfectants with a selective IGF-1R kinase inhibitor (AG1024) or a non-selective phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) abolished ability of the cells to promote EC tube formation. Bioinformatics

  7. Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer

    NARCIS (Netherlands)

    Oort, van I.M.; Witjes, J.A.; Kok, D.E.G.; Kiemeney, L.A.; Hulsbergen-van de Kaa, C.A.

    2008-01-01

    Previous studies suggest that maximum tumor diameter (MTD) is a predictor of recurrence in prostate cancer (PC). This study investigates the prognostic value of MTD for biochemical recurrence (BCR) in patients with PC, after radical prostatectomy (RP), with emphasis on high-risk localized prostate

  8. Dasatinib inhibits both osteoclast activation and prostate cancer PC-3 cell-induced osteoclast formation

    Science.gov (United States)

    Araujo, John C.; Poblenz, Ann; Corn, Paul G.; Parikh, Nila U.; Starbuck, Michael W.; Thompson, Jerry T.; Lee, Francis; Logothetis, Christopher J.; Darnay, Bryant G.

    2013-01-01

    Purpose Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. Results Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC50 of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. Experimental design We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. Conclusion Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases. PMID:19855158

  9. Impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    Science.gov (United States)

    Chen, Zhe (Jay); Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-01-01

    Previous studies have shown that the procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations depends strongly on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al. (Int. J. Radiat. Oncol. Biol. Phys. 41, 1069–1077–1998) was used to characterize the edema evolutions observed previously during clinical PIB for prostate cancer. The concept of biologically effective dose (BED), taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not taken into account appropriately, can increase the cell survival and decrease the probability of local control of PIB. The edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life for radioactive decay and decreasing energy of the photons energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days

  10. The impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    International Nuclear Information System (INIS)

    Chen Zhe; Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-01-01

    Previous studies have shown that procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations strongly depends on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131 Cs, 125 I and 103 Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al (1998 Int. J. Radiat. Oncol. Biol. Phys. 41 1069-77) was used to characterize the edema evolutions previously observed during clinical PIB for prostate cancer. The concept of biologically effective dose, taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not appropriately taken into account, can increase the cell survival and decrease the probability of local control of PIB. The magnitude of an edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life of radioactive decay and decreasing photon energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125 I sources was less affected by edema than PIB using 131 Cs or 103 Pd sources due to the long radioactive decay half-life of 125 I. The effect of edema on PIB using 131 Cs or 103 Pd was similar. The effect of edema on 103 Pd PIB was slightly greater, even though the decay half-life of 103 Pd (17 days) is

  11. Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

    International Nuclear Information System (INIS)

    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, André; Gnanasekar, Munirathinam

    2012-01-01

    Highlights: ► Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. ► Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. ► Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. ► Knock down of RAGE abrogates prostate tumor growth in vivo. ► Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

  12. ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0277 TITLE: ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer PRINCIPAL INVESTIGATOR: Dr...Rohit Bose CONTRACTING ORGANIZATION: Sloan Kettering Institute for Cancer Research New York NY 10065 REPORT DATE: October 2017 TYPE OF REPORT...4. TITLE AND SUBTITLE ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0277 5c

  13. FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

    Science.gov (United States)

    Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

    2012-02-01

    Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. Correlation of bone scintigraphy findings and tumor markers during follow-up prostate cancer

    International Nuclear Information System (INIS)

    Aizawa, Taku

    1996-01-01

    In the last 9 years, 217 patients with prostate cancer were treated at our department. Of these patients 153 cases treated by estrogen therapy were followed up by bone scintigraphy and tumor marker examinations (prostate specific antigen [PSA], prostate acid phosphatase [PAP], gamma-seminoprotein [γ-SM) . The correlation between changes on bone scintigrams and synchronous changes in tumor markers was evaluated retrospectively. In cases in which bone metastasis was not recognized on bone scintigrams before treatment, changes of tumor markers corresponded with subsequent changes on bone scintigrams in more than 90%. However, in cases with bone metastasis on bone scintigrams before treatment, changes of bone scintigrams and changes of tumor markers corresponded in only 55% of cases. Changes of bone scintigrams do not always correspond with changes of tumor markers. However, by taking into consideration physical examination parameters such as bone pain, in addition to changes of tumor markers, most changes on bone scintigrams can be anticipated. The reasons for lack of correspondence between changes of bone scintigrams and changes of tumor markers may be, changes of tumor markers are more rapid than the changes on bone scintigram, some poorly differentiated cancers do not have increased tumor marker levels and bone scintigrams do not demonstrate soft tissue involvement. In the follow-up of patients with prostate cancer, it is not necessary to perform bone scintigraphy regularly at 3-month intervals. Bone scintigraphy should only be performed when serum levels of tumor markers increase or bone pain appears. (author)

  15. Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes.

    Science.gov (United States)

    Shui, Irene M; Wong, Chao-Jen; Zhao, Shanshan; Kolb, Suzanne; Ebot, Ericka M; Geybels, Milan S; Rubicz, Rohina; Wright, Jonathan L; Lin, Daniel W; Klotzle, Brandy; Bibikova, Marina; Fan, Jian-Bing; Ostrander, Elaine A; Feng, Ziding; Stanford, Janet L

    2016-07-15

    DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies

  16. DEPDC1 promotes cell proliferation and tumor growth via activation of E2F signaling in prostate cancer.

    Science.gov (United States)

    Huang, Lin; Chen, Keng; Cai, Zhao-Peng; Chen, Fu-Chao; Shen, Hui-Yong; Zhao, Wei-Hua; Yang, Song-Jie; Chen, Xu-Biao; Tang, Guo-Xue; Lin, Xi

    2017-08-26

    DEP domain containing 1 (DEPDC1) is recently reported to be overexpressed in several types of human cancer; however the role of DEPDC1 in prostate cancer remains to be investigated. Herein, we identified that the DEPDC1 mRNA and protein expression levels were dramatically increased in prostate cancer tissues and cell lines. Overexpression of DEPDC1 promoted, but depletion of DEPDC1 inhibited cell proliferation by regulating the G1-S phase cell cycle transition. Importantly, we found that DEPDC1 was essential for the tumor growth and formation of bone metastases of prostate cancer cells in vivo. Finally, we demonstrated that DEPDC1 interacted with E2F1 and increased its transcriptional activity, leading to hyper-activation of E2F signaling in prostate cancer cells. Our findings reveal an oncogenic role of DEPDC1 in prostate cancer progression via activation of E2F signaling, and suggest DEPDC1 might be a potential therapeutic target against the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression.

    Science.gov (United States)

    Ahearn, Thomas U; Tchrakian, Nairi; Wilson, Kathryn M; Lis, Rosina; Nuttall, Elizabeth; Sesso, Howard D; Loda, Massimo; Giovannucci, Edward; Mucci, Lorelei A; Finn, Stephen; Shui, Irene M

    2016-06-01

    Prostate cancer metastases preferentially target bone, and the calcium-sensing receptor (CaSR) may play a role in promoting this metastatic progression. We evaluated the association of prostate tumor CaSR expression with lethal prostate cancer. A validated CaSR immunohistochemistry assay was performed on tumor tissue microarrays. Vitamin D receptor (VDR) expression and phosphatase and tensin homolog tumor status were previously assessed in a subset of cases by immunohistochemistry. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and pathological tumor node metastasis stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of CaSR expression with lethal prostate cancer. The investigation was conducted in the Health Professionals Follow-up Study and Physicians' Health Study. We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009. Participants were followed up or cancer-specific mortality or development of metastatic disease. On average, men were followed up 13.6 years, during which there were 83 lethal events. High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables (HR 2.0; 95% CI 1.2-3.3). Additionally, there was evidence of effect modification by VDR expression; CaSR was associated with lethal progression among men with low tumor VDR expression (HR 3.2; 95% CI 1.4-7.3) but not in cases with high tumor VDR expression (HR 0.8; 95% CI 0.2-3.0). Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases.

  18. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mayu O Frank

    2010-09-01

    Full Text Available Studies of patients with paraneoplastic neurologic disorders (PND have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC vaccine.We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002, decrease in prostate specific antigen (PSA slope (p = 0.016, and a two-fold increase in PSA doubling time (p = 0.003 were identified when we compared data before and after vaccination.An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine.ClinicalTrials.gov NCT00289341.

  19. Cell Competition Drives the Formation of Metastatic Tumors in a Drosophila Model of Epithelial Tumor Formation

    DEFF Research Database (Denmark)

    Eichenlaub, Teresa; Cohen, Stephen M; Herranz, Héctor

    2016-01-01

    . The mechanisms that allow for ongoing cell competition during adult life could, in principle, contribute to tumorigenesis. However, direct evidence supporting this hypothesis has been lacking. Here, we provide evidence that cell competition drives tumor formation in a Drosophila model of epithelial cancer. Cells...

  20. Evaluation of Tumor Heterogeneity of Prostate Carcinoma by Flow- and Image DNA Cytometry and Histopathological Grading

    Directory of Open Access Journals (Sweden)

    Naining Wang

    2000-01-01

    Full Text Available Background. Heterogeneity of prostate carcinoma is one of the reasons for pretreatment underestimation of tumor aggressiveness. We studied tumor heterogeneity and the probability of finding the highest tumor grade and DNA aneuploidy with relation to the number of biopsies. Material and methods. Specimens simulating core biopsies from five randomly selected tumor areas from each of 16 Böcking’s grade II and 23 grade III prostate carcinomas were analyzed for tumor grade and DNA ploidy by flow‐ and fluorescence image cytometry (FCM, FICM. Cell cycle composition was measured by FCM. Results. By determination of ploidy and cell cycle composition, morphologically defined tumors can further be subdivided. Heterogeneity of tumor grade and DNA ploidy (FCM was 54% and 50%. Coexistence of diploid tumor cells in aneuploid specimens represents another form of tumor heterogeneity. The proportion of diploid tumor cells decreased significantly with tumor grade and with increase in the fraction of proliferating cell of the aneuploid tumor part. The probability of estimating the highest tumor grade or aneuploidy increased from 40% for one biopsy to 95% for 5 biopsies studied. By combining the tumor grade with DNA ploidy, the probability of detecting a highly aggressive tumor increased from 40% to 70% and 90% for one and two biopsies, respectively. Conclusion. Specimens of the size of core biopsies can be used for evaluation of DNA ploidy and cell cycle composition. Underestimation of aggressiveness of prostate carcinoma due to tumor heterogeneity is minimized by simultaneous study of the tumor grade and DNA ploidy more than by increasing the number of biopsies. The biological significance of coexistent diploid tumor cell in aneuploid lesions remains to be evaluated.

  1. Rare incidence of tumor lysis syndrome in metastatic prostate cancer following treatment with docetaxel.

    Science.gov (United States)

    Bhardwaj, Sharonlin; Varma, Seema

    2018-03-01

    Tumor lysis syndrome is a serious and sometimes lethal complication of cancer treatment that is comprised of a set of metabolic disturbances along with clinical manifestations. Initiating chemotherapy in bulky, rapidly proliferating tumors causes rapid cell turnover that in turn releases metabolites into circulation that give rise to metabolic derangements that can be dangerous. This syndrome is usually seen in high-grade hematological malignancies. Less commonly, tumor lysis syndrome can present in solid tumors and even rarely in genitourinary tumors. In this report, the authors describe a specific case of tumor lysis syndrome in a patient with metastatic prostate cancer following treatment with docetaxel.

  2. Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells During Prostate Cancer Metastasis

    Science.gov (United States)

    Ruscetti, Marcus; Quach, Bill; Dadashian, Eman L.; Mulholland, David J.; Wu, Hong

    2015-01-01

    The epithelial-mesenchymal transition (EMT) has been postulated as a mechanism by which cancer cells acquire the invasive and stem-like traits necessary for distant metastasis. However, direct in vivo evidence for the role of EMT in the formation of cancer stem-like cells (CSC) and the metastatic cascade remains lacking. Here we report the first isolation and characterization of mesenchymal and EMT tumor cells, which harbor both epithelial and mesenchymal characteristics, in an autochthonous murine model of prostate cancer. By crossing the established Pb-Cre+/−;PtenL/L;KrasG12D/+ prostate cancer model with a vimentin-GFP reporter strain, generating CPKV mice, we were able to isolate epithelial, EMT and mesenchymal cancer cells based on expression of vimentin and EpCAM. CPKV mice (but not mice with Pten deletion alone) exhibited expansion of cells with EMT (EpCAM+/Vim-GFP+) and mesenchymal (EpCAM−/Vim-GFP+) characteristics at the primary tumor site and in circulation. These EMT and mesenchymal tumor cells displayed enhanced stemness and invasive character compared to epithelial tumor cells. Moreover, they displayed an enriched tumor-initiating capacity and could regenerate epithelial glandular structures in vivo, indicative of epithelia-mesenchyme plasticity. Interestingly, while mesenchymal tumor cells could persist in circulation and survive in the lung following intravenous injection, only epithelial and EMT tumor cells could form macrometastases. Our work extends the evidence that mesenchymal and epithelial states in cancer cells contribute differentially to their capacities for tumor initiation and metastatic seeding, respectively, and that EMT tumor cells exist with plasticity that can contribute to multiple stages of the metastatic cascade. PMID:25948589

  3. Differential splicing of oncogenes and tumor suppressor genes in African and Caucasian American populations: contributing factor in prostate cancer disparities

    Science.gov (United States)

    2017-12-01

    populations: contributing factor in prostate cancer disparities? PRINCIPAL INVESTIGATOR: Norman H Lee, PhD CONTRACTING ORGANIZATION: George Washington...splicing of oncogenes and tumor suppressor genes in African and Caucasian American populations: contributing factor in prostate cancer disparities? 5b...American (AA) versus Caucasian American (CA) prostate cancer (PCa). We focused our efforts on two oncogenes, phosphatidylinositol-4,5-bisphosphate 3

  4. Cellular Angiofibroma of the Prostate: A Rare Tumor in an Unusual Location

    Directory of Open Access Journals (Sweden)

    Inez Wyn

    2014-01-01

    Full Text Available We report the unusual occurrence of a cellular angiofibroma in prostatic tissue. In this case, a 84-year-old man presented in the emergency room with urinary retention. Ultrasound revealed an enlarged prostate, which was suggestive for benign prostatic hyperplasia. The patient was treated with a Millin retropubic prostatectomy. Macroscopically the prostate contained multiple circumscribed nodules. Microscopic examination of the tumor showed the appearance of cellular angiofibroma, consisting of bland spindle cells and prominent, hyalinized vessels. The diagnosis was supported by FISH, which revealed monoallelic loss of RB1/13q14 region, as seen in spindle cell lipoma, (extra- mammary myofibroblastoma, and cellular angiofibroma. Cellular angiofibromas are rare, benign soft tissue tumours and were never reported in the prostatic gland.

  5. Building a high-resolution T2-weighted MR-based probabilistic model of tumor occurrence in the prostate.

    Science.gov (United States)

    Nagarajan, Mahesh B; Raman, Steven S; Lo, Pechin; Lin, Wei-Chan; Khoshnoodi, Pooria; Sayre, James W; Ramakrishna, Bharath; Ahuja, Preeti; Huang, Jiaoti; Margolis, Daniel J A; Lu, David S K; Reiter, Robert E; Goldin, Jonathan G; Brown, Matthew S; Enzmann, Dieter R

    2018-02-19

    We present a method for generating a T2 MR-based probabilistic model of tumor occurrence in the prostate to guide the selection of anatomical sites for targeted biopsies and serve as a diagnostic tool to aid radiological evaluation of prostate cancer. In our study, the prostate and any radiological findings within were segmented retrospectively on 3D T2-weighted MR images of 266 subjects who underwent radical prostatectomy. Subsequent histopathological analysis determined both the ground truth and the Gleason grade of the tumors. A randomly chosen subset of 19 subjects was used to generate a multi-subject-derived prostate template. Subsequently, a cascading registration algorithm involving both affine and non-rigid B-spline transforms was used to register the prostate of every subject to the template. Corresponding transformation of radiological findings yielded a population-based probabilistic model of tumor occurrence. The quality of our probabilistic model building approach was statistically evaluated by measuring the proportion of correct placements of tumors in the prostate template, i.e., the number of tumors that maintained their anatomical location within the prostate after their transformation into the prostate template space. Probabilistic model built with tumors deemed clinically significant demonstrated a heterogeneous distribution of tumors, with higher likelihood of tumor occurrence at the mid-gland anterior transition zone and the base-to-mid-gland posterior peripheral zones. Of 250 MR lesions analyzed, 248 maintained their original anatomical location with respect to the prostate zones after transformation to the prostate. We present a robust method for generating a probabilistic model of tumor occurrence in the prostate that could aid clinical decision making, such as selection of anatomical sites for MR-guided prostate biopsies.

  6. Targeting MEK5 Enhances Radiosensitivity of Human Prostate Cancer and Impairs Tumor-Associated Angiogenesis

    Science.gov (United States)

    2016-09-01

    analysis of tumor necrosis factor - alpha resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype...AWARD NUMBER: W81XWH-15-1-0296 TITLE: Targeting MEK5 Enhances Radiosensitivity of Human Prostate Cancer and Impairs Tumor - Associated...Cancer and Impairs Tumor -Associated Angiogenesis 5b. GRANT NUMBER W81XWH-15-1-0296 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER

  7. Detection of Tumor Markers in Prostate Cancer and Comparison of Sensitivity between Real Time and Nested PCR

    OpenAIRE

    Matsuoka, Takayuki; Shigemura, Katsumi; Yamamichi, Fukashi; Fujisawa, Masato; Kawabata, Masato; Shirakawa, Toshiro

    2012-01-01

    The objective of this study is to investigate and compare the sensitivity in conventional PCR, quantitative real time PCR, nested PCR and western blots for detection of prostate cancer tumor markers using prostate cancer (PCa) cells. We performed conventional PCR, quantitative real time PCR, nested PCR, and western blots using 5 kinds of PCa cells. Prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), and androgen receptor (AR) were compared for their detection sensitivi...

  8. Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer.

    Science.gov (United States)

    Hadaschik, Boris; Su, Yun; Huter, Eva; Ge, Yingzi; Hohenfellner, Markus; Beckhove, Philipp

    2012-04-01

    Immunotherapy is a promising approach in an effort to control castration resistant prostate cancer. We characterized tumor antigen reactive T cells in patients with prostate cancer and analyzed the suppression of antitumor responses by regulatory T cells. Peripheral blood samples were collected from 57 patients with histologically confirmed prostate cancer, 8 patients with benign prostatic hyperplasia and 16 healthy donors. Peripheral blood mononuclear cells were isolated and antigen specific interferon-γ secretion of isolated T cells was analyzed by enzyme-linked immunospot assay. T cells were functionally characterized and T-cell responses before and after regulatory T-cell depletion were compared. As test tumor antigens, a panel of 11 long synthetic peptides derived from a total of 8 tumor antigens was used, including prostate specific antigen and prostatic acid phosphatase. In patients with prostate cancer we noted a 74.5% effector T-cell response rate compared with only 25% in patients with benign prostatic hyperplasia and 31% in healthy donors. In most patients 2 or 3 tumor antigens were recognized. Comparing various disease stages there was a clear increase in the immune response against prostate specific antigens from intermediate to high risk tumors and castration resistant disease. Regulatory T-cell depletion led to a significant boost in effector T-cell responses against prostate specific antigen and prostatic acid phosphatase. Tumor specific effector T cells were detected in most patients with prostate cancer, especially those with castration resistant prostate cancer. Since effector T-cell responses against prostate specific antigens strongly increased after regulatory T-cell depletion, our results indicate that immunotherapy efficacy could be enhanced by decreasing regulatory T cells. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  9. Identification of Different Classes of Luminal Progenitor Cells within Prostate Tumors

    Directory of Open Access Journals (Sweden)

    Supreet Agarwal

    2015-12-01

    Full Text Available Primary prostate cancer almost always has a luminal phenotype. However, little is known about the stem/progenitor properties of transformed cells within tumors. Using the aggressive Pten/Tp53-null mouse model of prostate cancer, we show that two classes of luminal progenitors exist within a tumor. Not only did tumors contain previously described multipotent progenitors, but also a major population of committed luminal progenitors. Luminal cells, sorted directly from tumors or grown as organoids, initiated tumors of adenocarcinoma or multilineage histological phenotypes, which is consistent with luminal and multipotent differentiation potentials, respectively. Moreover, using organoids we show that the ability of luminal-committed progenitors to self-renew is a tumor-specific property, absent in benign luminal cells. Finally, a significant fraction of luminal progenitors survived in vivo castration. In all, these data reveal two luminal tumor populations with different stem/progenitor cell capacities, providing insight into prostate cancer cells that initiate tumors and can influence treatment response.

  10. Relative biological effectiveness (RBE) of fast neutrons with the Dunning rat prostate tumor R3327-HI

    International Nuclear Information System (INIS)

    Wenz, F.; Lohr, F.; Peschke, P.; Wolber, G.; Hoever, K.H.; Hahn, E.W.

    1993-01-01

    Human prostate tumors are known to be good candidates for neutron therapy. The Dunning rat prostate tumor system R3327 was found in many studies to be an excellent model for human prostate tumors. There is still a paucity of studies on the response of the Dunning tumors to fast neutrons. Tumors of the R3327-HI subline are moderately well differentiated and mucin producing. They show one euploid cell population, a bromodeoxyuridine labelling index of 5%, a potential doubling time of 8.9 days, a volume doubling time of about ten days and a cell loss rate of 10%. Tumors were transplanted s.c. in the distal thigh of Copenhagen rats and treated with 60 Co-photons (10, 20, 30, 40 Gy, 45 cGy/min) and 14-MeV-neutrons (8, 10, 12 Gy, 7 to 11 cGy/min). Tumor volumes were measured twice weekly. Growth delay was defined as time in days until the tumors reached twice their treatment volume. Linear regressions on the median growth delays of the different treatment groups were calculated. The ratio of the neutron- and photon-slopes yielded an RBE of 3.1±0.3. Additionally isoeffect-RBE values between 2.3 and 2.6 were graphically estimated. (orig.) [de

  11. Possible application of tumor marker radioimmunoassay in diagnosis of testicular and prostatic carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Kausitz, J

    1988-10-01

    Determinations of alpha fetoprotein and chorionic gonadotropin levels by radioimmunoassay in 340 patients with germ cell tumors of the testes have confirmed that tumor markers are suitable prognostic parameters, facilitate assessment of the clinical stage, are sensitive parameters of the efficacy of chemotherapy and enable early detection of relapses. In a group of 71 patients with prostate cancer, systematic determination of prostate specific antigen levels proved to be a reliable method of monitoring and a sensitive method of detecting remote metastases. (author). 5 figs., 13 tabs., 23 refs.

  12. Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation

    Directory of Open Access Journals (Sweden)

    Piergiuseppe Colombo

    2010-10-01

    Full Text Available Stromal tumors of the prostate are rare and only a few cases have been described in the literature, including exceptional cases of stromal tumors with unknown malignant potential (STUMP and a fatal outcome in young patients. Morphologically distinguishing a STUMP from a stromal sarcoma of the prostate (PSS is still a challenge. We describe the histopathological and immunohistochemical findings in a 34-year-old man with a malignant specialized cell stromal tumor of the prostate that was diagnosed initially as STUMP, and he developed lung metastases within a few months. The patient attended our hospital because of lower urinary tract symptoms, after having excreted tissue through the urethra a few months before. Ultrasonography and urethrocystoscopy examinations showed a mass arising from the verumontanum, and a transurethral resection (TUR revealed a high-grade spindle cell sarcoma reminiscent of a phyllode tumor of the breast. The tumor cells were immunoreactive for vimentin, progesterone receptor and, focally, CD34. The preliminary histo­logical findings were subsequently confirmed after radical prostatectomy. The patient developed bilateral lung metastases and died 25 months after the initial diagnosis. Although rare in young patients, the challenging differential diagnosis of STUMP and PSS means that a prostate STUMP diagnosis made on the basis of biopsy or TUR specimens also requires urethrocystoscopic monitoring for the early detection of any progression to PSS. Radical prostatectomy should also be carefully considered.

  13. Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three-Dimensional Ultrasound Imaging Technique

    Directory of Open Access Journals (Sweden)

    Jie Ni

    2016-02-01

    Full Text Available Prostate cancer (CaP is the most commonly diagnosed and the second leading cause of death from cancer in males in USA. Prostate orthotopic mouse model has been widely used to study human CaP in preclinical settings. Measurement of changes in tumor size obtained from noninvasive diagnostic images is a standard method for monitoring responses to anticancer modalities. This article reports for the first time the usage of a three-dimensional (3D ultrasound system equipped with photoacoustic (PA imaging in monitoring longitudinal prostate tumor growth in a PC-3 orthotopic NODSCID mouse model (n = 8. Two-dimensional and 3D modes of ultrasound show great ability in accurately depicting the size and shape of prostate tumors. PA function on two-dimensional and 3D images showed average oxygen saturation and average hemoglobin concentration of the tumor. Results showed a good fit in representative exponential tumor growth curves (n = 3; r2 = 0.948, 0.955, and 0.953, respectively and a good correlation of tumor volume measurements performed in vivo with autopsy (n = 8, r = 0.95, P < .001. The application of 3D ultrasound imaging proved to be a useful imaging modality in monitoring tumor growth in an orthotopic mouse model, with advantages such as high contrast, uncomplicated protocols, economical equipment, and nonharmfulness to animals. PA mode also enabled display of blood oxygenation surrounding the tumor and tumor vasculature and angiogenesis, making 3D ultrasound imaging an ideal tool for preclinical cancer research.

  14. Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone

    Science.gov (United States)

    Kolonin, Mikhail G.; Sergeeva, Anna; Staquicini, Daniela I.; Smith, Tracey L.; Tarleton, Christy A.; Molldrem, Jeffrey J.; Sidman, Richard L.; Marchiò, Serena; Pasqualini, Renata; Arap, Wadih

    2017-01-01

    Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. PMID:28428279

  15. Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

    Directory of Open Access Journals (Sweden)

    Samantha Morley

    2014-08-01

    Full Text Available Prostate cancer (PCa remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, 'amoeboid' phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

  16. Evaluation of the effect of prostate volume change on tumor control probability in LDR brachytherapy

    Directory of Open Access Journals (Sweden)

    Courtney Knaup

    2011-09-01

    Full Text Available Purpose: This study evaluates low dose-rate brachytherapy (LDR prostate plans to determine the biological effectof dose degradation due to prostate volume changes. Material and methods: In this study, 39 patients were evaluated. Pre-implant prostate volume was determinedusing ultrasound. These images were used with the treatment planning system (Nucletron Spot Pro 3.1® to create treatmentplans using 103Pd seeds. Following the implant, patients were imaged using CT for post-implant dosimetry. Fromthe pre and post-implant DVHs, the biologically equivalent dose and the tumor control probability (TCP were determinedusing the biologically effective uniform dose. The model used RBE = 1.75 and α/β = 2 Gy. Results: The prostate volume changed between pre and post implant image sets ranged from –8% to 110%. TCP andthe mean dose were reduced up to 21% and 56%, respectively. TCP is observed to decrease as the mean dose decreasesto the prostate. The post-implant tumor dose was generally observed to decrease, compared to the planned dose.A critical uniform dose of 130 Gy was established. Below this dose, TCP begins to fall-off. It was also determined thatpatients with a small prostates were more likely to suffer TCP decrease. Conclusions: The biological effect of post operative prostate growth due to operative trauma in LDR was evaluatedusing the concept. The post-implant dose was lower than the planned dose due to an increase of prostate volumepost-implant. A critical uniform dose of 130 Gy was determined, below which TCP begun to decline.

  17. Evaluation of the effect of prostate volume change on tumor control probability in LDR brachytherapy.

    Science.gov (United States)

    Knaup, Courtney; Mavroidis, Panayiotis; Stathakis, Sotirios; Smith, Mark; Swanson, Gregory; Papanikolaou, Niko

    2011-09-01

    This study evaluates low dose-rate brachytherapy (LDR) prostate plans to determine the biological effect of dose degradation due to prostate volume changes. In this study, 39 patients were evaluated. Pre-implant prostate volume was determined using ultrasound. These images were used with the treatment planning system (Nucletron Spot Pro 3.1(®)) to create treatment plans using (103)Pd seeds. Following the implant, patients were imaged using CT for post-implant dosimetry. From the pre and post-implant DVHs, the biologically equivalent dose and the tumor control probability (TCP) were determined using the biologically effective uniform dose. The model used RBE = 1.75 and α/β = 2 Gy. The prostate volume changed between pre and post implant image sets ranged from -8% to 110%. TCP and the mean dose were reduced up to 21% and 56%, respectively. TCP is observed to decrease as the mean dose decreases to the prostate. The post-implant tumor dose was generally observed to decrease, compared to the planned dose. A critical uniform dose of 130 Gy was established. Below this dose, TCP begins to fall-off. It was also determined that patients with a small prostates were more likely to suffer TCP decrease. The biological effect of post operative prostate growth due to operative trauma in LDR was evaluated using the concept. The post-implant dose was lower than the planned dose due to an increase of prostate volume post-implant. A critical uniform dose of 130 Gy was determined, below which TCP begun to decline.

  18. Prostatitis

    Science.gov (United States)

    Prostatitis Overview Prostatitis is swelling and inflammation of the prostate gland, a walnut-sized gland situated directly below the bladder in ... produces fluid (semen) that nourishes and transports sperm. Prostatitis often causes painful or difficult urination. Other symptoms ...

  19. 1H-MRSI of prostate cancer: The relationship between metabolite ratio and tumor proliferation

    International Nuclear Information System (INIS)

    Wang Xizhen; Wang Bin; Gao Zhiqin; Liu Jingang; Liu Zuoqin; Niu Qingliang; Sun Zhenkui; Yuan Yuxiao

    2010-01-01

    Purpose: To investigate whether 1H-MRSI can be used to predict the proliferative activity of prostate cancer. Materials and methods: Thirty-eight patients with prostate cancer (PCa) and thirty-three patients with benign prostate hyperplasia (BPH) were included in this study. Patients were examined in supine position using a 1.5 T superconducting magnetic scanner equipped with a pelvic phased-array multi-coil and CSI-3D-PROSTATE sequence. Commercial software was used to acquire and process MR spectroscopic imaging data. Mean (Cho + Cr)/Cit ratios of PCa, BPH, and peripheral zone (PZ) were calculated. Cellularity of PCa was recorded based on hematoxylin and eosin staining. PCNA was detected using immunohistochemical techniques. Results: The mean (Cho + Cr)/Cit ratio of the peripheral zone (0.38 ± 0.09) was lower than that of BPH (0.51 ± 0.19) (P < 0.05). The average value of (Cho + Cr)/Cit ratio of prostate cancer was 3.98 ± 0.12. The (Cho + Cr)/Cit ratio of prostate cancer was higher than that of the peripheral zone and BPH (P < 0.05). The cellularity and PCNA LI of prostate cancer were 12.90 ± 4.07% and 72.1 ± 19.01%, respectively. The (Cho + Cr)/Cit ratio of prostate cancer positively correlated with tumor cellularity (r = 0.582, P = 0.027) and PCNA LI (r = 0.495, P = 0.022). Conclusion: The (Cho + Cr)/Cit ratio of PCa can reveal the differences in proliferative activity between PCa and BPH. MRSIs are therefore able to predict the proliferative rate of variously differentiated prostate cancers.

  20. Molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood

    Directory of Open Access Journals (Sweden)

    Kinnunen Martin

    2010-07-01

    Full Text Available Abstract Background Prostate cancer is the second leading cause of cancer mortality in American men. Although serum PSA testing is widely used for early detection, more specific prognostic tests are needed to guide treatment decisions. Recently, the enumeration of circulating prostate epithelial cells has been shown to correlate with disease recurrence and metastasis following definitive treatment. The purpose of our study was to investigate an immunomagnetic fractionation procedure to enrich circulating prostate tumor cells (CTCs from peripheral blood specimens, and to apply amplified molecular assays for the detection of prostate-specific markers (PSA, PCA3 and TMPRSS2:ERG gene fusion mRNAs. Results As few as five prostate cancer cells were detected per 5 mL of whole blood in model system experiments using anti-EpCAM magnetic particles alone or in combination with anti-PSMA magnetic particles. In our experiments, anti-EpCAM magnetic particles alone exhibited equivalent or better analytical performance with patient samples compared to a combination of anti-EpCAM + anti-PSMA magnetic particles. Up to 39% of men with advanced prostate cancer tested positive with one or more of the molecular assays tested, whereas control samples from men with benign prostate hyperplasia gave consistently negative results as expected. Interestingly, for the vast majority of men who tested positive for PSA mRNA following CTC enrichment, their matched plasma samples also tested positive, although CTC enrichment gave higher overall mRNA copy numbers. Conclusion CTCs were successfully enriched and detected in men with advanced prostate cancer using an immunomagnetic enrichment procedure coupled with amplified molecular assays for PSA, PCA3, and TMPRSS2:ERG gene fusion mRNAs. Our results indicate that men who test positive following CTC enrichment also exhibit higher detectable levels of non-cellular, circulating prostate-specific mRNAs.

  1. Elemental mapping by synchrotron radiation X-Ray microfluorescence in cellular spheroid of prostate tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Leitao, R.G.; Anjos, M.J.; Lopes, R.T., E-mail: roberta@lin.ufrj.br [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Lab. de Instrumentacao Nuclear; Santos, C.A.N. [Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Duque de Caxias, RJ (Brazil). Lab. de Biotecnologia; Palumbo Junior, A.; Souza, P.A.V.R.; Nasciutti, L.E. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Instituto de Ciencias Biomedicas; Pereira, G.R. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Lab. de Ensaios Nao Destrutivos, Corrosao e Soldagem

    2013-08-15

    Prostate cancer is the sixth most common type of cancer and the third most common in males in Western industrialized countries. Cellular spheroid serves as excellent physiologic tumor models as they mimic avascular tumors and micrometastases. Trace elements play a significant role in biological processes. They are capable of affecting human health by competing with essential elements for available binding sites and by the activation or inhibition of reactions between metabolic enzymes. It is well known that zinc levels in the peripheral zone of dorsal and lateral lobes of the prostate are almost 10 times higher than in other soft tissues. Prostate tumor cells were isolated of the prostate tissue samples that were collected from patients submitted to surgery. The measurements were performed in XRF beam line at the Synchrotron Light National Laboratory (LNLS) in Campinas, Brazil. The results showed that all elements were heterogeneously distributed in different areas of the spheroids analyzed. P, S and Cl showed similar elemental distribution in all the samples analyzed while K, Ca, Fe, and Cu showed different elemental distribution. In all spheroids analyzed, Zn presented more intense distributions in the central region of the spheroid. The relationship between the function of Zn in the secretory epithelial cells and the carcinogenic process suggests that more studies on elemental mapping in spheroids are necessary. (author)

  2. Origin of Androgen-Insensitive Poorly Differentiated Tumors in the Transgenic Adenocarcinoma of Mouse Prostate Model

    Directory of Open Access Journals (Sweden)

    Wendy J. Huss

    2007-11-01

    Full Text Available Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR. Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag-expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.

  3. Elemental mapping by synchrotron radiation X-Ray microfluorescence in cellular spheroid of prostate tumor cells

    International Nuclear Information System (INIS)

    Leitao, R.G.; Anjos, M.J.; Lopes, R.T.; Santos, C.A.N.; Palumbo Junior, A.; Souza, P.A.V.R.; Nasciutti, L.E.; Pereira, G.R.

    2013-01-01

    Prostate cancer is the sixth most common type of cancer and the third most common in males in Western industrialized countries. Cellular spheroid serves as excellent physiologic tumor models as they mimic avascular tumors and micrometastases. Trace elements play a significant role in biological processes. They are capable of affecting human health by competing with essential elements for available binding sites and by the activation or inhibition of reactions between metabolic enzymes. It is well known that zinc levels in the peripheral zone of dorsal and lateral lobes of the prostate are almost 10 times higher than in other soft tissues. Prostate tumor cells were isolated of the prostate tissue samples that were collected from patients submitted to surgery. The measurements were performed in XRF beam line at the Synchrotron Light National Laboratory (LNLS) in Campinas, Brazil. The results showed that all elements were heterogeneously distributed in different areas of the spheroids analyzed. P, S and Cl showed similar elemental distribution in all the samples analyzed while K, Ca, Fe, and Cu showed different elemental distribution. In all spheroids analyzed, Zn presented more intense distributions in the central region of the spheroid. The relationship between the function of Zn in the secretory epithelial cells and the carcinogenic process suggests that more studies on elemental mapping in spheroids are necessary. (author)

  4. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

    DEFF Research Database (Denmark)

    Denmeade, Samuel R; Mhaka, Annastasiah M; Rosen, D Marc

    2012-01-01

    adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment...... of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host...

  5. RNAi-mediated knockdown of pituitary tumor-transforming gene-1 (PTTG1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells

    International Nuclear Information System (INIS)

    Huang, S.Q.; Liao, Q.J.; Wang, X.W.; Xin, D.Q.; Chen, S.X.; Wu, Q.J.; Ye, G.

    2012-01-01

    Pituitary tumor-transforming gene-1 (PTTG1) is a proto-oncogene that promotes tumorigenesis and metastasis in numerous cell types and is overexpressed in a variety of human tumors. We have demonstrated that PTTG1 expression was up-regulated in both human prostate cancer specimens and prostate cancer cell lines. For a more direct assessment of the function of PTTG1 in prostate tumorigenesis, RNAi-mediated knockdown was used to selectively decrease PTTG1 expression in PC3 human prostate tumor cells. After three weeks of selection, colonies stably transfected with PTTG1-targeted RNAi (the knockdown PC3 cell line) or empty vector (the control PC3 cell line) were selected and expanded to investigate the role of PTTG1 expression in PC3 cell growth and invasion. Cell proliferation rate was significantly slower (28%) in the PTTG1 knockdown line after 6 days of growth as indicated by an MTT cell viability assay (P < 0.05). Similarly, a soft agar colony formation assay revealed significantly fewer (66.7%) PTTG1 knockdown PC3 cell colonies than control colonies after three weeks of growth. In addition, PTTG1 knockdown resulted in cell cycle arrest at G1 as indicated by fluorescence-activated cell sorting. The PTTG1 knockdown PC3 cell line also exhibited significantly reduced migration through Matrigel in a transwell assay of invasive potential, and down-regulation of PTTG1 could lead to increased sensitivity of these prostate cancer cells to a commonly used anticancer drug, taxol. Thus, PTTG1 expression is crucial for PC3 cell proliferation and invasion, and could be a promising new target for prostate cancer therapy

  6. Growth and Progression of TRAMP Prostate Tumors in Relationship to Diet and Obesity

    Directory of Open Access Journals (Sweden)

    Melissa J. L. Bonorden

    2012-01-01

    Full Text Available To clarify effects of diet and body weight on prostate cancer development, three studies were undertaken using the TRAMP mouse model of this disease. In the first experiment, obesity was induced by injection of gold thioglucose (GTG. Age of prostate tumor detection (~33 wk and death (~43 wk was not significantly different among the groups. In the second study, TRAMP-C2 cells were injected into syngeneic C57BL6 mice and tumor progression was evaluated in mice fed either high-fat or low-fat diets. The high fat fed mice had larger tumors than did the low-fat fed mice. In the third study, tumor development was followed in TRAMP mice fed a high fat diet from 6 weeks of age. There were no significant effects of body weight status or diet on tumor development among the groups. When the tumors were examined for the neuroendocrine marker synaptophysin, there was no correlation with either body weight or diet. However, there was a significant correlation of the expression of synaptophysin with earlier age to tumor detection and death. In summary, TRAMP-C2 cells grew faster when the mice were fed a high-fat diet. Further synaptophysin may be a marker of poor prognosis independent of weight and diet.

  7. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    International Nuclear Information System (INIS)

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S.

    2006-01-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents

  8. Response of rat prostate and lung tumors to ionizing radiation combined with the angiogenesis inhibitor AMCA

    Energy Technology Data Exchange (ETDEWEB)

    Kal, H.B. [Dept. of Radiotherapy, Univ. Medical Centre Utrecht (Netherlands); Struikmans, H. [Dept. of Radiotherapy, Univ. Medical Centre Utrecht (Netherlands); Dept. of Radiotherapy, Medical Centre Haaglanden, Westeinde Hospital, The Hague (Netherlands); Gebbink, M.F.B.G.; Voest, E.E. [Dept. of Medical Oncology, Univ. Medical Centre Utrecht (Netherlands)

    2004-12-01

    Aim: to determine whether radiation combined with Trans-4-AminoMethyl cyclohexane carboxylic acid (AMCA, or tranexamic acid, Cyklokapron registered) results in a better tumor response than radiation alone. Materials and methods: we evaluated the responses of the L44 lung tumor in BN rats and R3327-MATLyLu (MLL) prostate tumor in Copenhagen rats, to single and fractionated X-ray doses with and without AMCA (1.5 g/kg). Tumors were grown subcutaneously in the flank of the animal. AMCA was administered subcutaneously twice daily for at least 2 weeks. Response to treatment was evaluated according to excess growth delay and specific growth delay. Results: L44 and MLL tumors treated with AMCA only experienced a non-significant growth delay. L44 tumors treated with 4 daily dose fractions of 2.5 Gy had a significant excess and specific growth delay when treated with AMCA, the enhancement ratio was 1.6-1.7. The enhancement ratio based on the calculated excess biologically effective dose of the linear-quadratic concept was 1.4-1.5. MLL tumors treated with a single dose of 20 Gy and AMCA had no significant excess growth delay. Conclusion: the enhancement ratio of 1.4-1.7 for the L44 tumor, but not for the MLL tumor, due to AMCA treatment, indicates that AMCA may potentiate the anti-tumor effect of ionizing radiation in distinct tumor types. (orig.)

  9. Response of rat prostate and lung tumors to ionizing radiation combined with the angiogenesis inhibitor AMCA

    International Nuclear Information System (INIS)

    Kal, H.B.; Struikmans, H.; Gebbink, M.F.B.G.; Voest, E.E.

    2004-01-01

    Aim: to determine whether radiation combined with Trans-4-AminoMethyl cyclohexane carboxylic acid (AMCA, or tranexamic acid, Cyklokapron registered) results in a better tumor response than radiation alone. Materials and methods: we evaluated the responses of the L44 lung tumor in BN rats and R3327-MATLyLu (MLL) prostate tumor in Copenhagen rats, to single and fractionated X-ray doses with and without AMCA (1.5 g/kg). Tumors were grown subcutaneously in the flank of the animal. AMCA was administered subcutaneously twice daily for at least 2 weeks. Response to treatment was evaluated according to excess growth delay and specific growth delay. Results: L44 and MLL tumors treated with AMCA only experienced a non-significant growth delay. L44 tumors treated with 4 daily dose fractions of 2.5 Gy had a significant excess and specific growth delay when treated with AMCA, the enhancement ratio was 1.6-1.7. The enhancement ratio based on the calculated excess biologically effective dose of the linear-quadratic concept was 1.4-1.5. MLL tumors treated with a single dose of 20 Gy and AMCA had no significant excess growth delay. Conclusion: the enhancement ratio of 1.4-1.7 for the L44 tumor, but not for the MLL tumor, due to AMCA treatment, indicates that AMCA may potentiate the anti-tumor effect of ionizing radiation in distinct tumor types. (orig.)

  10. Tumor thrombus formation in two dogs with insulinomas.

    Science.gov (United States)

    Hambrook, Lydia E; Kudnig, Simon T

    2012-10-15

    A 9-year-old sexually intact male Staffordshire Bull Terrier and a 9-year-old neutered male Boxer were evaluated for intermittent neurologic signs including muscle tremors, ataxia, episodic collapse, disorientation, and seizures. Both dogs had low blood glucose and high serum insulin concentrations. Results of abdominal ultrasonography were unremarkable for both dogs. Exploratory laparotomy revealed a mass that extended from the body of the pancreas into the pancreaticoduodenal vein in each dog. Marginal resection of pancreatic masses was performed, and tumor thrombi were removed via venotomy in both dogs. Histologic evaluation indicated the masses were pancreatic islet cell tumors with tumor thrombi. Clinical signs resolved following surgical resection of tumors and tumor thrombi, and the dogs were euglycemic during the follow-up period (17 and 45 months after surgery). Although gross tumor thrombus formation has been identified in humans with insulinomas, tumor thrombi have not been previously reported for dogs with insulinomas. Surgical removal of tumor thrombi via venotomy seemed to be well tolerated by the dogs. Tumor thrombus formation did not seem to adversely affect prognosis for the 2 dogs of this report.

  11. [Calculus formation in the prostatic cavity after transurethral resection of the prostate: causes, treatment and prevention].

    Science.gov (United States)

    Wei, Zhi-Feng; Xu, Xiao-Feng; Cheng, Wen; Zhou, Wen-Quan; Ge, Jing-Ping; Zhang, Zheng-Yu; Gao, Jian-Ping

    2012-05-01

    To study the causes, clinical manifestations, treatment and prevention of calculus that develops in the prostatic cavity after transurethral resection of the prostate. We reported 11 cases of calculus that developed in the prostatic cavity after transurethral resection or transurethral plasmakinetic resection of prostate. The patients complained of repeated symptoms of frequent micturition, urgent micturition and urodynia after operation, accompanied with urinary tract infection and some with urinary obstruction, which failed to respond to anti-infective therapies. Cystoscopy revealed calculi in the prostatic cavity, with eschar, sphacelus, uneven wound surface and small diverticula in some cases. After diagnosis, 1 case was treated by holmium laser lithotripsy and a second transurethral resection of the prostate, while the other 10 had the calculi removed under the cystoscope, followed by 1 -2 weeks of anti-infective therapy. After treatment, all the 11 cases showed normal results of routine urinalysis, and no more symptoms of frequent micturition, urgent micturition and urodynia. Three- to six-month follow-up found no bladder irritation symptoms and urinary tract infection. Repeated symptoms of frequent micturition, urgent micturition, urodynia and urinary tract infection after transurethral resection of the prostate should be considered as the indicators of calculus in the prostatic cavity, which can be confirmed by cystoscopy. It can be treated by lithotripsy or removal of the calculus under the cystoscope, or even a second transurethral resection of the prostate. For its prevention, excessive electric coagulation and uneven wound surface should be avoided and anti-infection treatment is needed.

  12. Selenite Treatment Inhibits LAPC-4 Tumor Growth and Prostate-Specific Antigen Secretion in a Xenograft Model of Human Prostate Cancer

    International Nuclear Information System (INIS)

    Bhattacharyya, Rumi S.; Husbeck, Bryan; Feldman, David; Knox, Susan J.

    2008-01-01

    Purpose: Selenium compounds have known chemopreventive effects on prostate cancer. However selenite, an inorganic form of selenium, has not been extensively studied as a treatment option for prostate cancer. Our previous studies have demonstrated the inhibition of androgen receptor expression and androgen stimulated prostate-specific antigen (PSA) expression by selenite in human prostate cancer cell lines. In this study, we investigated the in vivo effects of selenite as a therapy to treat mice with established LAPC-4 tumors. Methods and Materials: Male mice harboring androgen-dependent LAPC-4 xenograft tumors were treated with selenite (2 mg/kg intraperitoneally three times per week) or vehicle for 42 days. In addition, androgen-independent LAPC-4 xenograft tumors were generated in female mice over 4 to 6 months. Once established, androgen-independent LAPC-4 tumor fragments were passaged into female mice and were treated with selenite or vehicle for 42 days. Changes in tumor volume and serum PSA levels were assessed. Results: Selenite significantly decreased androgen-dependent LAPC-4 tumor growth in male mice over 42 days (p < 0.001). Relative tumor volume was decreased by 41% in selenite-treated animals compared with vehicle-treated animals. The inhibition of LAPC-4 tumor growth corresponded to a marked decrease in serum PSA levels (p < 0.01). In the androgen-independent LAPC-4 tumors in female mice, selenite treatment decreased tumor volume by 58% after 42 days of treatment (p < 0.001). Conclusions: These results suggest that selenite may have potential as a novel therapeutic agent to treat both androgen-dependent and androgen-independent prostate cancer

  13. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy.

    Science.gov (United States)

    Denmeade, Samuel R; Mhaka, Annastasiah M; Rosen, D Marc; Brennen, W Nathaniel; Dalrymple, Susan; Dach, Ingrid; Olesen, Claus; Gurel, Bora; Demarzo, Angelo M; Wilding, George; Carducci, Michael A; Dionne, Craig A; Møller, Jesper V; Nissen, Poul; Christensen, S Brøgger; Isaacs, John T

    2012-06-27

    Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.

  14. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    International Nuclear Information System (INIS)

    Guo, Jia; Liu, Xiuheng; Wang, Min

    2015-01-01

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo

  15. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jia; Liu, Xiuheng, E-mail: l_xiuheng@163.com; Wang, Min

    2015-09-04

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.

  16. Assessment of nucleosides as putative tumor biomarkers in prostate cancer screening by CE-UV.

    Science.gov (United States)

    Buzatto, Adriana Zardini; de Oliveira Silva, Mariana; Poppi, Ronei Jesus; Simionato, Ana Valéria Colnaghi

    2017-05-01

    Cancer is responsible for millions of deaths worldwide, but most base diseases may be cured if detected early. Screening tests may be used to identify early-stage malignant neoplasms. However, the major screening tool for prostate cancer, the prostate-specific antigen test, has unsuitable sensitivity. Since cancer cells may affect the pattern of consumption and excretion of nucleosides, such biomolecules are putative biomarkers that can be used for diagnosis and treatment evaluation. Using a previously validated method for the analysis of nucleosides in blood serum by capillary electrophoresis with UV-vis spectroscopy detection, we investigated 60 samples from healthy individuals and 42 samples from prostate cancer patients. The concentrations of nucleosides in both groups were compared and a multivariate partial least squares-discriminant analysis classification model was optimized for prediction of prostate cancer. The validation of the model with an independent sample set resulted in the correct classification of 82.4% of the samples, with sensitivity of 90.5% and specificity of 76.7%. A significant downregulation of 5-methyluridine and inosine was observed, which can be indicative of the carcinogenic process. Therefore, such analytes are potential candidates for prostate cancer screening. Graphical Abstract Separation of the studied nucleosides and the internal standard 8-Bromoguanosine by CE-UV (a); classification of the external validation samples (30 from healthy volunteers and 21 from prostate cancer patients) by the developed Partial Least Square - Discriminant Analysis (PLS-DA) model with accuracy of 82.4% (b); Receiver Operating Characteristics (ROC) curve (c); and Variable Importance in the Projection (VIP) values for the studied nucleosides (d). A significant down-regulation of 5- methyluridine (5mU) and inosine (I) was observed, which can be indicative of the presence of prostate tumors.

  17. Quantitation of circulating tumor cells in blood samples from ovarian and prostate cancer patients using tumor-specific fluorescent ligands.

    Science.gov (United States)

    He, Wei; Kularatne, Sumith A; Kalli, Kimberly R; Prendergast, Franklyn G; Amato, Robert J; Klee, George G; Hartmann, Lynn C; Low, Philip S

    2008-10-15

    Quantitation of circulating tumor cells (CTCs) can provide information on the stage of a malignancy, onset of disease progression and response to therapy. In an effort to more accurately quantitate CTCs, we have synthesized fluorescent conjugates of 2 high-affinity tumor-specific ligands (folate-AlexaFluor 488 and DUPA-FITC) that bind tumor cells >20-fold more efficiently than fluorescent antibodies. Here we determine whether these tumor-specific dyes can be exploited for quantitation of CTCs in peripheral blood samples from cancer patients. A CTC-enriched fraction was isolated from the peripheral blood of ovarian and prostate cancer patients by an optimized density gradient centrifugation protocol and labeled with the aforementioned fluorescent ligands. CTCs were then quantitated by flow cytometry. CTCs were detected in 18 of 20 ovarian cancer patients (mean 222 CTCs/ml; median 15 CTCs/ml; maximum 3,118 CTCs/ml), whereas CTC numbers in 16 gender-matched normal volunteers were negligible (mean 0.4 CTCs/ml; median 0.3 CTCs/ml; maximum 1.5 CTCs/ml; p < 0.001, chi(2)). CTCs were also detected in 10 of 13 prostate cancer patients (mean 26 CTCs/ml, median 14 CTCs/ml, maximum 94 CTCs/ml) but not in 18 gender-matched healthy donors (mean 0.8 CTCs/ml, median 1, maximum 3 CTC/ml; p < 0.0026, chi(2)). Tumor-specific fluorescent antibodies were much less efficient in quantitating CTCs because of their lower CTC labeling efficiency. Use of tumor-specific fluorescent ligands to label CTCs in peripheral blood can provide a simple, accurate and sensitive method for determining the number of cancer cells circulating in the bloodstream.

  18. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2003-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  19. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2004-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  20. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas S

    2005-01-01

    ...). The novelty in our approach is our ability to enhance the selectivity of VSV-induced killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  1. Gold nanorod-mediated hyperthermia enhances the efficacy of HPMA copolymer-90Y conjugates in treatment of prostate tumors

    International Nuclear Information System (INIS)

    Buckway, Brandon; Frazier, Nick; Gormley, Adam J.; Ray, Abhijit; Ghandehari, Hamidreza

    2014-01-01

    Introduction: The treatment of prostate cancer using a radiotherapeutic 90 Y labeled N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer can be enhanced with localized tumor hyperthermia. An 111 In labeled HPMA copolymer system for single photon emission computerized tomography (SPECT) was developed to observe the biodistribution changes associated with hyperthermia. Efficacy studies were conducted in prostate tumor bearing mice using the 90 Y HPMA copolymer with hyperthermia. Methods: HPMA copolymers containing 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were synthesized by reversible addition-fragmentation transfer (RAFT) copolymerization and subsequently labeled with either 111 In for imaging or 90 Y for efficacy studies. Radiolabel stability was characterized in vitro with mouse serum. Imaging and efficacy studies were conducted in DU145 prostate tumor bearing mice. Imaging was performed using single photon emission computerized tomography (SPECT). Localized mild tumor hyperthermia was achieved by plasmonic photothermal therapy using gold nanorods. Results: HPMA copolymer-DOTA conjugates demonstrated efficient labeling and stability for both radionuclides. Imaging analysis showed a marked increase of radiolabeled copolymer within the hyperthermia treated prostate tumors, with no significant accumulation in non-targeted tissues. The greatest reduction in tumor growth was observed in the hyperthermia treated tumors with 90 Y HPMA copolymer conjugates. Histological analysis confirmed treatment efficacy and safety. Conclusion: HPMA copolymer-DOTA conjugates radiolabeled with both the imaging and treatment radioisotopes, when combined with hyperthermia can serve as an image guided approach for efficacious treatment of prostate tumors

  2. MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Oyama, Nobuyuki; Kim, Joonyoung; Jones, Lynne A.; Mercer, Nicole M.; Engelbach, John A.; Sharp, Terry L.; Welch, Michael J. E-mail: welchm@mir.wustl.edu

    2002-11-01

    PET has been used to monitor changes in tumor metabolism in breast cancer following hormonal therapy. This study was undertaken to determine whether PET imaging could evaluate early metabolic changes in prostate tumor following androgen ablation therapy. Studies were performed comparing two positron-emitting tracers, {sup 18}F-FDG and {sup 11}C-acetate, in Sprague-Dawley male rats to monitor metabolic changes in normal prostate tissue. Additional studies were performed in nude mice bearing the CWR22 androgen-dependent human prostate tumor to evaluate metabolic changes in prostate tumor. In rats, for the androgen ablation pretreatment, 1 mg diethylstilbestrol (DES) was injected subcutaneously 3 and 24 hours before tracer injection. For androgen pretreatment, 500 {mu}g dihydrotestosterone (DHT) was injected intraperitoneally 2 and 6 hours before tracer injection. The rats were divided into three groups, Group A (no-DES, no-DHT, n = 18), Group B (DES, no-DHT, n = 18) and Group C (DES, DHT, n = 18). In each group, 10 animals received {sup 18}F-FDG, whereas the remaining eight animals were administered {sup 11}C-acetate. Rats were sacrificed at 120 min post-injection of {sup 18}F-FDG or 30 min post-injection of {sup 11}C-acetate. Pretreatment of the mouse model using DHT (200 {mu}g of DHT in 0.1 mL of sunflower seed oil) or DES (200 {mu}g of DES in 0.1 mL of sunflower seed oil) was conducted every 2 days for one week. Mice were imaged with both tracers in the microPET scanner (Concorde Microsystems Inc.). DES treatment caused a decrease in acetate and glucose metabolism in the rat prostate. Co-treatment with DHT maintained the glucose metabolism levels at baseline values. In the tumor bearing mice, similar effects were seen in {sup 18}F-FDG study, while there was no significant difference in {sup 11}C-acetate uptake. These results indicate that changes in serum testosterone levels influence {sup 18}F-FDG uptake in the prostate gland, which is closely tied to glucose

  3. Relaxin of prostatic origin might be linked to perineal hernia formation in dogs.

    Science.gov (United States)

    Niebauer, Gert W; Shibly, Sarina; Seltenhammer, Monika; Pirker, Armin; Brandt, Sabine

    2005-05-01

    Perineal hernia occurs spontaneously in older male dogs after idiopathic weakening of the pelvic diaphragm. Hernias invariably contain cystic paraprostatic tissues. Castration reduces incidence and recurrence after surgical repair. Although cystic prostatic hypertrophy is a consistent feature in patients with perineal hernia, an endocrine link of the disease to steroid sex hormones has not been demonstrated. Employing immunohistochemistry, we found intense relaxin immunoreactivity in dogs with perineal hernia within the epithelia of hypertrophic prostates and in periprostatic tissues. The prostate of normal dogs exhibited similar but less intense relaxin staining. In neutered dogs with prostatic atrophy, relaxin immunostaining was weak or absent. Periprostatic cysts highly expressed relaxin precursors in the fluid phase as shown by SDS-gel electrophoresis. Relaxin of prostatic origin, therefore, is possibly a local factor in connective tissue weakening and subsequently in perineal hernia formation.

  4. Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry.

    Science.gov (United States)

    Kami, Kenjiro; Fujimori, Tamaki; Sato, Hajime; Sato, Mutsuko; Yamamoto, Hiroyuki; Ohashi, Yoshiaki; Sugiyama, Naoyuki; Ishihama, Yasushi; Onozuka, Hiroko; Ochiai, Atsushi; Esumi, Hiroyasu; Soga, Tomoyoshi; Tomita, Masaru

    2013-04-01

    Metabolic microenvironment of tumor cells is influenced by oncogenic signaling and tissue-specific metabolic demands, blood supply, and enzyme expression. To elucidate tumor-specific metabolism, we compared the metabolomics of normal and tumor tissues surgically resected pairwise from nine lung and seven prostate cancer patients, using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Phosphorylation levels of enzymes involved in central carbon metabolism were also quantified. Metabolomic profiles of lung and prostate tissues comprised 114 and 86 metabolites, respectively, and the profiles not only well distinguished tumor from normal tissues, but also squamous cell carcinoma from the other tumor types in lung cancer and poorly differentiated tumors from moderately differentiated tumors in prostate cancer. Concentrations of most amino acids, especially branched-chain amino acids, were significantly higher in tumor tissues, independent of organ type, but of essential amino acids were particularly higher in poorly differentiated than moderately differentiated prostate cancers. Organ-dependent differences were prominent at the levels of glycolytic and tricarboxylic acid cycle intermediates and associated energy status. Significantly high lactate concentrations and elevated activating phosphorylation levels of phosphofructokinase and pyruvate kinase in lung tumors confirmed hyperactive glycolysis. We highlighted the potential of CE-TOFMS-based metabolomics combined with phosphorylated enzyme analysis for understanding tissue-specific tumor microenvironments, which may lead to the development of more effective and specific anticancer therapeutics.

  5. Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

    Science.gov (United States)

    2013-07-01

    2010). Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older. Diseases of the Esophagus , 23:316-23. Epub 2009...Circulating Tumor Cells in Prostate Cancer PRINCIPAL INVESTIGATOR: David T. Miyamoto, M.D., Ph.D... Cancer 5b. GRANT NUMBER W81XWH-12-1-0153 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER David T. Miyamoto, M.D., Ph.D. 5e

  6. LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality.

    Science.gov (United States)

    Fiano, Valentina; Zugna, Daniela; Grasso, Chiara; Trevisan, Morena; Delsedime, Luisa; Molinaro, Luca; Gillio-Tos, Anna; Merletti, Franco; Richiardi, Lorenzo

    2017-01-02

    Aberrant DNA methylation seems to be associated with prostate cancer behavior. We investigated LINE-1 methylation in prostate cancer and non-neoplastic tissue adjacent to tumor (NTAT) in association with mortality from prostate cancer. We selected 157 prostate cancer patients with available NTAT from 2 cohorts of patients diagnosed between 1982-1988 and 1993-1996, followed up until 2010. An association between LINE-1 hypomethylation and prostate cancer mortality in tumor was suggested [hazard ratio per 5% decrease in LINE-1 methylation levels: 1.40, 95% confidence interval (CI): 0.95-2.01]. After stratification of the patients for Gleason score, the association was present only for those with a Gleason score of at least 8. Among these, low (80%) LINE-1 methylation was associated with a hazard ratio of 4.68 (95% CI: 1.03-21.34). LINE-1 methylation in the NTAT was not associated with prostate cancer mortality. Our results are consistent with the hypothesis that tumor tissue global hypomethylation may be a late event in prostate cancerogenesis and is associated with tumor progression.

  7. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo.

    Science.gov (United States)

    Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E; Henning, Susanne M; Vadgama, Jaydutt V

    2017-06-01

    The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa , has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo , which provides a high promise in its translation to human application.

  8. 13C and 31P NMR [Nuclear Magnetic Resonance] studies of prostate tumor metabolism

    International Nuclear Information System (INIS)

    Sillerud, L.O.; Halliday, K.R.; Freyer, J.P; Griffey, R.H.; Fenoglio-Preiser, C.

    1989-01-01

    The current research on prostate cancer by NMR spectroscopy and microscopy will most significantly contribute to tumor diagnosis and characterization only if sound biochemical models of tumor metabolism are established and tested. Prior searches focused on universal markers of malignancy, have to date, revealed no universal markers by any method. It is unlikely that NMRS will succeed where other methods have failed, however, NMR spectroscopy does provide a non-invasive means to analyze multiple compounds simultaneously in vivo. In order to fully evaluate the ability of NMRS to differentiate non-malignant from malignant tissues it is necessary to determine sufficient multiple parameters from specific, well-diagnosed, histological tumor types that, in comparison to normal tissue and non-neoplastic, non-normal pathologies from which the given neoplasm must be differentiated, one has enough degrees of freedom to make a mathematically and statistically significant determination. Confounding factors may consist of tumor heterogeneity arising from regional variations in differentiation, ischemia, necrosis, hemorrhage, inflammation and the presence of intermingled normal tissue. One related aspect of our work is the development of { 13 C}- 1 H metabolic imaging of 13 C for metabolic characterization, with enhanced spatial localization (46). This should markedly extend the range of potential clinical NMR uses because the spatial variation in prostate metabolism may prove to be just as important in tumor diagnoses as bulk (volume-averaged) properties themselves. It is our hope that NMRS and spectroscopic imaging will reveal a sound correlation between prostate metabolism and tumor properties that will be clinically straightforward and useful for diagnosis

  9. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

    Science.gov (United States)

    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-07

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

    Science.gov (United States)

    Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E.; Henning, Susanne M.; Vadgama, Jaydutt V.

    2017-01-01

    The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its translation to human application

  11. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Piwen Wang

    2017-06-01

    Full Text Available The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (<2 μM significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30–50% at 48 h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50 mg/kg (LD or 100 mg/kg (HD b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD and 70% (HD compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its

  12. Inhibiting Vimentin or beta 1-integrin Reverts Prostate Tumor Cells in IrECM and Reduces Tumor Growth

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xueping; Fournier, Marcia V.; Ware, Joy L.; Bissell, Mina J.; Zehner, Zendra E.

    2009-07-27

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphological changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional (3D) lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the parental prostate epithelial P69 cell line by selection in nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin or {alpha}6-, {beta}4- and {beta}1-integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via siRNA interference or {beta}1-integrin expression by the addition of the blocking antibody, AIIB2, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by subcutaneous injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in 3D lrECM gels. These studies suggest that the levels of vimentin and {beta}1-integrin play a key role in the homeostasis of the normal acini in prostate and that their dysregulation may lead to tumorigenesis.

  13. Increased aPKC Expression Correlates with Prostatic Adenocarcinoma Gleason Score and Tumor Stage in the Japanese Population

    Directory of Open Access Journals (Sweden)

    Anthony S. Perry

    2014-01-01

    Full Text Available Background. Levels of the protein kinase aPKC have been previously correlated with prostate cancer prognosis in a British cohort. However, prostate cancer incidence and progression rates, as well as genetic changes in this disease, show strong ethnic variance, particularly in Asian populations. Objective. The aim of this study was to validate association of aPKC expression with prostatic adenocarcinoma stages in a Japanese cohort. Methods. Tissue microarrays consisting of 142 malignant prostate cancer cases and 21 benign prostate tissues were subject to immunohistological staining for aPKC. aPKC staining intensity was scored by three independent pathologists and categorized as absent (0, dim (1+, intermediate (2+, and bright (3+. aPKC staining intensities were correlated with Gleason score and tumor stage. Results. Increased aPKC staining was observed in malignant prostate cancer, in comparison to benign tissue. Additionally, aPKC staining levels correlated with Gleason score and tumor stage. Our results extend the association of aPKC with prostate cancer to a Japanese population and establish the suitability of aPKC as a universal prostate cancer biomarker that performs consistently across ethnicities.

  14. The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells

    International Nuclear Information System (INIS)

    Khwaja, Fatima; Tabassum, Arshia; Allen, Jeff; Djakiew, Daniel

    2006-01-01

    The p75 neurotrophin receptor (p75 NTR ) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75 NTR retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (ΔDD) dominant-negative antagonist of p75 NTR showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75 NTR -dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75 NTR expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75 NTR rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75 NTR was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75 NTR -dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75 NTR expressing prostate cancer cells

  15. The p75{sup NTR} tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Khwaja, Fatima [Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057-1436 (United States); Tabassum, Arshia [Toronto Western Hospital, Toronto, ON, M5T258 (Canada); Allen, Jeff [National Center for Complementary and Alternative Medicine, N.I.H., Bethesda, MD 20892 (United States); Djakiew, Daniel [Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057-1436 (United States) and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1436 (United States)

    2006-03-24

    The p75 neurotrophin receptor (p75{sup NTR}) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75{sup NTR} retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted ({delta}DD) dominant-negative antagonist of p75{sup NTR} showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75{sup NTR}-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75{sup NTR} expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75{sup NTR} rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75{sup NTR} was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75{sup NTR}-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75{sup NTR} expressing prostate cancer cells.

  16. 3D Porous Chitosan-Alginate Scaffolds as an In Vitro Model for Evaluating Nanoparticle-Mediated Tumor Targeting and Gene Delivery to Prostate Cancer.

    Science.gov (United States)

    Wang, Kui; Kievit, Forrest M; Florczyk, Stephen J; Stephen, Zachary R; Zhang, Miqin

    2015-10-12

    Cationic nanoparticles (NPs) for targeted gene delivery are conventionally evaluated using 2D in vitro cultures. However, this does not translate well to corresponding in vivo studies because of the marked difference in NP behavior in the presence of the tumor microenvironment. In this study, we investigated whether prostate cancer (PCa) cells cultured in three-dimensional (3D) chitosan-alginate (CA) porous scaffolds could model cationic NP-mediated gene targeted delivery to tumors in vitro. We assessed in vitro tumor cell proliferation, formation of tumor spheroids, and expression of marker genes that promote tumor malignancy in CA scaffolds. The efficacy of NP-targeted gene delivery was evaluated in PCa cells in 2D cultures, PCa tumor spheroids grown in CA scaffolds, and PCa tumors in a mouse TRAMP-C2 flank tumor model. PCa cells cultured in CA scaffolds grew into tumor spheroids and displayed characteristics of higher malignancy as compared to those in 2D cultures. Significantly, targeted gene delivery was only observed in cells cultured in CA scaffolds, whereas cells cultured on 2D plates showed no difference in gene delivery between targeted and nontarget control NPs. In vivo NP evaluation confirmed targeted gene delivery, indicating that only CA scaffolds correctly modeled NP-mediated targeted delivery in vivo. These findings suggest that CA scaffolds serve as a better in vitro platform than 2D cultures for evaluation of NP-mediated targeted gene delivery to PCa.

  17. Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression

    International Nuclear Information System (INIS)

    Sanità, Patrizia; Capulli, Mattia; Teti, Anna; Galatioto, Giuseppe Paradiso; Vicentini, Carlo; Chiarugi, Paola; Bologna, Mauro; Angelucci, Adriano

    2014-01-01

    Cancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism. Role of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression. Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive

  18. Hsp90 inhibitor 17-AAG inhibits progression of LuCaP35 xenograft prostate tumors to castration resistance.

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    O'Malley, Katherine J; Langmann, Gabrielle; Ai, Junkui; Ramos-Garcia, Raquel; Vessella, Robert L; Wang, Zhou

    2012-07-01

    Advanced prostate cancer is currently treated with androgen deprivation therapy (ADT). ADT initially results in tumor regression; however, all patients eventually relapse with castration-resistant prostate cancer. New approaches to delay the progression of prostate cancer to castration resistance are in desperate need. This study addresses whether targeting Heat shock protein 90 (HSP90) regulation of androgen receptor (AR) can inhibit prostate cancer progression to castration resistance. The HSP90 inhibitor 17-AAG was injected intraperitoneally into nude mice bearing LuCaP35 xenograft tumors to determine the effect of HSP90 inhibition on prostate cancer progression to castration resistance and host survival. Administration of 17-AAG maintained androgen-sensitivity, delayed the progression of LuCaP35 xenograft tumors to castration resistance, and prolonged the survival of host. In addition, 17-AAG prevented nuclear localization of endogenous AR in LuCaP35 xenograft tumors in castrated nude mice. Targeting Hsp90 or the mechanism by which HSP90 regulates androgen-independent AR nuclear localization and activation may lead to new approaches to prevent and/or treat castration-resistant prostate cancer. Copyright © 2011 Wiley Periodicals, Inc.

  19. Revisiting the TCA cycle: signaling to tumor formation.

    Science.gov (United States)

    Raimundo, Nuno; Baysal, Bora E; Shadel, Gerald S

    2011-11-01

    A role for mitochondria in tumor formation is suggested by mutations in enzymes of the TCA cycle: isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH) and fumarate hydratase (FH). Although they are all components of the TCA cycle, the resulting clinical presentations do not overlap. Activation of the hypoxia pathway can explain SDH phenotypes, but recent data suggest that FH and IDH mutations lead to tumor formation by repressing cellular differentiation. In this review, we discuss recent findings in the context of both mitochondrial and cytoplasmic components of the TCA cycle, and we propose that extrametabolic roles of TCA cycle metabolites result in reduced cellular differentiation. Furthermore, activation of the pseudohypoxia pathway likely promotes the growth of these neoplasias into tumors. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. Inhibitor of differentiation 4 (Id4) is a potential tumor suppressor in prostate cancer

    International Nuclear Information System (INIS)

    Carey, Jason PW; Asirvatham, Ananthi J; Galm, Oliver; Ghogomu, Tandeih A; Chaudhary, Jaideep

    2009-01-01

    Inhibitor of differentiation 4 (Id4), a member of the Id gene family is also a dominant negative regulator of basic helix loop helix (bHLH) transcription factors. Some of the functions of Id4 appear to be unique as compared to its other family members Id1, Id2 and Id3. Loss of Id4 gene expression in many cancers in association with promoter hypermethylation has led to the proposal that Id4 may act as a tumor suppressor. In this study we provide functional evidence that Id4 indeed acts as a tumor suppressor and is part of a cancer associated epigenetic re-programming. Data mining was used to demonstrate Id4 expression in prostate cancer. Methylation specific polymerase chain reaction (MSP) analysis was performed to understand molecular mechanisms associated with Id4 expression in prostate cancer cell lines. The effect of ectopic Id4 expression in DU145 cells was determined by cell cycle analysis (3H thymidine incorporation and FACS), expression of androgen receptor, p53 and cyclin dependent kinase inhibitors p27 and p21 by a combination of RT-PCR, real time-PCR, western blot and immuno-cytochemical analysis. Id4 expression was down-regulated in prostate cancer. Id4 expression was also down-regulated in prostate cancer line DU145 due to promoter hyper-methylation. Ectopic Id4 expression in DU145 prostate cancer cell line led to increased apoptosis and decreased cell proliferation due in part by an S-phase arrest. In addition to S-phase arrest, ectopic Id4 expression in PC3 cells also resulted in prolonged G2/M phase. At the molecular level these changes were associated with increased androgen receptor (AR), p21, p27 and p53 expression in DU145 cells. The results suggest that Id4 acts directly as a tumor suppressor by influencing a hierarchy of cellular processes at multiple levels that leads to a decreased cell proliferation and change in morphology that is possibly mediated through induction of previously silenced tumor suppressors

  1. Inhibitor of differentiation 4 (Id4 is a potential tumor suppressor in prostate cancer

    Directory of Open Access Journals (Sweden)

    Carey Jason PW

    2009-06-01

    Full Text Available Abstract Background Inhibitor of differentiation 4 (Id4, a member of the Id gene family is also a dominant negative regulator of basic helix loop helix (bHLH transcription factors. Some of the functions of Id4 appear to be unique as compared to its other family members Id1, Id2 and Id3. Loss of Id4 gene expression in many cancers in association with promoter hypermethylation has led to the proposal that Id4 may act as a tumor suppressor. In this study we provide functional evidence that Id4 indeed acts as a tumor suppressor and is part of a cancer associated epigenetic re-programming. Methods Data mining was used to demonstrate Id4 expression in prostate cancer. Methylation specific polymerase chain reaction (MSP analysis was performed to understand molecular mechanisms associated with Id4 expression in prostate cancer cell lines. The effect of ectopic Id4 expression in DU145 cells was determined by cell cycle analysis (3H thymidine incorporation and FACS, expression of androgen receptor, p53 and cyclin dependent kinase inhibitors p27 and p21 by a combination of RT-PCR, real time-PCR, western blot and immuno-cytochemical analysis. Results Id4 expression was down-regulated in prostate cancer. Id4 expression was also down-regulated in prostate cancer line DU145 due to promoter hyper-methylation. Ectopic Id4 expression in DU145 prostate cancer cell line led to increased apoptosis and decreased cell proliferation due in part by an S-phase arrest. In addition to S-phase arrest, ectopic Id4 expression in PC3 cells also resulted in prolonged G2/M phase. At the molecular level these changes were associated with increased androgen receptor (AR, p21, p27 and p53 expression in DU145 cells. Conclusion The results suggest that Id4 acts directly as a tumor suppressor by influencing a hierarchy of cellular processes at multiple levels that leads to a decreased cell proliferation and change in morphology that is possibly mediated through induction of previously

  2. Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors.

    Science.gov (United States)

    Bendinger, Alina L; Glowa, Christin; Peter, Jörg; Karger, Christian P

    2018-03-01

    A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity. (2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

  3. Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors

    Science.gov (United States)

    Bendinger, Alina L.; Glowa, Christin; Peter, Jörg; Karger, Christian P.

    2018-03-01

    A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity.

  4. Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors

    International Nuclear Information System (INIS)

    Tuomela, Johanna; Valta, Maija; Seppänen, Jani; Tarkkonen, Kati; Väänänen, H Kalervo; Härkönen, Pirkko

    2009-01-01

    Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood. We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig) and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice. VEGFR3-Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p < 0.05) and inhibited metastasis to iliac and sacral lymph nodes. In addition, tumor volumes were smaller in the VEGFR3-Ig-treated group compared with the control group (p < 0.05). Transfection of PC-3 cells with the VEGF-C gene led to a high level of 29/31 kD VEGF-C expression in PC-3 cells. The size of orthotopic and subcutaneous PC-3/VEGF-C tumors was significantly greater than that of PC-3/mock tumors (both p < 0.001). Interestingly, while most orthotopic PC-3 and PC-3/mock tumors grown for 4 weeks metastasized to prostate-draining lymph nodes, orthotopic PC-3/VEGF-C tumors primarily metastasized to the lungs. PC-3/VEGF-C tumors showed highly angiogenic morphology with an increased density of blood capillaries compared with PC-3/mock tumors (p < 0.001). The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites

  5. Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location.

    Science.gov (United States)

    Faisal, Farzana A; Sundi, Debasish; Tosoian, Jeffrey J; Choeurng, Voleak; Alshalalfa, Mohammed; Ross, Ashley E; Klein, Eric; Den, Robert; Dicker, Adam; Erho, Nicholas; Davicioni, Elai; Lotan, Tamara L; Schaeffer, Edward M

    2016-07-01

    Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, pprostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships. Copyright © 2015. Published by Elsevier B.V.

  6. Non-invasive pre-clinical MR imaging of prostate tumor hypoxia for radiation therapy prognosis

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    Derek White

    2014-03-01

    Full Text Available Purpose: To investigate the usefulness of Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI changes in signal intensity related to oxygen challenge for predicting tumor response to radiation therapy.Methods: Dynamic MR signal changes were acquired using Varian 4.7T small animal MR scanner prior to image-guided radiation therapy (IGRT of small (n = 6 and large subcutaneous (n = 5 prostate tumors in adult male rats. An interleaved blood-oxygen level dependent (BOLD and tissue-oxygen level dependent (TOLD data acquisition or (IBT was performed using a baseline of medical air as positive control and using medical oxygen as a breathing challenge. BOLD used a 2-D multi-slice spoiled gradient-echo with multi-echo sequence. TOLD used a 2-D multi-slice spoiled gradient-echo sequence. Voxel changes in signal intensity were determined by a correlation coefficient mapping technique. Irradiation technique planned consisted of 1F × 15 Gy AP/PA or 2F × 7.5 Gy AP/PA to the gross tumor volume (GTV. Tumor growth measurements were recorded over time to assess the response to IGRT.Results: BOLD and TOLD signals variously illustrated positive or negative impulse responses in the tumor ROI due to inhaling medical oxygen. Correlation coefficient mapping demonstrated heterogeneity in tumors after inhaling medical oxygen. BOLD and TOLD signals exhibited increased changes in signal intensities after the first fraction of dose. Multi-fractionation had minimum effect until the second fraction of dose was applied. Tumor growth delays were observed when inhaling medical oxygen during IGRT.Conclusion: OE-MRI is a non-invasive imaging modality that can provide insight to the oxygen status of tumors. Observed increase percent changes in BOLD and TOLD signal intensities after the first fraction of dose suggest tumors experienced reoxygenation. OE-MRI could be used for predicting tumor response to IGRT when using medical oxygen for increasing GTV radiosensitivity, suggesting

  7. CCR 20th Anniversary Commentary: Circulating Tumor Cells in Prostate Cancer.

    Science.gov (United States)

    Mehra, Niven; Zafeiriou, Zafeiris; Lorente, David; Terstappen, Leon W M M; de Bono, Johann S

    2015-11-15

    Circulating tumor cells (CTC) have substantial promise for multipurpose biomarker studies in prostate cancer. The IMMC-38 trial conducted by de Bono and colleagues, which was published in the October 1, 2008, issue of Clinical Cancer Research, demonstrated for the first time that CTCs are the most accurate and independent predictor of overall survival in metastatic prostate cancer. Since the publication of prospective trials demonstrating prognostic utility, CTCs have been utilized for nucleic acid analyses, for protein analyses, and in intermediate endpoint studies. CTC studies are also now facilitating the analysis of intrapatient heterogeneity. See related article by de Bono et al., Clin Cancer Res 2008;14(19) October 1, 2008;6302-9. ©2015 American Association for Cancer Research.

  8. A Paracrine Role for IL6 in Prostate Cancer Patients: Lack of Production by Primary or Metastatic Tumor Cells

    Science.gov (United States)

    Yu, Shu-Han; Zheng, Qizhi; Esopi, David; Macgregor-Das, Anne; Luo, Jun; Antonarakis, Emmanuel S.; Drake, Charles G.; Vessella, Robert; Morrissey, Colm; De Marzo, Angelo M.; Sfanos, Karen S.

    2015-01-01

    Correlative human studies suggest that the pleiotropic cytokine interleukin-6 (IL6) contributes to the development and/or progression of prostate cancer. However, the source of IL6 production in the prostate microenvironment in patients has yet to be determined. The cellular origin of IL6 in primary and metastatic prostate cancer was examined in formalin-fixed, paraffin-embedded (FFPE) tissues using a highly sensitive and specific chromogenic in situ hybridization (CISH) assay that underwent extensive analytical validation. Quantitative RT-PCR (q-RT-PCR) showed that benign prostate tissues often had higher expression of IL6 mRNA than matched tumor specimens. CISH analysis further indicated that both primary and metastatic prostate adenocarcinoma cells do not express IL6 mRNA. IL6 expression was highly heterogeneous across specimens and was nearly exclusively restricted to the prostate stromal compartment – including endothelial cells and macrophages among other cell types. The number of IL6-expressing cells correlated positively with the presence of acute inflammation. In metastatic disease, tumor cells were negative in all lesions examined and IL6 expression was restricted to endothelial cells within the vasculature of bone metastases. Finally, IL6 was not detected in any cells in soft tissue metastases. These data suggest that, in prostate cancer patients, paracrine rather than autocrine IL6 production is likely associated with any role for the cytokine in disease progression. PMID:26048576

  9. Detection of high GS risk group prostate tumors by diffusion tensor imaging and logistic regression modelling.

    Science.gov (United States)

    Ertas, Gokhan

    2018-07-01

    To assess the value of joint evaluation of diffusion tensor imaging (DTI) measures by using logistic regression modelling to detect high GS risk group prostate tumors. Fifty tumors imaged using DTI on a 3 T MRI device were analyzed. Regions of interests focusing on the center of tumor foci and noncancerous tissue on the maps of mean diffusivity (MD) and fractional anisotropy (FA) were used to extract the minimum, the maximum and the mean measures. Measure ratio was computed by dividing tumor measure by noncancerous tissue measure. Logistic regression models were fitted for all possible pair combinations of the measures using 5-fold cross validation. Systematic differences are present for all MD measures and also for all FA measures in distinguishing the high risk tumors [GS ≥ 7(4 + 3)] from the low risk tumors [GS ≤ 7(3 + 4)] (P Logistic regression modelling provides a favorable solution for the joint evaluations easily adoptable in clinical practice. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

    Science.gov (United States)

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-11-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

  11. Understanding PSA and its derivatives in prediction of tumor volume: Addressing health disparities in prostate cancer risk stratification.

    Science.gov (United States)

    Chinea, Felix M; Lyapichev, Kirill; Epstein, Jonathan I; Kwon, Deukwoo; Smith, Paul Taylor; Pollack, Alan; Cote, Richard J; Kryvenko, Oleksandr N

    2017-03-28

    To address health disparities in risk stratification of U.S. Hispanic/Latino men by characterizing influences of prostate weight, body mass index, and race/ethnicity on the correlation of PSA derivatives with Gleason score 6 (Grade Group 1) tumor volume in a diverse cohort. Using published PSA density and PSA mass density cutoff values, men with higher body mass indices and prostate weights were less likely to have a tumor volume PSA derivatives when predicting for tumor volume. In receiver operator characteristic analysis, area under the curve values for all PSA derivatives varied across race/ethnicity with lower optimal cutoff values for Hispanic/Latino (PSA=2.79, PSA density=0.06, PSA mass=0.37, PSA mass density=0.011) and Non-Hispanic Black (PSA=3.75, PSA density=0.07, PSA mass=0.46, PSA mass density=0.008) compared to Non-Hispanic White men (PSA=4.20, PSA density=0.11 PSA mass=0.53, PSA mass density=0.014). We retrospectively analyzed 589 patients with low-risk prostate cancer at radical prostatectomy. Pre-operative PSA, patient height, body weight, and prostate weight were used to calculate all PSA derivatives. Receiver operating characteristic curves were constructed for each PSA derivative per racial/ethnic group to establish optimal cutoff values predicting for tumor volume ≥0.5 cm3. Increasing prostate weight and body mass index negatively influence PSA derivatives for predicting tumor volume. PSA derivatives' ability to predict tumor volume varies significantly across race/ethnicity. Hispanic/Latino and Non-Hispanic Black men have lower optimal cutoff values for all PSA derivatives, which may impact risk assessment for prostate cancer.

  12. Selenium, but not lycopene or vitamin E, decreases growth of transplantable dunning R3327-H rat prostate tumors.

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    Brian L Lindshield

    Full Text Available BACKGROUND: Lycopene, selenium, and vitamin E are three micronutrients commonly consumed and supplemented by men diagnosed with prostate cancer. However, it is not clear whether consumption of these compounds, alone or in combination, results in improved outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the effects of dietary lycopene (250 mg/kg diet, selenium (methylselenocysteine, 1 mg/kg diet, and vitamin E (gamma-tocopherol, 200 mg/kg diet alone and in combination on the growth of androgen-dependent Dunning R3327-H rat prostate adenocarcinomas in male, Copenhagen rats. AIN-93G diets containing these micronutrients were prefed for 4 to 6 weeks prior to tumor implantation by subcutaneous injection. Tumors were allowed to grow for approximately 18 weeks. Across diet groups, methylselenocysteine consumption decreased final tumor area (P = 0.003, tumor weight (P = 0.003, and the tumor weight/body weight ratio (P = 0.003, but lycopene and gamma-tocopherol consumption intake did not alter any of these measures. There were no significant interactions among nutrient combinations on tumor growth. Methylselenocysteine consumption also led to small, but significant decreases in body weight (P = 0.007, food intake (P = 0.012, and body weight gain/food intake ratio (P = 0.022. However, neither body weight nor gain/food intake ratio was correlated with tumor weight. Methylselenocysteine, lycopene, and gamma-tocopherol consumed alone and in combination did not alter serum testosterone or dihydrotestosterone concentrations; tumor proliferation or apoptosis rates. In addition, the diets also did not alter tumor or prostate androgen receptor, probasin, selenoprotein 15, selenoprotein P, or selenium binding protein 2 mRNA expression. However, using castration and finasteride-treated tissues from a previous study, we found that androgen ablation altered expression of these selenium-associated proteins. CONCLUSIONS: Of the three micronutrients tested, only

  13. Acidosis-Induced Changes in Proteome Patterns of the Prostate Cancer-Derived Tumor Cell Line AT-1.

    Science.gov (United States)

    Ihling, Angelika; Ihling, Christian H; Sinz, Andrea; Gekle, Michael

    2015-09-04

    Under various pathological conditions, such as inflammation, ischemia and in solid tumors, physiological parameters (local oxygen tension or extracellular pH) show distinct tissue abnormalities (hypoxia and acidosis). For tumors, the prevailing microenvironment exerts a strong influence on the phenotype with respect to proliferation, invasion, and metastasis formation and therefore influences prognosis. In this study, we investigate the impact of extracellular metabolic acidosis (pH 7.4 versus 6.6) on the proteome patterns of a prostate cancer-derived tumor cell type (AT-1) using isobaric labeling and LC-MS/MS analysis. In total, 2710 proteins were identified and quantified across four biological replicates, of which seven were significantly affected with changes >50% and used for validation. Glucose transporter 1 and farnesyl pyrophosphatase were found to be down-regulated after 48 h of acidic treatment, and metallothionein 2A was reduced after 24 h and returned to control values after 48 h. After 24 and 48 h at pH 6.6, glutathione S transferase A3 and NAD(P)H dehydrogenase 1, cellular retinoic acid-binding protein 2, and Na-bicarbonate transporter 3 levels were found to be increased. The changes in protein levels were confirmed by transcriptome and functional analyses. In addition to the experimental in-depth investigation of proteins with changes >50%, functional profiling (statistical enrichment analysis) including proteins with changes >20% revealed that acidosis upregulates GSH metabolic processes, citric acid cycle, and respiratory electron transport. Metabolism of lipids and cholesterol biosynthesis were downregulated. Our data comprise the first comprehensive report on acidosis-induced changes in proteome patterns of a tumor cell line.

  14. Lectin-like oxidized LDL receptor-1 is an enhancer of tumor angiogenesis in human prostate cancer cells.

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    Iván González-Chavarría

    Full Text Available Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.

  15. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

    Science.gov (United States)

    Labrecque, Mark P.; Takhar, Mandeep K.; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J.; Massah, Shabnam; Haegert, Anne; Bell, Robert H.; Altamirano-Dimas, Manuel; Collins, Colin C.; Lee, Frank J.S.; Prefontaine, Gratien G.; Cox, Michael E.; Beischlag, Timothy V.

    2016-01-01

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. PMID:27015368

  16. [Fluorine-18 labeled androgens and progestins; imaging agents for tumors of prostate and breast]: Technical progress report, February 1, 1987-January 31, 1988

    International Nuclear Information System (INIS)

    Katzenellenbogen, J.A.

    1987-01-01

    This project develops fluorine-18 labeled steroids that possess high binding affinity and selectivity for androgen and progesterone receptors and can be used as positron-emission tomographic imaging agents for prostate tumors and breast tumors, respectively. These novel diagnostic agents may enable an accurate estimation of tumor dissemination, such as metastasis of prostate cancer and lymph node involvement of breast cancer, and an in vivo determination of the endocrine responsiveness of these tumors. They will provide essential information for the selection of alternative therapies thereby improving the management of prostate and breast cancer patients. 14 refs., 1 tab

  17. Stabilization of beta-catenin induces pancreas tumor formation.

    Science.gov (United States)

    Heiser, Patrick W; Cano, David A; Landsman, Limor; Kim, Grace E; Kench, James G; Klimstra, David S; Taketo, Maketo M; Biankin, Andrew V; Hebrok, Matthias

    2008-10-01

    beta-Catenin signaling within the canonical Wnt pathway is essential for pancreas development. However, the pathway is normally down-regulated in the adult organ. Increased cytoplasmic and nuclear localization of beta-catenin can be detected in nearly all human solid pseudopapillary neoplasms (SPN), a rare tumor with low malignant potential. Conversely, pancreatic ductal adenocarcinoma (PDA) accounts for the majority of pancreatic tumors and is among the leading causes of cancer death. Whereas activating mutations within beta-catenin and other members of the canonical Wnt pathway are rare, recent reports have implicated Wnt signaling in the development and progression of human PDA. Here, we sought to address the role of beta-catenin signaling in pancreas tumorigenesis. Using Cre/lox technology, we conditionally activated beta-catenin in a subset of murine pancreatic cells in vivo. Activation of beta-catenin results in the formation of large pancreatic tumors at a high frequency in adult mice. These tumors resemble human SPN based on morphologic and immunohistochemical comparisons. Interestingly, stabilization of beta-catenin blocks the formation of pancreatic intraepithelial neoplasia (PanIN) in the presence of an activating mutation in Kras that is known to predispose individuals to PDA. Instead, mice in which beta-catenin and Kras are concurrently activated develop distinct ductal neoplasms that do not resemble PanIN lesions. These results demonstrate that activation of beta-catenin is sufficient to induce pancreas tumorigenesis. Moreover, they indicate that the sequence in which oncogenic mutations are acquired has profound consequences on the phenotype of the resulting tumor.

  18. Molecular Ultrasound Imaging of Early Vascular Response in Prostate Tumors Irradiated with Carbon Ions

    Directory of Open Access Journals (Sweden)

    Moritz Palmowski

    2009-09-01

    Full Text Available Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1 and of αvβ3-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of αvβ3-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of αvβ3-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and αvβ3-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.

  19. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

    Science.gov (United States)

    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  20. PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice.

    Science.gov (United States)

    Langut, Yael; Talhami, Alaa; Mamidi, Samarasimhareddy; Shir, Alexei; Zigler, Maya; Joubran, Salim; Sagalov, Anna; Flashner-Abramson, Efrat; Edinger, Nufar; Klein, Shoshana; Levitzki, Alexander

    2017-12-26

    There is an urgent need for an effective treatment for metastatic prostate cancer (PC). Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). We designed a nonviral vector, PEI-PEG-DUPA (PPD), comprising polyethylenimine-polyethyleneglycol (PEI-PEG) tethered to the PSMA ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid (DUPA), to treat PC. The purpose of PEI is to bind polyinosinic/polycytosinic acid (polyIC) and allow endosomal release, while DUPA targets PC cells. PolyIC activates multiple pathways that lead to tumor cell death and to the activation of bystander effects that harness the immune system against the tumor, attacking nontargeted neighboring tumor cells and reducing the probability of acquired resistance and disease recurrence. Targeting polyIC directly to tumor cells avoids the toxicity associated with systemic delivery. PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs). PSMA-overexpressing tumors in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with partially reconstituted immune systems were significantly shrunken following PPD/polyIC treatment, in all cases. Half of the tumors showed complete regression. PPD/polyIC invokes antitumor immunity, but unlike many immunotherapies does not need to be personalized for each patient. The potent antitumor effects of PPD/polyIC should spur its development for clinical use.

  1. CT analysis of intratumoral gas formation after hepatic tumor embolization

    International Nuclear Information System (INIS)

    Kim, Hyun Sook; Ahn, In Oak; Kim, Hyung Jin; Lee, Goo; Chung, Sung Hoon

    1994-01-01

    To evaluate the prevalence and the patterns of sterile gas shown at computed tomography(CT) after transarterial embolization(TAE) for primary hepatic tumor. Among 102 patients who performed TAE for hepatoma, thirty-four in whom follow-up CT was underwent constituted the basis of our study. At CT, we evaluated the patterns and locations of intratumoral gas. We also reviewed the clinical data to exclude an infectious origin of intratumoral gas. Of 34 patients, intratumoral gas was detected in 11 patients(32%), in all of whom Gelfoam was used as an embolic material. The initial tumor size measured at pre-TAE CT was larger in patients with intratumoral gas than in patients without it(p < 0.005). No specific patterns or locations of intratumoral gas were noted on CT scans. No patients had clinical signs and symptoms that suggested infection. Intratumoral gas formation without clinical evidence of infection is not an infrequent finding after TAE for hepatoma, especially when Gelfoam is used and when the tumor is larger in size. This finding may be a part of postinfarction syndrome and should not be misinterpreted as an postprocedural abscess formation

  2. Inorganic Arsenic?Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell?Conditioned Media Model

    OpenAIRE

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal?epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate...

  3. Radiologic-pathologic findings of solitary fibrous tumor of the prostate presenting as a large mass with delayed filling-in on MRI.

    Science.gov (United States)

    Bhargava, Puneet; Lee, Jean Hwa; Gupta, Saurabh; Seyal, Adeel Rahim; Vakar-Lopez, Funda; Moshiri, Mariam; Dighe, Manjiri Kiran

    2012-01-01

    We report a case of a solitary fibrous tumor of prostate presenting with urinary retention and a large prostate mass. We describe the clinical presentation, magnetic resonance imaging findings, and histopathology of this rare, benign tumor. Although clinical and radiologic appearances embrace various differential diagnoses including sarcoma, this mass was confirmed by histologic analysis following surgical resection. We report this rare, benign tumor to help the radiologist suggest the diagnosis when presented with a similar case.

  4. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

    Science.gov (United States)

    Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

    2018-01-01

    ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

  5. Inhibition of prostate cancer osteoblastic progression with VEGF121/rGel, a single agent targeting osteoblasts, osteoclasts, and tumor neovasculature

    Science.gov (United States)

    Mohamedali, Khalid A.; Li, Zhi Gang; Starbuck, Michael W.; Wan, Xinhai; Yang, Jun; Kim, Sehoon; Zhang, Wendy; Rosenblum, Michael G.; Navone, Nora M.

    2011-01-01

    Purpose A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF121/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting non-tumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa. Experimental Design Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF121/rGel. Results VEGF121/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF121/rGel internalization into osteoblasts was VEGF121 receptor driven. Furthermore, VEGF121/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, VEGF121/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomography analysis revealed that VEGF121/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non–tumor bearing) femurs. VEGF121/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF121/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF121/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation. Conclusions Targeting VEGFR-1 – or VEGFR-2–expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. PMID:21343372

  6. Osteogenic sarcoma of the prostate

    Energy Technology Data Exchange (ETDEWEB)

    Nishiyama, Tsutomu; Terunuma, Masahiro [Koseiren Nagaoka Chuo General Hospital, Niigata (Japan); Ikarashi, Toshihiko; Ishizaki, Satoshi

    2001-04-01

    A 76-year-old man was treated with bilateral orchiectomy, estramustine phosphate and pelvic irradiation for prostate cancer. Osteogenic sarcoma of the prostate developed 18 months after the treatment. Postmortem examination revealed that the tumor was 8 cm in diameter and had infiltrated into the bladder and rectal walls and had resulted in peritoneal dissemination. There was no distant metastasis. Macroscopically, the tumor was ashen, firm and relatively homogenous and diffusely spread. Histologically, it was composed of spindle and pleomorphic cells, which were making osteoid with calcification. There was no ordinary tubular formation as shown in adenocarcinoma of the prostate. No positive immunostaining for prostate-specific antigen, epithelial membrane antigen and cytokeratin (AE-1, AE-3) were confirmed. Positive immunostaining for nonepithelial marker vimentin was confirmed. The ultimate diagnosis was osteogenic sarcoma of the prostate. (author)

  7. MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.

    Science.gov (United States)

    Chiu, Tsuicheng D; Arai, Tatsuya J; Campbell Iii, James; Jiang, Steve B; Mason, Ralph P; Stojadinovic, Strahinja

    2018-01-01

    Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT) imaging alone. In this study, we characterized a research magnetic resonance (MR) scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV) was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This novel protocol

  8. Detection of tumor markers in prostate cancer and comparison of sensitivity between real time and nested PCR.

    Science.gov (United States)

    Matsuoka, Takayuki; Shigemura, Katsumi; Yamamichi, Fukashi; Fujisawa, Masato; Kawabata, Masato; Shirakawa, Toshiro

    2012-06-27

    The objective of this study is to investigate and compare the sensitivity in conventional PCR, quantitative real time PCR, nested PCR and western blots for detection of prostate cancer tumor markers using prostate cancer (PCa) cells. We performed conventional PCR, quantitative real time PCR, nested PCR, and western blots using 5 kinds of PCa cells. Prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), and androgen receptor (AR) were compared for their detection sensitivity by real time PCR and nested PCR. In real time PCR, there was a significant correlation between cell number and the RNA concentration obtained (R(2)=0.9944) for PSA, PSMA, and AR. We found it possible to detect these markers from a single LNCaP cell in both real time and nested PCR. By comparison, nested PCR reached a linear curve in fewer PCR cycles than real time PCR, suggesting that nested PCR may offer PCR results more quickly than real time PCR. In conclusion, nested PCR may offer tumor maker detection in PCa cells more quickly (with fewer PCR cycles) with the same high sensitivity as real time PCR. Further study is necessary to establish and evaluate the best tool for PCa tumor marker detection.

  9. Inhibition of prostate cancer osteoblastic progression with VEGF121/rGel, a single agent targeting osteoblasts, osteoclasts, and tumor neovasculature.

    Science.gov (United States)

    Mohamedali, Khalid A; Li, Zhi Gang; Starbuck, Michael W; Wan, Xinhai; Yang, Jun; Kim, Sehoon; Zhang, Wendy; Rosenblum, Michael G; Navone, Nora M

    2011-04-15

    A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF(121)/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting nontumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa. Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF(121)/rGel. VEGF(121)/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF(121)/rGel internalization into osteoblasts was VEGF(121) receptor driven. Furthermore, VEGF(121)/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, VEGF(121)/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomographic analysis revealed that VEGF(121)/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non-tumor-bearing) femurs. VEGF(121)/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF(121)/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF(121)/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation. Targeting VEGF receptor (VEGFR)-1- or VEGFR-2-expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. ©2011 AACR.

  10. Overexpression of prostate tumor overexpressed 1 correlates with tumor progression and predicts poor prognosis in breast cancer

    International Nuclear Information System (INIS)

    Lei, Fangyong; Zhang, Longjuan; Li, Xinghua; Lin, Xi; Wu, Shu; Li, Fengyan; Liu, Junling

    2014-01-01

    Prostate tumor overexpressed 1 (PTOV1) was demonstrated to play an important role in cancer progression and was correlated with unfavorable clinical outcome. However, the clinical role of PTOV1 in cancer remains largely unknown. This study aimed to investigate the expression and clinicopathological significance of PTOV1 in breast cancer. The mRNA and protein expression levels of PTOV1 were analyzed in 12 breast cancer cell lines and eight paired breast cancer tumors by semi-quantitative real time-PCR and western blotting, respectively. Immunohistochemistry was performed to assess PTOV1 protein expression in 169 paraffin-embedded, archived breast cancer samples. Survival analysis and Cox regression analysis were performed to investigate the clinicopathological significance of PTOV1 expression. Our data revealed that PTOV1 was frequently overexpressed in breast cancer cell lines compared to normal human breast epithelial cells and in primary breast cancer samples compared to adjacent noncancerous breast tissues, at both the mRNA and protein levels. Moreover, high expression of PTOV1 in breast cancer is strongly associated with clinicopathological characteristics and estrogen receptor expression status (P = 0.003). Breast cancer patients with higher PTOV1 expression had substantially shorter survival times than patients with lower PTOV1 expression (P < 0.001). Univariate and multivariate analysis revealed that PTOV1 might be an independent prognostic factor for breast cancer patients (P = 0.005). Our study showed that PTOV1 is upregulated in breast cancer cell lines and clinical samples, and its expression was positively associated with progression and aggressiveness of breast cancer, suggesting that PTOV1 could serve as an independent prognostic marker

  11. mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Gordon M Cann

    Full Text Available Circulating tumor cells (CTC mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

  12. mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer.

    Science.gov (United States)

    Cann, Gordon M; Gulzar, Zulfiqar G; Cooper, Samantha; Li, Robin; Luo, Shujun; Tat, Mai; Stuart, Sarah; Schroth, Gary; Srinivas, Sandhya; Ronaghi, Mostafa; Brooks, James D; Talasaz, Amirali H

    2012-01-01

    Circulating tumor cells (CTC) mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

  13. An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer.

    Science.gov (United States)

    Miyamoto, David T; Lee, Richard J; Kalinich, Mark; LiCausi, Joseph A; Zheng, Yu; Chen, Tianqi; Milner, John D; Emmons, Erin; Ho, Uyen; Broderick, Katherine; Silva, Erin; Javaid, Sarah; Kwan, Tanya Todorova; Hong, Xin; Dahl, Douglas M; McGovern, Francis J; Efstathiou, Jason A; Smith, Matthew R; Sequist, Lecia V; Kapur, Ravi; Wu, Chin-Lee; Stott, Shannon L; Ting, David T; Giobbie-Hurder, Anita; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A

    2018-03-01

    Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTC M score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTC L score predicts microscopic dissemination to seminal vesicles and/or lymph nodes ( P digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288-303. ©2018 AACR. See related commentary by Heitzer and Speicher, p. 269 This article is highlighted in the In This Issue feature, p. 253 . ©2018 American Association for Cancer Research.

  14. A comparison of prostate tumor targeting strategies using magnetic resonance imaging-targeted, transrectal ultrasound-guided fusion biopsy.

    Science.gov (United States)

    Martin, Peter R; Cool, Derek W; Fenster, Aaron; Ward, Aaron D

    2018-03-01

    Magnetic resonance imaging (MRI)-targeted, three-dimensional (3D) transrectal ultrasound (TRUS)-guided prostate biopsy aims to reduce the 21-47% false-negative rate of clinical two-dimensional (2D) TRUS-guided systematic biopsy, but continues to yield false-negative results. This may be improved via needle target optimization, accounting for guidance system errors and image registration errors. As an initial step toward the goal of optimized prostate biopsy targeting, we investigated how needle delivery error impacts tumor sampling probability for two targeting strategies. We obtained MRI and 3D TRUS images from 49 patients. A radiologist and radiology resident assessed these MR images and contoured 81 suspicious regions, yielding tumor surfaces that were registered to 3D TRUS. The biopsy system's root-mean-squared needle delivery error (RMSE) and systematic error were modeled using an isotropic 3D Gaussian distribution. We investigated two different prostate tumor-targeting strategies using (a) the tumor's centroid and (b) a ring in the lateral-elevational plane. For each simulation, targets were spaced at equal arc lengths on a ring with radius equal to the systematic error magnitude. A total of 1000 biopsy simulations were conducted for each tumor, with RMSE and systematic error magnitudes ranging from 1 to 6 mm. The difference in median tumor sampling probability and probability of obtaining a 50% core involvement was determined for ring vs centroid targeting. Our simulation results indicate that ring targeting outperformed centroid targeting in situations where systematic error exceeds RMSE. In these instances, we observed statistically significant differences showing 1-32% improvement in sampling probability due to ring targeting. Likewise, we observed statistically significant differences showing 1-39% improvement in 50% core involvement probability due to ring targeting. Our results suggest that the optimal targeting scheme for prostate biopsy depends on

  15. Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate

    International Nuclear Information System (INIS)

    Carlsson, Jessica; Helenius, Gisela; Karlsson, Mats G; Andrén, Ove; Klinga-Levan, Karin; Olsson, Björn

    2013-01-01

    The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate. Patients with prostate cancer were included in the study if they had a tumor with Gleason grade 3 in the PZ, the TZ, or both (n=16). Normal prostate tissue was collected from men undergoing cystoprostatectomy (n=20). The expression of 667 unique miRNAs was investigated using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs, followed by hierarchical clustering and principal component analysis (PCA) to study the separation of the tissues. The ADtree algorithm was used to identify markers for classification of tissues and a cross-validation procedure was used to test the generality of the identified miRNA-based classifiers. The t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentially expressed miRNAs between normal and malignant tissues showed perfect separation between samples, while the corresponding analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmed these results and several potential miRNA markers were identified. The results of this study indicate that the major differences in the transcription program are those arising during tumor development, rather than during normal tissue development. In addition, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ. The results also indicate that separate mi

  16. Walnuts lower TRAMP prostate tumor growth by altering IGF-1, energy and cholesterol metabolism and is not due to their fatty acids

    Science.gov (United States)

    Dietary changes could potentially reduce prostate cancer morbidity and mortality. Prostate tumor size, gene expression, metabolite and plasma responses to a 100 g of fat/kg diet (whole walnuts, walnut oil and other oils; balanced for macronutrients, tocopherols (a-and ' ) for 18 weeks were assessed ...

  17. Does resectoscope size play a role in formation of urethral stricture following transurethral prostate resection?

    Directory of Open Access Journals (Sweden)

    Mustafa Günes

    2015-08-01

    Full Text Available ABSTRACTBackground and aims:To investigate the possible effect of resectoscope size on urethral stricture rate after monopolar TURP.Materials and Methods:A retrospective study of 71 men undergoing TURP was conducted at two centers’ from November 2009 to May 2013. The patients were divided into one of two groups according to the resectoscope diameter used for TURP. Resectoscope diameter was 24 F in group 1 (n=35 or 26 F in group 2 (n=36. Urethral catheter type, catheter removal time and energy type were kept constant for all patients. Urethral stricture formation in different localizations after TURP was compared between groups.Results:There was no significant difference between the two groups in terms of age, pre-operative prostate gland volume (PV, prostate-specific antigen (PSA, maximal urinary flow rates (Qmax, International Prostate Symptom Score (IPSS and post-voiding residual urine volume (PVR. The resection time and weight of resected prostate tissue were similar for both groups (p>0.05. A statistically significant higher incidence of bulbar stricture was detected in group 2 compared to group1 (p=0.018.Conclusions:The use of small-diameter resectoscope shafts may cause a reduction in the incidence of uretral strictures in relation to urethral friction and mucosal damage.

  18. Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species

    Science.gov (United States)

    Alcayaga-Miranda, Francisca; González, Paz L.; Lopez-Verrilli, Alejandra; Varas-Godoy, Manuel; Aguila-Díaz, Carolina; Contreras, Luis; Khoury, Maroun

    2016-01-01

    Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies. PMID:27286448

  19. Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer.

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    Takeshi Chiyomaru

    Full Text Available Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs. In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1 and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as 'Pathways in cancer', 'Jak-STAT signaling pathway', and 'Wnt signaling pathway'. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 3' UTR of several target genes (such as RAC1, EGFR and EP300 that are components of 'Pathways in cancer'. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa.

  20. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Paolo Kunderfranco

    2010-05-01

    Full Text Available ETS transcription factors regulate important signaling pathways involved in cell differentiation and development in many tissues and have emerged as important players in prostate cancer. However, the biological impact of ETS factors in prostate tumorigenesis is still debated.We performed an analysis of the ETS gene family using microarray data and real-time PCR in normal and tumor tissues along with functional studies in normal and cancer cell lines to understand the impact in prostate tumorigenesis and identify key targets of these transcription factors. We found frequent dysregulation of ETS genes with oncogenic (i.e., ERG and ESE1 and tumor suppressor (i.e., ESE3 properties in prostate tumors compared to normal prostate. Tumor subgroups (i.e., ERG(high, ESE1(high, ESE3(low and NoETS tumors were identified on the basis of their ETS expression status and showed distinct transcriptional and biological features. ERG(high and ESE3(low tumors had the most robust gene signatures with both distinct and overlapping features. Integrating genomic data with functional studies in multiple cell lines, we demonstrated that ERG and ESE3 controlled in opposite direction transcription of the Polycomb Group protein EZH2, a key gene in development, differentiation, stem cell biology and tumorigenesis. We further demonstrated that the prostate-specific tumor suppressor gene Nkx3.1 was controlled by ERG and ESE3 both directly and through induction of EZH2.These findings provide new insights into the role of the ETS transcriptional network in prostate tumorigenesis and uncover previously unrecognized links between aberrant expression of ETS factors, deregulation of epigenetic effectors and silencing of tumor suppressor genes. The link between aberrant ETS activity and epigenetic gene silencing may be relevant for the clinical management of prostate cancer and design of new therapeutic strategies.

  1. Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice.

    Science.gov (United States)

    Kim, Sungjin; Yang, Xiangkun; Li, Qianjin; Wu, Meng; Costyn, Leah; Beharry, Zanna; Bartlett, Michael G; Cai, Houjian

    2017-11-10

    Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis in vivo Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Differential Patterns of Large Tumor Antigen-Specific Immune Responsiveness in Patients with BK Polyomavirus-Positive Prostate Cancer or Benign Prostatic Hyperplasia

    Science.gov (United States)

    Sais, Giovanni; Wyler, Stephen; Hudolin, Tvrtko; Banzola, Irina; Mengus, Chantal; Bubendorf, Lukas; Wild, Peter J.; Hirsch, Hans H.; Sulser, Tullio; Spagnoli, Giulio C.

    2012-01-01

    The role of the polyomavirus BK (BKV) large tumor antigen (L-Tag) as a target of immune response in patients with prostate cancer (PCa) has not been investigated thus far. In this study, we comparatively analyzed humoral and cellular L-Tag-specific responsiveness in age-matched patients bearing PCa or benign prostatic hyperplasia, expressing or not expressing BKV L-Tag-specific sequences in their tissue specimens, and in non-age-matched healthy individuals. Furthermore, results from patients with PCa were correlated to 5-year follow-up clinical data focusing on evidence of biochemical recurrence (BR) after surgery (prostate specific antigen level of ≥0.2 ng/ml). In peripheral blood mononuclear cells (PBMC) from patients with PCa with evidence of BR and BKV L-Tag-positive tumors, stimulation with peptides derived from the BKV L-Tag but not those derived from Epstein-Barr virus, influenza virus, or cytomegalovirus induced a peculiar cytokine gene expression profile, characterized by high expression of interleukin-10 (IL-10) and transforming growth factor β1 and low expression of gamma interferon genes. This pattern was confirmed by protein secretion data and correlated with high levels of anti-BKV L-Tag IgG. Furthermore, in PBMC from these PCa-bearing patients, L-Tag-derived peptides significantly expanded an IL-10-secreting CD4+ CD25+(high) CD127− FoxP3+ T cell population with an effector memory phenotype (CD103+) capable of inhibiting proliferation of autologous anti-CD3/CD28-triggered CD4+ CD25− T cells. Collectively, our findings indicate that potentially tolerogenic features of L-Tag-specific immune response are significantly associated with tumor progression in patients with BKV+ PCa. PMID:22647697

  3. Markers of epithelial-to-mesenchymal transition reflect tumor biology according to patient age and Gleason score in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Dorota Jędroszka

    Full Text Available Prostate carcinoma (PRAD is one of the most frequently diagnosed malignancies amongst men worldwide. It is well-known that androgen receptor (AR plays a pivotal role in a vast majority of prostate tumors. However, recent evidence emerged stating that estrogen receptors (ERs may also contribute to prostate tumor development. Moreover, progression and aggressiveness of prostate cancer may be associated with differential expression genes of epithelial-to-mesenchymal transition (EMT. Therefore we aimed to assess the significance of receptors status as well as EMT marker genes expression among PRAD patients in accordance to their age and Gleason score.We analyzed TCGA gene expression profiles of 497 prostate tumor samples according to 43 genes involved in EMT and 3 hormone receptor genes (AR, ESR1, ESR2 as well as clinical characteristic of cancer patients. Then patients were divided into four groups according to their age and 5 groups according to Gleason score. Next, we evaluated PRAD samples according to relationship between the set of variables in different combinations and compared differential expression in subsequent groups of patients. The analysis was applied using R packages: FactoMineR, gplots, RColorBrewer and NMF.MFA analysis resulted in distinct grouping of PRAD patients into four age categories according to expression level of AR, ESR1 and ESR2 with the most distinct group of age less than 50 years old. Further investigations indicated opposite expression profiles of EMT markers between different age groups as well as strong association of EMT gene expression with Gleason score. We found that depending on age of prostate cancer patients and Gleason score EMT genes with distinctly altered expression are: KRT18, KRT19, MUC1 and COL4A1, CTNNB1, SNAI2, ZEB1 and MMP3.Our major observation is that prostate cancer from patients under 50 years old compared to older ones has entirely different EMT gene expression profiles showing potentially

  4. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

    International Nuclear Information System (INIS)

    Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie; Oakley, Gregory G.; Wahl, James K.; Simpson, Melanie A.

    2011-01-01

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and β-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  5. Adenovirus E2F1 Overexpression Sensitizes LNCaP and PC3 Prostate Tumor Cells to Radiation In Vivo

    International Nuclear Information System (INIS)

    Udayakumar, Thirupandiyur S.; Stoyanova, Radka; Hachem, Paul; Ahmed, Mansoor M.; Pollack, Alan

    2011-01-01

    Purpose: We previously showed that E2F1 overexpression radiosensitizes prostate cancer cells in vitro. Here, we demonstrate the radiosensitization efficacy of adenovirus (Ad)-E2F1 infection in growing (orthotopic) LNCaP and (subcutaneous) PC3 nude mice xenograft tumors. Methods and Materials: Ad-E2F1 was injected intratumorally in LNCaP (3 x 10 8 plaque-forming units [PFU]) and PC3 (5 x 10 8 PFU) tumors treated with or without radiation. LNCaP tumor volumes (TV) were measured by magnetic resonance imaging, caliper were used to measure PC3 tumors, and serum prostate-specific antigen (PSA) levels were determined by enzyme-linked immunosorbent assay. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, and key proteins involved in cell death signaling were analyzed by Western blotting. Results: Intracellular overexpression of Ad-E2F1 had a significant effect on the regression of TV and reduction of PSA levels relative to that of adenoviral luciferase (Ad-Luc)-infected control. The in vivo regressing effect of Ad-E2F1 on LNCaP tumor growth was significant (PSA, 34 ng/ml; TV, 142 mm 3 ) compared to that of Ad-Luc control (PSA, 59 ng/ml; TV, 218 mm 3 ; p 3 to Ad-Luc+RT/PSA, 42 ng/ml, and TV, 174 mm 3 , respectively; p <0.05). For PC3 tumors, the greatest effect was observed with Ad-E2F1 infection alone; there was little or no effect when radiotherapy (RT) was combined. However, addition of RT enhanced the level of in situ apoptosis in PC3 tumors. Molecularly, addition of Ad-E2F1 in a combination treatment abrogated radiation-induced BCL-2 protein expression and was associated with an increase in activated BAX, and together they caused a potent radiosensitizing effect, irrespective of p53 and androgen receptor functional status. Conclusions: We show here for the first time that ectopic overexpression of E2F1 in vivo, using an adenoviral vector, significantly inhibits orthotopic p53 wild-type LNCaP tumors and subcutaneous

  6. Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

    Science.gov (United States)

    Garcia, Emmanuel; Becker, Veronika G C; McCullough, Danielle J; Stabley, John N; Gittemeier, Elizabeth M; Opoku-Acheampong, Alexander B; Sieman, Dietmar W; Behnke, Bradley J

    2016-07-01

    Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. Copyright © 2016 the American Physiological Society.

  7. MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.

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    Tsuicheng D Chiu

    Full Text Available Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT imaging alone. In this study, we characterized a research magnetic resonance (MR scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This

  8. Is IGSF1 involved in human pituitary tumor formation?

    Science.gov (United States)

    Faucz, Fabio R; Horvath, Anelia D; Azevedo, Monalisa F; Levy, Isaac; Bak, Beata; Wang, Ying; Xekouki, Paraskevi; Szarek, Eva; Gourgari, Evgenia; Manning, Allison D; de Alexandre, Rodrigo Bertollo; Saloustros, Emmanouil; Trivellin, Giampaolo; Lodish, Maya; Hofman, Paul; Anderson, Yvonne C; Holdaway, Ian; Oldfield, Edward; Chittiboina, Prashant; Nesterova, Maria; Biermasz, Nienke R; Wit, Jan M; Bernard, Daniel J; Stratakis, Constantine A

    2015-02-01

    IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation. © 2015 Society for Endocrinology.

  9. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers

    DEFF Research Database (Denmark)

    Sturgeon, Catharine M.; Duffy, Michael J.; Stenman, Ulf-Håkan

    2008-01-01

    BACKGROUND: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS: Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast...... for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign...... prostatic disease when total PSA is cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50...

  10. Preclinical Evaluation of a Novel 177Lu- Radiopharmaceutical Based on Bombesin Structure for Prostate Tumor Diagnosis and Radionuclide Therapy

    International Nuclear Information System (INIS)

    Pujatti, P.B.; Santos, J.S.; Mengatti, J.; Araujo, E.B. de; Suzuki, M.F.; Soares, C.R.J.

    2009-01-01

    Prostate cancer is the most frequently diagnosed cancer in men in Brazil. Treatment options have varied, but once the tumor has metastasized, treatment become less effective and the cancer can progresses to a hormone refractory state characterized by high morbidity and mortality. Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor - have been shown to be massively overexpressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel peptide based on bombesin structure - DOTA-X-BBN(6-14), where X is a spacer of six aminoacids. - with lutetium-177, a β- emitter with optimal physical characteristics for RNT of small tumors and metastases, and to evaluate its in vitro and in vivo properties in Balb-c and Nude mice bearing prostate tumor (PC-3) xenografts. Preliminary studies were done to determine the best labeling conditions of BBNp6 and both ITLC and HPLC were applied to evaluate the radiochemical purity of the preparations. The stability of the radiolabeled peptide was assayed either after storing at 4 o C or incubation in human plasma at 37 deg. C. Biodistribution, pharmacokinetics, whole body and scintigraphic studies were performed in both healthy Balb-c and xenografted Nude mice, in order to characterize the biological properties of labeled peptide. In addition, the specificity of labeled bombesin derivative targeting to PC-3 tumor cells was analysed by in vivo competition assays. In vitro studies involved the

  11. Multicriteria plan optimization in the hands of physicians: a pilot study in prostate cancer and brain tumors.

    Science.gov (United States)

    Müller, Birgit S; Shih, Helen A; Efstathiou, Jason A; Bortfeld, Thomas; Craft, David

    2017-11-06

    The purpose of this study was to demonstrate the feasibility of physician driven planning in intensity modulated radiotherapy (IMRT) with a multicriteria optimization (MCO) treatment planning system and template based plan optimization. Exploiting the full planning potential of MCO navigation, this alternative planning approach intends to improve planning efficiency and individual plan quality. Planning was retrospectively performed on 12 brain tumor and 10 post-prostatectomy prostate patients previously treated with MCO-IMRT. For each patient, physicians were provided with a template-based generated Pareto surface of optimal plans to navigate, using the beam angles from the original clinical plans. We compared physician generated plans to clinically delivered plans (created by dosimetrists) in terms of dosimetric differences, physician preferences and planning times. Plan qualities were similar, however physician generated and clinical plans differed in the prioritization of clinical goals. Physician derived prostate plans showed significantly better sparing of the high dose rectum and bladder regions (p(D1) plans indicated higher doses for targets and brainstem (p(D1) plan comparisons physicians preferred the clinical plans more often (brain: 6:3 out of 12, prostate: 2:6 out of 10) (not statistically significant). While times of physician involvement were comparable for prostate planning, the new workflow reduced the average involved time for brain cases by 30%. Planner times were reduced for all cases. Subjective benefits, such as a better understanding of planning situations, were observed by clinicians through the insight into plan optimization and experiencing dosimetric trade-offs. We introduce physician driven planning with MCO for brain and prostate tumors as a feasible planning workflow. The proposed approach standardizes the planning process by utilizing site specific templates and integrates physicians more tightly into treatment planning. Physicians

  12. Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits.

    Science.gov (United States)

    Rhie, Suhn Kyong; Guo, Yu; Tak, Yu Gyoung; Yao, Lijing; Shen, Hui; Coetzee, Gerhard A; Laird, Peter W; Farnham, Peggy J

    2016-01-01

    Although technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach toward understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements. Using DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called Tracing Enhancer Networks using Epigenetic Traits that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors. Our studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms

  13. Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

    Science.gov (United States)

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL

  14. Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts

    International Nuclear Information System (INIS)

    El-Zawahry, Ahmed; McKillop, John; Voelkel-Johnson, Christina

    2005-01-01

    Prostate cancer is a significant health problem among American men. Treatment strategies for androgen-independent cancer are currently not available. Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a death receptor ligand that can induce apoptosis in a variety of cancer cell lines, including androgen-independent PC3 prostate carcinoma cells. In vitro, TRAIL-mediated apoptosis of prostate cancer cell lines can be enhanced by doxorubicin and correlates with the downregulation of the anti-apoptotic protein c-FLIP. This study evaluated the effects of doxorubicin on c-FLIP expression and tumor growth in combination with Apo2L/TRAIL in a xenograft model. In vitro cytotoxic effects of TRAIL were measured using a MTS-based viability assay. For in vivo studies, PC3 prostate carcinoma cells were grown subcutaneously in athymic nude mice and tumor growth was measured following treatment with doxorubicin and/or Apo2L/TRAIL. c-FLIP expression was determined by western blot analysis. Apoptosis in xenografts was detected using TUNEL. Statistical analysis was performed using the student t-test. In vitro experiments show that PC3 cells are partially susceptible to Apo2L/TRAIL and that susceptibility is enhanced by doxorubicin. In mice, doxorubicin did not significantly affect the growth of PC3 xenografts but reduced c-FLIP expression in tumors. Expression of c-FLIP in mouse heart was decreased only at the high doxorubicin concentration (8 mg/kg). Combination of doxorubicin with Apo2L/TRAIL resulted in more apoptotic cell death and tumor growth inhibition than Apo2L/TRAIL alone. Combination of doxorubicin and Apo2L/TRAIL is more effective in growth inhibition of PC3 xenografts in vivo than either agent alone and could present a novel treatment strategy against hormone-refractory prostate cancer. The intracellular mechanism by which doxorubicin enhances the effect of Apo2L/TRAIL on PC3 xenografts may be by reducing expression of c-FLIP

  15. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Matthew A Ingersoll

    Full Text Available Prostate cancer (PCa is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  16. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    Science.gov (United States)

    Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel; D'Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G; Bu, Xiu R; Batra, Surinder K; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  17. Focal degeneration of basal cells and the resultant auto-immunoreactions: a novel mechanism for prostate tumor progression and invasion.

    Science.gov (United States)

    Man, Yan-Gao; Gardner, William A

    2008-01-01

    The development of human prostate cancer is believed to be a multistep process, progressing sequentially from normal, to hyperplasia, to prostatic intraepithelial neoplasia (PIN), and to invasive and metastatic lesions. High grade PIN has been generally considered as the direct precursor of invasive lesions, and the progression of PIN is believed to be triggered primarily, if not solely, by the overproduction of proteolytic enzymes predominately by cancer cells, which result in the degradation of the basement membrane. These theories, however, are hard to reconcile with two main facts: (1) only about 30% untreated PIN progress to invasive stage, while none of the current approaches could accurately identify the specific PIN or individuals at greater risk for progression, and (2) results from recent world-wide clinical trials with a wide variety of proteolytic enzyme inhibitors have been very disappointing, casting doubt on the validity of the proteolytic enzyme theory. Since over 90% of prostate cancer-related deaths result from invasion-related illness and the incidence of PIN could be up to 16.5-25% in routine or ultrasound guided prostate biopsy, there is an urgent need to uncover the intrinsic mechanism of prostate tumor invasion. Promoted by the facts that the basal cell population is the source of several tumor suppressors and the absence of the basal cell layer is the most distinct feature of invasive lesions, our recent studies have intended to identify the early alterations of basal cell layers and their impact on tumor invasion using multidisciplinary approaches. Our studies revealed that a subset of pre-invasive tumors contained focal disruptions (the absence of basal cells resulting in a gap greater than the combined size of at least three epithelial cells) in surrounding basal cell layers. Compared to their non-disrupted counterparts, focally disrupted basal cell layers had several unique features: (1) significantly lower proliferation; (2

  18. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are

  19. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

    International Nuclear Information System (INIS)

    Echchgadda, Ibtissam; Chang, Te-Hung; Sabbah, Ahmed; Bakri, Imad; Ikeno, Yuji; Hubbard, Gene B; Chatterjee, Bandana; Bose, Santanu

    2011-01-01

    Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further

  20. Xanthogranulomatous Prostatitis, a Rare Prostatic Entity

    Directory of Open Access Journals (Sweden)

    Alejandro Noyola

    2017-01-01

    Full Text Available There are several benign prostatic pathologies that can clinically mimic a prostate adenocarcinoma. Xanthogranulomatous prostatitis is a benign inflammatory condition of the prostate and a rare entity. A 47-year old male, with 3 years of lower urinary tract symptoms, with a palpable hypogastric tumor, digital rectal examination: solid prostate, of approximately 60 g. Initial PSA was 0.90 ng/mL. He underwent surgical excision of the lower abdominal nodule and prostatectomy. Histopathology showed xanthogranulomatous prostatitis, without malignancy. Xanthogranulomatous prostatitis is an extremely rare entity that can simulate prostate adenocarcinoma, therefore having a correct histopathological diagnosis is essential.

  1. Danish Prostate Cancer Registry

    DEFF Research Database (Denmark)

    Helgstrand, J Thomas; Klemann, Nina; Røder, Martin Andreas

    2016-01-01

    of SNOMED codes were identified. A computer algorithm was developed to transcode SNOMED codes into an analyzable format including procedure (eg, biopsy, transurethral resection, etc), diagnosis, and date of diagnosis. For validation, ~55,000 pathological reports were manually reviewed. Prostate-specific...... antigen, vital status, causes of death, and tumor-node-metastasis classification were integrated from national registries. RESULTS: Of the 161,525 specimens from 113,801 males identified, 83,379 (51.6%) were sets of prostate biopsies, 56,118 (34.7%) were transurethral/transvesical resections......BACKGROUND: Systematized Nomenclature of Medicine (SNOMED) codes are computer-processable medical terms used to describe histopathological evaluations. SNOMED codes are not readily usable for analysis. We invented an algorithm that converts prostate SNOMED codes into an analyzable format. We...

  2. Effect of serum testosterone and percent tumor volume on extra-prostatic extension and biochemical recurrence after laparoscopic radical prostatectomy

    Directory of Open Access Journals (Sweden)

    Eu Chang Hwang

    2016-01-01

    Full Text Available Several studies have revealed that the preoperative serum testosterone and percent tumor volume (PTV predict extra-prostatic extension (EPE and biochemical recurrence (BCR after radical prostatectomy. This study investigated the prognostic significance of serum testosterone and PTV in relation to EPE and BCR after laparoscopic radical prostatectomy (LRP. We reviewed 520 patients who underwent LRP between 2004 and 2012. PTV was determined as the sum of all visually estimated tumor foci in every section. BCR was defined as two consecutive increases in the postoperative prostate-specific antigen (PSA >0.2 ng ml−1 . The threshold for serum total testosterone was 3.0 ng ml−1 . Multivariate logistic regression was used to define the effect of variables on the risk of EPE and BCR. A low serum testosterone (<3.0 ng ml−1 was associated with a high serum PSA, Gleason score, positive core percentage of the prostate biopsy, PTV, and all pathological variables. On multivariate analysis, similar to previous studies, the serum PSA, biopsy positive core percentage, Gleason score, and pathological variables predicted EPE and BCR. In addition, low serum testosterone (<3.0 ng ml−1 , adjusted OR, 8.52; 95% CI, 5.04-14.4, P= 0.001 predicted EPE and PTV (adjusted OR, 1.02; 95% CI, 1.01-1.05, P= 0.046 predicted BCR. In addition to previous predictors of EPE and BCR, low serum testosterone and PTV are valuable predictors of EPE and BCR after LRP.

  3. The discovery of putative urine markers for the specific detection of prostate tumor by integrative mining of public genomic profiles.

    Directory of Open Access Journals (Sweden)

    Min Chen

    Full Text Available Urine has emerged as an attractive biofluid for the noninvasive detection of prostate cancer (PCa. There is a strong imperative to discover candidate urinary markers for the clinical diagnosis and prognosis of PCa. The rising flood of various omics profiles presents immense opportunities for the identification of prospective biomarkers. Here we present a simple and efficient strategy to derive candidate urine markers for prostate tumor by mining cancer genomic profiles from public databases. Prostate, bladder and kidney are three major tissues from which cellular matters could be released into urine. To identify urinary markers specific for PCa, upregulated entities that might be shed in exosomes of bladder cancer and kidney cancer are first excluded. Through the ontology-based filtering and further assessment, a reduced list of 19 entities encoding urinary proteins was derived as putative PCa markers. Among them, we have found 10 entities closely associated with the process of tumor cell growth and development by pathway enrichment analysis. Further, using the 10 entities as seeds, we have constructed a protein-protein interaction (PPI subnetwork and suggested a few urine markers as preferred prognostic markers to monitor the invasion and progression of PCa. Our approach is amenable to discover and prioritize potential markers present in a variety of body fluids for a spectrum of human diseases.

  4. SU-D-207A-03: Potential Role of BOLD MRI in Discrimination of Aggressive Tumor Habitat in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ford, J; Lopez, C; Tschudi, Y; Breto, A; Padgett, K; Pollack, A; Stoyanova, R [University of Miami Miller School of Medicine, Miami, FL (United States)

    2016-06-15

    Purpose: To determine whether blood oxygenation level dependent (BOLD) MRI signal measured in prostate cancer patients, in addition to quantitative diffusion and perfusion parameters from multiparametric (mp)MRI exams, can help discriminate aggressive and/or radioresistant lesions. Methods: Several ongoing clinical trials in our institution require mpMRI exam to determine eligibility (presence of identifiable tumor lesion on mpMRI) and prostate volumes for dose escalation. Upon consent, patients undergo fiducial markers placement and a T2*-weighted imaging at the time of CT sim to facilitate the fusion. In a retrospective analysis eleven clinical trial patients were identified who had undergone mpMRI on GE 3T magnet, followed by T2*-weighted imaging (time-period mean±SD = 48±20 days) using a consistent protocol (gradient echo, TR/TE=30/11.8ms, flip angle=12, matrix=256×256×75, voxel size=1.25×1.25×2.5mm). ROIs for prostate tumor lesions were automatically determined using ADC threshold ≤1200 µm2/s. Although the MR protocol was not intended for BOLD analysis, we utilized the T2*-weighted signal normalized to that in nearby muscle; likewise, T2-weighted lesion signal was normalized to muscle, following rigid registration of the T2 to T2* images. The ratio of these normalized signals, T2*/T2, is a measure of BOLD effect in the prostate tumors. Perfusion parameters (Ktrans, ve, kep) were also calculated. Results: T2*/T2 (mean±SE) was found to be substantially lower for Gleason score (GS) 8&9 (0.82±0.04) compared to GS 7 (1.08±0.07). A k-means cluster analysis of T2*/T2 versus kep = Ktrans/ve revealed two distinct clusters, one with higher T2*/T2 and lower kep, containing only GS 7 lesions, and another with lower T2*/T2 and higher kep, associated with tumor aggressiveness. This latter cluster contained all GS 8&9 lesions, as well as some GS 7. Conclusion: BOLD MRI, in addition to ADC and kep, may play a role (perhaps orthogonal to Gleason score) in

  5. Strategies to reduce the systematic error due to tumor and rectum motion in radiotherapy of prostate cancer

    International Nuclear Information System (INIS)

    Hoogeman, Mischa S.; Herk, Marcel van; Bois, Josien de; Lebesque, Joos V.

    2005-01-01

    carried out later in the treatment (based on the data of more scans) the overall reduction was less. For the rectum, the first strategy performed best at the upper anterior side, where a reduction of the anterior-posterior displacement of 30% could be achieved. The systematic error could be reduced by 43% for the whole rectum by using the data of 4 repeat CT scans and the planning CT scan. Conclusions: Both the pre-treatment as well as the adaptive correction strategy reduced the systematic error in the prostate position and rectum position and shape. A smaller systematic error makes it possible to safely reduce the margin around the clinical tumor volume, so that normal tissues can be spared or the prescription dose can be escalated

  6. In Vivo Imaging of Prostate Cancer Tumors and Metastasis Using Non-Specific Fluorescent Nanoparticles in Mice

    Directory of Open Access Journals (Sweden)

    Coralie Genevois

    2017-12-01

    Full Text Available With the growing interest in the use of nanoparticles (NPs in nanomedicine, there is a crucial need for imaging and targeted therapies to determine NP distribution in the body after systemic administration, and to achieve strong accumulation in tumors with low background in other tissues. Accumulation of NPs in tumors results from different mechanisms, and appears extremely heterogeneous in mice models and rather limited in humans. Developing new tumor models in mice, with their low spontaneous NP accumulation, is thus necessary for screening imaging probes and for testing new targeting strategies. In the present work, accumulation of LipImageTM 815, a non-specific nanosized fluorescent imaging agent, was compared in subcutaneous, orthotopic and metastatic tumors of RM1 cells (murine prostate cancer cell line by in vivo and ex vivo fluorescence imaging techniques. LipImageTM 815 mainly accumulated in liver at 24 h but also in orthotopic tumors. Limited accumulation occurred in subcutaneous tumors, and very low fluorescence was detected in metastasis. Altogether, these different tumor models in mice offered a wide range of NP accumulation levels, and a panel of in vivo models that may be useful to further challenge NP targeting properties.

  7. The development of fluoroandrogens and fluoroprogestins as potential imaging agents for receptor-positive prostate and breast tumors

    International Nuclear Information System (INIS)

    Brandes, S.J.; Katzenellenbogen, J.A.

    1986-01-01

    The assay of progesterone receptor (PR) concentration in breast tumors and androgen receptor (AR) concentration in prostate tumors enables hormone responsive neoplasms to be distinguished from those that are non-responsive. In principle, a positron-emitting progestin or androgen with suitably high affinity and selectivity for PR and AR, respectively, and an adequately high specific activity might provide a means for imaging receptor-positive tumors and quantifying their receptor content in vivo. The use of fluorine-18 as a radiolabel, coupled with the use of positron emission transaxial tomography, appears to be a most favorable approach in the development of receptor binding radiopharmaceuticals for in vivo imaging. Therefore, we have begun a systematic investigation of the development of fluorine-substituted androgens and progestins that might be prepared in F-18 labeled form as probes for AR and PR. (author)

  8. A novel mouse model of human prostate cancer to study intraprostatic tumor growth and the development of lymph node metastases.

    Science.gov (United States)

    Linxweiler, Johannes; Körbel, Christina; Müller, Andreas; Hammer, Markus; Veith, Christian; Bohle, Rainer M; Stöckle, Michael; Junker, Kerstin; Menger, Michael D; Saar, Matthias

    2018-06-01

    In this study, we aimed to establish a versatile in vivo model of prostate cancer, which adequately mimics intraprostatic tumor growth, and the natural routes of metastatic spread. In addition, we analyzed the capability of high-resolution ultrasonography (hrUS), in vivo micro-CT (μCT), and 9.4T MRI to monitor tumor growth and the development of lymph node metastases. A total of 5 × 10 5 VCaP cells or 5 × 10 5 cells of LuCaP136- or LuCaP147 spheroids were injected into the prostate of male CB17-SCID mice (n = 8 for each cell type). During 12 weeks of follow-up, orthotopic tumor growth, and metastatic spread were monitored by repetitive serum-PSA measurements and imaging studies including hrUS, μCT, and 9.4T MRI. At autopsy, primary tumors and metastases were harvested and examined by histology and immunohistochemistry (CK5, CK8, AMACR, AR, Ki67, ERG, and PSA). From imaging results and PSA-measurements, tumor volume doubling time, tumor-specific growth rate, and PSA-density were calculated. All 24 mice developed orthotopic tumors. The tumor growth could be reliably monitored by a combination of hrUS, μCT, MRI, and serum-PSA measurements. In most animals, lymph node metastases could be detected after 12 weeks, which could also be well visualized by hrUS, and MRI. Immunohistochemistry showed positive signals for CK8, AMACR, and AR in all xenograft types. CK5 was negative in VCaP- and focally positive in LuCaP136- and LuCaP147-xenografts. ERG was positive in VCaP- and negative in LuCaP136- and LuCaP147-xenografts. Tumor volume doubling times and tumor-specific growth rates were 21.2 days and 3.9 %/day for VCaP-, 27.6 days and 3.1 %/day for LuCaP136- and 16.2 days and 4.5 %/day for LuCaP147-xenografts, respectively. PSA-densities were 433.9 ng/mL per milliliter tumor for VCaP-, 6.5 ng/mL per milliliter tumor for LuCaP136-, and 11.2 ng/mL per milliliter tumor for LuCaP147-xenografts. By using different monolayer and 3D spheroid cell cultures in an

  9. Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.

    Directory of Open Access Journals (Sweden)

    Marie Lundholm

    Full Text Available Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

  10. Image-guided diagnosis of prostate cancer can increase detection of tumors

    Science.gov (United States)

    In the largest prospective study to date of image-guided technology for identifying suspicious regions of the prostate to biopsy, researchers compared the ability of this technology to detect high-risk prostate cancer with that of the current standard of

  11. A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats.

    Science.gov (United States)

    Allan, George; Lai, Muh-Tsann; Sbriscia, Tifanie; Linton, Olivia; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Dodds, Robert; Fiordeliso, James; Lanter, James; Sui, Zhihua; Lundeen, Scott

    2007-01-01

    The pharmacological activity of JNJ-26146900 is described. JNJ-26146900 is a nonsteroidal androgen receptor (AR) ligand with tissue-selective activity in rats. The compound was evaluated in in vitro and in vivo models of AR activity. It binds to the rat AR with a K(i) of 400nM and acts as a pure androgen antagonist in an in vitro cell-based assay. Its in vitro profile is similar to the androgen antagonist bicalutamide (Casodex). In intact rats, JNJ-26146900 reduces ventral prostate weight with an oral potency (ED(50)) of 20-30mg/kg, again comparable to that of bicalutamide. JNJ-26146900 prevented prostate tumor growth in the Dunning rat model, maximally inhibiting growth at a dose of 10mg/kg. It slowed tumor growth significantly in a CWR22-LD1 mouse xenograft model of human prostate cancer. It was tested in aged male rats for its ability to prevent bone loss and loss of lean body mass following orchidectomy. After 6 weeks of dosing, bone volume decreased by 33% in orchidectomized versus intact vehicle-treated rats with a probability (P) of less than 0.05, as measured by micro-computerized tomography analysis. At a dose of 30mg/kg, JNJ-26146900 significantly reduced castration-induced tibial bone loss as indicated by the following parameters: bone volume, trabecular connectivity, trabecular number and spacing between trabeculae. Bone mineral density decreased from 229+/-34mg/cm(3) of hydroxyapatite to 166+/-26mg/cm(3) following orchidectomy, and was maintained at 194+/-20mg/cm(3) with JNJ-26146900 treatment (Pselective androgen receptor modulators (SARMs) have the potential for anabolic effects on bone and muscle while maintaining therapeutic efficacy in prostate cancer.

  12. Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter.

    Science.gov (United States)

    Ahn, M; Lee, S-J; Li, X; Jiménez, J A; Zhang, Y-P; Bae, K-H; Mohammadi, Y; Kao, C; Gardner, T A

    2009-01-01

    Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 microg ml(-1)), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.

  13. The novel tumor-suppressor Mel-18 in prostate cancer: its functional polymorphism, expression and clinical significance.

    Science.gov (United States)

    Wang, Wei; Yuasa, Takeshi; Tsuchiya, Norihiko; Ma, Zhiyong; Maita, Shinya; Narita, Shintaro; Kumazawa, Teruaki; Inoue, Takamitsu; Tsuruta, Hiroshi; Horikawa, Yohei; Saito, Mitsuru; Hu, Weilie; Ogawa, Osamu; Habuchi, Tomonori

    2009-12-15

    Mel-18 is a member of the polycomb group (PcG) proteins, which are chromatin regulatory factors and play important roles in development and oncogenesis. This study was designed to investigate the clinical and prognostic significance of Mel-18 in patients with prostate cancer. A total of 539 native Japanese subjects consisting of 393 prostate cancer patients and 146 controls were enrolled in this study. Mel-18 genotyping was analyzed using a PCR-RFLP method and an automated sequencer using the GENESCAN software. Immunohistochemistry revealed that Mel-18 expression was diminished in high grade and high stage prostate cancers. Moreover, patients with positive Mel-18 expression had significantly longer PSA recurrence-free survival than patients negative for Mel-18 expression (p=0.038). A Mel-18 1805A/G SNP was located in the 3' untranslated region and was predicted to alter the secondary structure of the mRNA. Mel-18 mRNA expression of the 1805A allele was clearly higher than expression of the 1805G allele by allele specific quantitative RT-PCR. In multivariate analysis, a homozygous G allele genotype and negative Mel-18 expression were independent risk factors predicting high PSA recurrence after radical prostatectomy, with HRs of 2.757 (p=0.022) and 2.271 (p=0.045), respectively. Moreover, the G allele was also an independent predictor of poor cancer-specific survival with an HR of 4.658 (p=0.019) for patients with stage D2 prostate cancer. This is the first study to provide important evidence demonstrating that Mel-18 is a tumor suppressor and possible therapeutic target, as well as a diagnostic marker for poor prognosis in prostate cancer patients. Copyright (c) 2009 UICC.

  14. A completely calcified prostate

    Directory of Open Access Journals (Sweden)

    Vinod Priyadarshi

    2016-01-01

    Full Text Available Prostatic calcification and prostatic calculus formation is commonly seen in adult population with chronic prostatitis, however, gross prostatic calcification which involves more than 3 cm2 of the gland is quite rare. We are presenting here one such case in which almost whole glandular prostate was converted into stone which is never reported so far.

  15. Does Local Recurrence of Prostate Cancer After Radiation Therapy Occur at the Site of Primary Tumor? Results of a Longitudinal MRI and MRSI Study

    International Nuclear Information System (INIS)

    Arrayeh, Elnasif; Westphalen, Antonio C.; Kurhanewicz, John; Roach, Mack; Jung, Adam J.; Carroll, Peter R.; Coakley, Fergus V.

    2012-01-01

    Purpose: To determine if local recurrence of prostate cancer after radiation therapy occurs at the same site as the primary tumor before treatment, using longitudinal magnetic resonance (MR) imaging and MR spectroscopic imaging to assess dominant tumor location. Methods and Materials: This retrospective study was HIPAA compliant and approved by our Committee on Human Research. We identified all patients in our institutional prostate cancer database (1996 onward) who underwent endorectal MR imaging and MR spectroscopic imaging before radiotherapy for biopsy-proven prostate cancer and again at least 2 years after radiotherapy (n = 124). Two radiologists recorded the presence, location, and size of unequivocal dominant tumor on pre- and postradiotherapy scans. Recurrent tumor was considered to be at the same location as the baseline tumor if at least 50% of the tumor location overlapped. Clinical and biopsy data were collected from all patients. Results: Nine patients had unequivocal dominant tumor on both pre- and postradiotherapy imaging, with mean pre- and postradiotherapy dominant tumor diameters of 1.8 cm (range, 1–2.2) and 1.9 cm (range, 1.4–2.6), respectively. The median follow-up interval was 7.3 years (range, 2.7–10.8). Dominant recurrent tumor was at the same location as dominant baseline tumor in 8 of 9 patients (89%). Conclusions: Local recurrence of prostate cancer after radiation usually occurs at the same site as the dominant primary tumor at baseline, suggesting supplementary focal therapy aimed at enhancing local tumor control would be a rational addition to management.

  16. Prostate tumor progression in the TRAMP mouse. Protective effects of the aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

    Fritz, W.; Lin, T.M.; Peterson, R. [Wisconsin Univ., Madison, WI (United States)

    2004-09-15

    The developing male reproductive system is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD binds to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, to produce sustained alterations in gene expression. Mice lacking the AhR (AhRKO, Ahr{sup -/-}) have permitted further characterization of the role of the AhR in mediating TCDD effects and revealed a physiological role for the AhR in normal development. We previously demonstrated that in utero and lactational TCDD exposure significantly reduced ventral, dorsolateral and anterior prostate weights, and that these effects were dependent on the AhR5. However, reductions in prostate lobe weights in untreated, AhRKO mice compared to wild-type counterparts at various ages demonstrated that the AhR signaling pathway is involved in normal development of the dorsolateral and anterior prostates, but apparently not the ventral prostate. Unaltered serum testosterone concentrations and modest reduction in serum 5{alpha}-androstane-3{alpha},17{beta}a-diol concentrations could not account for reductions in prostate weights in mice lacking AhR (Ahr{sup -/-}). Normal histology and lack of alteration in androgen receptor mRNA levels further indicate that the reduction in prostate weights is not a result of reduced androgen action in AhRKO mice. The observation that regulation of early prostate growth in mice occurs following AhR activation by TCDD, as well as by loss of AhR, suggests that the AhR may also regulate aberrant prostate growth that results from ''reawakening'' of the prostate growth regulatory signals later in life. Our objective was to determine if the AhR signaling pathway has an effect on prostate cancer development.

  17. Contribution of Interstitial Deletion of 21q22.2-3 per se to Prostate Cancer Progression in Tumors Harboring TMPRSS2-ERG Translocations

    Science.gov (United States)

    2015-12-01

    harboring TMPRSS2- ERG translocations PRINCIPAL INVESTIGATOR: Yan Dong CONTRACTING ORGANIZATION: Tulane University New Orleans, LA 70112...0485 to prostate cancer progression in tumors harboring TMPRSS2- ERG translocations 5b. GRANT NUMBER W81XWH-14-1-0485 5c. PROGRAM ELEMENT NUMBER...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT TMPRSS2- ERG gene fusions are present in close to 50% of human prostate cancers. Approximately half of the

  18. Prostate cancer incidence and tumor severity in Georgia: descriptive epidemiology, racial disparity, and geographic trends.

    Science.gov (United States)

    Wagner, Sara E; Bauer, Sarah E; Bayakly, A Rana; Vena, John E

    2013-01-01

    Limited research has been conducted to describe the geographical clustering and distribution of prostate cancer (PrCA) incidence in Georgia (GA). This study describes and compares the temporal and geographic trends of PrCA incidence in GA with a specific focus on racial disparities. GA Comprehensive Cancer Registry PrCA incidence data were obtained for 1998-2008. Directly standardized age-adjusted PrCA incidence rates per 100,000 were analyzed by race, stage, grade, and county. County-level hotspots of PrCA incidence were analyzed with the Getis-Ord Gi* statistic in a geographic information system; a census tract-level cluster analysis was performed with a Discrete Poisson model and implemented in SaTScan(®) software. Significant (p incidence were observed in nine southwestern counties and six centrally located counties among men of both races. Six significant (p incidence rates were detected for men of both races in north and northwest central Georgia. When stratified by race, clusters among white and black men were similar, although centroids were slightly shifted. Most notably, a large (122 km radius) cluster in northwest central Georgia was detected only in whites, and two smaller clusters (0-32 km radii) were detected in Southwest Georgia only in black men. Clusters of high-grade and late-stage tumors were identified primarily in the northern portion of the state among men of both races. This study revealed a pattern of higher incidence and more advanced disease in northern and northwest central Georgia, highlighting geographic patterns that need more research and investigation of possible environmental determinants.

  19. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Giesel, Frederik L.; Vinsensia, M.; Mier, W.; Haberkorn, U.; Kratochwil, C. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Hadaschik, B.; Radtke, J.; Kesch, C. [University Hospital Heidelberg, Department of Urology, Heidelberg (Germany); Cardinale, J.; Schaefer, M.; Neels, O.C.; Kopka, K. [German Cancer Research Center (dkfz), Division of Radiopharmaceutical Chemistry, Heidelberg (Germany); Lehnert, W. [ABX-CRO, Dresden (Germany); Tolstov, Y.; Singer, S. [University Hospital Heidelberg, Section of Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, Heidelberg (Germany); Grabe, N. [University Hospital Heidelberg, Institute of Pathology, Heidelberg (Germany); University Hospital Heidelberg, Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg (Germany); University of Heidelberg, Hamamatsu Tissue Imaging and Analysis Center, Heidelberg (Germany); Duensing, S. [University Hospital Heidelberg, Department of Urology, Heidelberg (Germany); University Hospital Heidelberg, Section of Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, Heidelberg (Germany)

    2017-04-15

    The prostate-specific membrane antigen (PSMA) targeted positron-emitting-tomography (PET) tracer {sup 68}Ga-PSMA-11 shows great promise in the detection of prostate cancer. However, {sup 68}Ga has several shortcomings as a radiolabel including short half-life and non-ideal energies, and this has motivated consideration of {sup 18}F-labelled analogs. {sup 18}F-PSMA-1007 was selected among several {sup 18}F-PSMA-ligand candidate compounds because it demonstrated high labelling yields, outstanding tumor uptake and fast, non-urinary background clearance. Here, we describe the properties of {sup 18}F-PSMA-1007 in human volunteers and patients. Radiation dosimetry of {sup 18}F-PSMA-1007 was determined in three healthy volunteers who underwent whole-body PET-scans and concomitant blood and urine sampling. Following this, ten patients with high-risk prostate cancer underwent {sup 18}F-PSMA-1007 PET/CT (1 h and 3 h p.i.) and normal organ biodistribution and tumor uptakes were examined. Eight patients underwent prostatectomy with extended pelvic lymphadenectomy. Uptake in intra-prostatic lesions and lymph node metastases were correlated with final histopathology, including PSMA immunostaining. With an effective dose of approximately 4.4-5.5 mSv per 200-250 MBq examination, {sup 18}F-PSMA-1007 behaves similar to other PSMA-PET agents as well as to other {sup 18}F-labelled PET-tracers. In comparison to other PSMA-targeting PET-tracers, {sup 18}F-PSMA-1007 has reduced urinary clearance enabling excellent assessment of the prostate. Similar to {sup 18}F-DCFPyL and with slightly slower clearance kinetics than PSMA-11, favorable tumor-to-background ratios are observed 2-3 h after injection. In eight patients, diagnostic findings were successfully validated by histopathology. {sup 18}F-PSMA-1007 PET/CT detected 18 of 19 lymph node metastases in the pelvis, including nodes as small as 1 mm in diameter. {sup 18}F-PSMA-1007 performs at least comparably to {sup 68}Ga-PSMA-11, but its

  20. Prostate Tumor Growth Can Be Modulated by Dietarily Targeting the 15-Lipoxygenase-1 and Cyclooxygenase-2 Enzymes

    Directory of Open Access Journals (Sweden)

    Uddhav P. Kelavkar

    2009-07-01

    Full Text Available The main objectives of our study were to determine the bioavailability of omega-3 (ω-3 to the tumor, to understand its mechanisms, and to determine the feasibility of targeting the ω-6 polyunsaturated fatty acids (PUFAs metabolizing 15-lipoxygenase-1 (15-LO-1 and cyclooxygenase-2 (COX-2 pathways. Nude mice injected subcutaneously with LAPC-4 prostate cancer cells were randomly divided into three different isocaloric (and same percent [%] of total fat diet groups: high ω-6 linoleic acid (LA, high ω-3 stearidonic acid (SDA PUFAs, and normal (control diets. Tumor growth and apoptosis were examined as end points after administration of short-term (5 weeks ω-3 and ω-6 fatty acid diets. Tumor tissue membranes were examined for growth, lipids, enzyme activities, apoptosis, and proliferation. Tumors from the LA diet-fed mice exhibited the most rapid growth compared with tumors from the control and SDA diet-fed mice. Moreover, a diet switch from LA to SDA caused a dramatic decrease in the growth of tumors in 5 weeks, whereas tumors grew more aggressively when mice were switched from an SDA to an LA diet. Evaluating tumor proliferation (Ki-67 and apoptosis (caspase-3 in mice fed the LA and SDA diets suggested increased percentage proliferation index from the ω-6 diet-fed mice compared with the tumors from the ω-3 SDA-fed mice. Further, increased apoptosis was observed in tumors from ω-3 SDA diet-fed mice versus tumors from ω-6 diet-fed mice. Levels of membrane phospholipids of red blood cells reflected dietary changes and correlated with the levels observed in tumors. Linoleic or arachidonic acid and metabolites (eicosanoid/prostaglandins were analyzed for 15-LO-1 and COX-2 activities by high-performance liquid chromatography. We also examined the percent unsaturated or saturated fatty acids in the total phospholipids, PUFA ω-6/ω-3 ratios, and other major enzymes (elongase, Delta [Δ]-5-desaturase, and Δ-6-desaturase of ω-6 catabolic

  1. Inhibition of vimentin or B1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xueping; Fournier, Marcia V; Ware, Joy L; Bissell, Mina J; Yacoub, Adly; Zehner, Zendra E

    2008-06-12

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphologic changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the immortalized, prostate epithelial P69 cell line by selection in athymic, nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the parental, nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin, or {alpha}6 and {beta}1 integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via small interfering RNA interference or the expression of {alpha}6 and {beta}1 integrins by the addition of blocking antibodies, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by s.c. injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in three-dimensional lrECM gels. These studies suggest that the levels of vimentin and {beta}1 integrin play a key role in the homeostasis of the normal acinus in prostate and that their dysregulation may lead to tumorigenesis. [Mol Cancer Ther 2009;8(3):499-508].

  2. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-01-01

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

  3. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study.

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-08-23

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs.Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.

  4. RADIONUCLIDE STUDIES USING TUMOR-SEEKING RADIOPHARMACEUTICALS IN THE DIAGNOSIS OF PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    N. I. Tarassov

    2009-01-01

    Full Text Available Object: to evaluate the efficiency of prostate scintigraphy in the prebioptic diagnosis of prostate cancer (PC.Subjects and methods. Two hundred and two patients with suspected PC underwent comprehensive examination, including 99mTc-technetril prostate scintigraphy and a morphometric study of biopsy material columns. A computer program (official registration certificate No. 2007614475 dated October 24, 2007 was worked out and patented to calculate the intensity of accumulation of radiopharmaceuticals in different portions of the right and left prostate lobes.Results and discussion. When the division index point «pathological focus/background», 1.5; ≤ 1.5, healthy; > 1.5 suspected prostate cancer was used, the sensitivity of prostate scintigraphy was 81.65%; its specificity was 87.1%; the diagnostic effectiveness was 84.37%.Conclusion: The application of prostate scintigraphy can improve indicators for early detection of PC, due to the purposeful detection of the points, enhance the effectiveness of biopsy, and, having more grounds than the early ones, to exclude this disease at the prebioptic stage. The method is noninvasive and can be used to monitor patients with suspected PC.

  5. RADIONUCLIDE STUDIES USING TUMOR-SEEKING RADIOPHARMACEUTICALS IN THE DIAGNOSIS OF PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    N. I. Tarassov

    2014-08-01

    Full Text Available Object: to evaluate the efficiency of prostate scintigraphy in the prebioptic diagnosis of prostate cancer (PC.Subjects and methods. Two hundred and two patients with suspected PC underwent comprehensive examination, including 99mTc-technetril prostate scintigraphy and a morphometric study of biopsy material columns. A computer program (official registration certificate No. 2007614475 dated October 24, 2007 was worked out and patented to calculate the intensity of accumulation of radiopharmaceuticals in different portions of the right and left prostate lobes.Results and discussion. When the division index point «pathological focus/background», 1.5; ≤ 1.5, healthy; > 1.5 suspected prostate cancer was used, the sensitivity of prostate scintigraphy was 81.65%; its specificity was 87.1%; the diagnostic effectiveness was 84.37%.Conclusion: The application of prostate scintigraphy can improve indicators for early detection of PC, due to the purposeful detection of the points, enhance the effectiveness of biopsy, and, having more grounds than the early ones, to exclude this disease at the prebioptic stage. The method is noninvasive and can be used to monitor patients with suspected PC.

  6. Industasis, a promotion of tumor formation by nontumorigenic stray cells

    Czech Academy of Sciences Publication Activity Database

    Pajer, Petr; Karafiát, Vít; Pečenka, Vladimír; Průková, Dana; Dudlová, J.; Plachý, Jiří; Kašparová, P.; Dvořák, Michal

    2009-01-01

    Roč. 69, č. 11 (2009), s. 4605-4612 ISSN 0008-5472 R&D Projects: GA ČR GA204/06/1728; GA MŠk(CZ) LC06061; GA AV ČR IAA500520608 Institutional research plan: CEZ:AV0Z50520514 Keywords : tumor promotion * lung tumors * Fyn-related kinase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.543, year: 2009

  7. DWI-associated entire-tumor histogram analysis for the differentiation of low-grade prostate cancer from intermediate-high-grade prostate cancer.

    Science.gov (United States)

    Wu, Chen-Jiang; Wang, Qing; Li, Hai; Wang, Xiao-Ning; Liu, Xi-Sheng; Shi, Hai-Bin; Zhang, Yu-Dong

    2015-10-01

    To investigate diagnostic efficiency of DWI using entire-tumor histogram analysis in differentiating the low-grade (LG) prostate cancer (PCa) from intermediate-high-grade (HG) PCa in comparison with conventional ROI-based measurement. DW images (b of 0-1400 s/mm(2)) from 126 pathology-confirmed PCa (diameter >0.5 cm) in 110 patients were retrospectively collected and processed by mono-exponential model. The measurement of tumor apparent diffusion coefficients (ADCs) was performed with using histogram-based and ROI-based approach, respectively. The diagnostic ability of ADCs from two methods for differentiating LG-PCa (Gleason score, GS ≤ 6) from HG-PCa (GS > 6) was determined by ROC regression, and compared by McNemar's test. There were 49 LG-tumor and 77 HG-tumor at pathologic findings. Histogram-based ADCs (mean, median, 10th and 90th) and ROI-based ADCs (mean) showed dominant relationships with ordinal GS of Pca (ρ = -0.225 to -0.406, p Histogram 10th ADCs had dominantly high Az (0.738), Youden index (0.415), and positive likelihood ratio (LR+, 2.45) in stratifying tumor GS against mean, median and 90th ADCs, and ROI-based ADCs. Histogram mean, median, and 10th ADCs showed higher specificity (65.3%-74.1% vs. 44.9%, p histogram analysis had higher specificity, Az, Youden index, and LR+ for differentiation of PCa Gleason grade than ROI-based approach.

  8. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice

    Energy Technology Data Exchange (ETDEWEB)

    Moore, Robert W., E-mail: robert.moore@wisc.edu [School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705 (United States); Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706 (United States); Fritz, Wayne A., E-mail: Wayne.Fritz@covance.com [School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705 (United States); Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706 (United States); Schneider, Andrew J., E-mail: ajschnei@wisc.edu [School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705 (United States); Lin, Tien-Min, E-mail: tlin1@facstaff.wisc.edu [School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705 (United States); Branam, Amanda M., E-mail: bran2117@hotmail.com [School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705 (United States); Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706 (United States); Safe, Stephen, E-mail: SSAFE@cvm.tamu.edu [Department of Veterinary Physiology and Pharmacology, 4466 TAMU, Texas A& M University, College Station, TX 77843 (United States); Peterson, Richard E., E-mail: richard.peterson@wisc.edu [School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705 (United States); Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706 (United States)

    2016-08-15

    It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3′-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures. - Highlights: • TRAMP mice model aggressive neuroendocrine prostate carcinomas in men • In utero/lactational TCDD exposure raised prostate cancer incidence in TRAMP mice. • TCDD treatment in adulthood lowered prostate cancer incidence in TRAMP mice. • No significant protection was seen in TRAMP mice given I3C or DIM in adulthood. • This is the first report that TCDD alters prostate cancer incidence in lab animals.

  9. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice

    International Nuclear Information System (INIS)

    Moore, Robert W.; Fritz, Wayne A.; Schneider, Andrew J.; Lin, Tien-Min; Branam, Amanda M.; Safe, Stephen; Peterson, Richard E.

    2016-01-01

    It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3′-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures. - Highlights: • TRAMP mice model aggressive neuroendocrine prostate carcinomas in men • In utero/lactational TCDD exposure raised prostate cancer incidence in TRAMP mice. • TCDD treatment in adulthood lowered prostate cancer incidence in TRAMP mice. • No significant protection was seen in TRAMP mice given I3C or DIM in adulthood. • This is the first report that TCDD alters prostate cancer incidence in lab animals.

  10. Prostate cancer

    International Nuclear Information System (INIS)

    Bey, P.; Beckendorf, V.; Stines, J.

    2001-01-01

    Radiation therapy of prostate carcinoma with a curative intent implies to treat the whole prostate at high dose (at least 66 Gy). According to clinical stage, PSA level, Gleason's score, the clinical target volume may include seminal vesicles and less often pelvic lymph nodes. Microscopic extra-capsular extension is found in 15 to 60% of T1-T2 operated on, specially in apex tumors. On contrary, cancers developing from the transitional zone may stay limited to the prostate even with a big volume and with a high PSA level. Zonal anatomy of the prostate identifies internal prostate, including the transitional zone (5% of the prostate in young people). External prostate includes central and peripheral zones. The inferior limit of the prostate is not lower than the inferior border of the pubic symphysis. Clinical and radiological examination: ultrasonography, nuclear magnetic resonance (NMR), CT-scan identify prognostic factors as tumor volume, capsule effraction, seminal vesicles invasion and lymph node extension. The identification of the clinical target volume is now done mainly by CT-Scan which identifies prostate and seminal vesicles. NMR could be helpful to identify more precisely prostate apex. The definition of margins around the clinical target volume has to take in account daily reproducibility and organ motion and of course the maximum tolerable dose for organs at risk. (authors)

  11. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    ... (T) and dihydrotestosterone (DHT), and intraprostatic T and DHT in experimental animals. Thus, high fat diet is likely to modulate the ventral prostate weight via an androgen-independent mechanism...

  12. Investigation of the Candidate Tumor Suppressor Gene prk in Prostate Cancer

    National Research Council Canada - National Science Library

    Dai, Wei

    2002-01-01

    .... We have proposed to characterize the genetic and epigenetic basis of aberrant PLK3 transcripts detected in prostate cancer, their prevalence and possible clinical relevance, to test the functional...

  13. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    .... The dietary influence on ventral prostate weight does not seem to involve androgen action axis because dietary components did not influence the expression of several androgen-response genes, serum testosterone...

  14. Rapid In Vivo Validation of Tumor Suppressor Gene Function in Prostate Cancer Progression

    Science.gov (United States)

    2016-07-01

    identification of the best sgRNA sequences and accelerated our ability to move to the in vivo studies proposed in Aim2. Our goal was to use CRISPR / Cas ...and to initiate prostate cancer in the mouse after injection of lentiviral particles expressing CRISPR / Cas components and Cre recombinase. Our initial...in vivo Our goal was to use CRISPR / Cas lentiviral transduction of the adult prostate to inactivate p53 or Rb. We aimed to recapitulate the effects of

  15. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity

    DEFF Research Database (Denmark)

    Danovi, Davide; Meulmeester, Erik; Pasini, Diego

    2004-01-01

    has been established. However, a direct contribution of Mdmx to tumor formation remains to be demonstrated. Here we show that retrovirus-mediated Mdmx overexpression allows primary mouse embryonic fibroblast immortalization and leads to neoplastic transformation in combination with HRas(V12...

  16. Characteristics Studies of 125I- and total PSA antibody's Binding with prostate specific antigen (PSA) in Human Uterus Tumors

    International Nuclear Information System (INIS)

    Al-Mudaffar, S.; Al-Salihi, J.

    2005-01-01

    Two groups of uterus tumors (benign and malignant) postmenopausal patients were used to investigate the presence of prostate specific antigen (PSA). Preliminary experiments were performed to follow the binding of '1 25 I-anti total PSA antibody with PSA in uterus tissues homogenates of the two groups with their corresponding antigen and found to be (8.8,7.1%) for benign and malignant tumors, respectively. An Immuno Radio Metric Assay (IRMA) procedure was developed for measuring PSA in benign and malignant uterus tumors homogenates. The optimum conditions of the binding of 125 I-anti total PSA antibody with PSA were as follows: PSA concentration (150,200 μg protein),tracer antibody concentration (125,250 μg protein), p H (7.6,7.2), temp (15,25?C) and time (1.5 hrs) for postmenopausal benign and malignant uterus tumors tissue homogenates, respectively. The use of different concentrations of Na + and Mg 2+ ions were shown to cause an increase in the binding at concentration of (125,75 mΜ) of Na 1+ ions (75,225 mΜ) of Mg 2+ ions for benign and malignant uterus tumors homogenates, respectively, while the use of different concentrations of urea and polyethylene glycol (PEG) Caused a decrease in the binding with the increase in the concentration of each of urea and PEG in the both cases

  17. Larger Maximum Tumor Diameter at Radical Prostatectomy Is Associated With Increased Biochemical Failure, Metastasis, and Death From Prostate Cancer After Salvage Radiation for Prostate Cancer

    International Nuclear Information System (INIS)

    Johnson, Skyler B.; Hamstra, Daniel A.; Jackson, William C.; Zhou, Jessica; Foster, Benjamin; Foster, Corey; Song, Yeohan; Li, Darren; Palapattu, Ganesh S.; Kunju, Lakshmi; Mehra, Rohit; Sandler, Howard; Feng, Felix Y.

    2013-01-01

    Purpose: To investigate the maximum tumor diameter (MTD) of the dominant prostate cancer nodule in the radical prostatectomy specimen as a prognostic factor for outcome in patients treated with salvage external beam radiation therapy (SRT) for a rising prostate-specific antigen (PSA) value after radical prostatectomy. Methods and Materials: From an institutional cohort of 575 patients treated with SRT, data on MTD were retrospectively collected. The impact of MTD on biochemical failure (BF), metastasis, and prostate cancer-specific mortality (PCSM) was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox proportional hazards models. Results: In the 173 patients with MTD data available, median follow-up was 77 months (interquartile range, 47-104 months) after SRT, and median MTD was 18 mm (interquartile range, 13-22 mm). Increasing MTD correlated with increasing pT stage, Gleason score, presence of seminal vesicle invasion, and lymph node invasion. Receiver operating characteristic curve analysis identified MTD of >14 mm to be the optimal cut-point. On univariate analysis, MTD >14 mm was associated with an increased risk of BF (P=.02, hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.8), metastasis (P=.002, HR 4.0, 95% CI 2.1-7.5), and PCSM (P=.02, HR 8.0, 95% CI 2.9-21.8). On multivariate analysis MTD >14 mm remained associated with increased BF (P=.02, HR 1.9, 95% CI 1.1-3.2), metastasis (P=.02, HR 3.4, 95% CI 1.2-9.2), and PCSM (P=.05, HR 9.7, 95% CI 1.0-92.4), independent of extracapsular extension, seminal vesicle invasion, positive surgical margins, pre-RT PSA value, Gleason score, and pre-RT PSA doubling time. Conclusions: For patients treated with SRT for a rising PSA value after prostatectomy, MTD at time of radical prostatectomy is independently associated with BF, metastasis, and PCSM. Maximum tumor diameter should be incorporated into clinical decision making and future clinical risk assessment tools for those patients

  18. Pterostilbene acts through metastasis-associated protein 1 to inhibit tumor growth, progression and metastasis in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Kun Li

    Full Text Available The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1, which is a part of nucleosome remodeling and deacetylation (NuRD co-repressor complex that mediates gene silencing. We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa. In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER, found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.

  19. Expression of immunosuppresive B7-H3 ligand by hormone-treated prostate cancer tumors and metastases.

    Science.gov (United States)

    Chavin, Grant; Sheinin, Yuri; Crispen, Paul L; Boorjian, Stephen A; Roth, Timothy J; Rangel, Laureano; Blute, Michael L; Sebo, Thomas J; Tindall, Don J; Kwon, Eugene D; Karnes, R Jeffrey

    2009-03-15

    Prostate cancer cells uniformly express the immune cell inhibitory B7-H3 ligand. Enhanced B7-H3 expression correlates with increased disease progression and cancer-specific death after radical prostatectomy (RP). To further assess whether B7-H3 expression is hormone regulated and persists as a viable target during (or after) androgen-ablative therapy, we examined B7-H3 ligand expression within primary and metastatic cancer lesions in response to neoadjuvant hormone therapy (NHT) or palliative hormone deprivation. Tumor B7-H3 in RP specimens from men treated with >/=3 months of NHT was compared with B7-H3 in tumors from matched patients who received no therapy before RP. Hormone-treated and untreated metastatic lesions involving bone were also compared for levels of B7-H3 expression. Of 165 consecutive RP specimens in each cohort studied, sufficient tissues were available for 148 patients (89.7%) treated with NHT versus 127 patients (77.0%) treated with surgery alone. B7-H3 was expressed in 142 (95.9%) tumors from NHT patients compared with 122 (96.0%) tumors from patients treated with surgery alone (P = 0.91). B7-H3 expression intensity in RP specimens was not affected by NHT (P = 0.12). Bone metastases from 11 (32.4%) untreated and 23 (67.6%) androgen-ablated patients revealed that B7-H3 expression increased in response to hormone therapy (P = 0.04) relative to untreated lesions. Taken together, B7-H3 expression seems to remain stable (or may even increase) in response to hormone therapy. As such, B7-H3 may represent an attractive target to improve treatment of men with high-risk hormone-treated or refractory prostate cancer.

  20. Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity.

    Directory of Open Access Journals (Sweden)

    Jeong-Kook Kim

    Full Text Available Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3 contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2 or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.

  1. Diagnosis of prostate cancer in patients with persistently elevated PSA and tumor-negative biopsy in ambulatory care. Performance of MR imaging in a multi-reader environment

    International Nuclear Information System (INIS)

    Scheidler, J.; Weoeres, I.; Scharf, M.; Siebels, M.; Brinkschmidt, C.; Zeitler, H.; Heuck, A.; Panzer, S.

    2012-01-01

    Purpose: False-negative results are obtained in approx. 20 % of prostate cancer (PCa) patients (pts) at initial systematic transrectal biopsy (Bx), in particular when digital rectal examination (DRE) or transrectal ultrasound (TRUS) is negative. The aim of this study was to assess whether MR endorectal imaging of the prostate in a multi-reader ambulatory care setting may assist in patient selection for re-biopsy. Materials and Methods: 115 consecutive pts with persistent PSA elevation, negative Bx, DRE and TRUS were examined using T2w axial and coronal and T1w axial sequences for tumor diagnosis. MR images were prospectively read as tumor-suspicious or tumor-negative by the MR radiologist on duty. Additionally, a retrospective readout of a prostate MR expert and an abdominal imaging fellowship-trained radiologist was performed to evaluate the effect of the reader's experience on tumor detection. Imaging findings were compared to the results of the repeat Bx (61 pts) or the clinical course of at least two years. Results: For the prospective reading, the sensitivity of MRI was 83 %, the specificity was 69 %, the PPV was 33 % and the NPV was 96 %. ROC analysis revealed a significantly better performance of the prostate MR imaging expert compared to the abdominal imaging radiologist (area under ROC 0.88 vs. 0.66, p < 0.001). Based on the prospective reading, a pre-test probability for PCa of 17.4 % as in our study can be reduced to 5 % when obtaining a tumor-negative result in MRI. Conclusion: MR imaging in a multi-reader ambulatory care setting assists in patient selection for re-biopsy. Reducing the post-test probability for PCa to 5 % allows for further follow-up instead of re-biopsy in MR tumor-negative patients. Specific training and experience improve tumor detection in prostate MR imaging. (orig.)

  2. Diagnosis of prostate cancer in patients with persistently elevated PSA and tumor-negative biopsy in ambulatory care. Performance of MR imaging in a multi-reader environment

    Energy Technology Data Exchange (ETDEWEB)

    Scheidler, J. [Radiologisches Zentrum Muenchen-Pasing, Muenchen (Germany); Weoeres, I.; Scharf, M.; Siebels, M. [Urologische Gemeinschaftspraxis Pasing (Germany); Brinkschmidt, C. [Gemeinschaftspraxis Pathologie, Starnberg (Germany); Zeitler, H.; Heuck, A. [Radiologisches Zentrum Muenchen (Germany); Panzer, S. [Unfallklinik Murnau (Germany). Radiologie

    2012-02-15

    Purpose: False-negative results are obtained in approx. 20 % of prostate cancer (PCa) patients (pts) at initial systematic transrectal biopsy (Bx), in particular when digital rectal examination (DRE) or transrectal ultrasound (TRUS) is negative. The aim of this study was to assess whether MR endorectal imaging of the prostate in a multi-reader ambulatory care setting may assist in patient selection for re-biopsy. Materials and Methods: 115 consecutive pts with persistent PSA elevation, negative Bx, DRE and TRUS were examined using T2w axial and coronal and T1w axial sequences for tumor diagnosis. MR images were prospectively read as tumor-suspicious or tumor-negative by the MR radiologist on duty. Additionally, a retrospective readout of a prostate MR expert and an abdominal imaging fellowship-trained radiologist was performed to evaluate the effect of the reader's experience on tumor detection. Imaging findings were compared to the results of the repeat Bx (61 pts) or the clinical course of at least two years. Results: For the prospective reading, the sensitivity of MRI was 83 %, the specificity was 69 %, the PPV was 33 % and the NPV was 96 %. ROC analysis revealed a significantly better performance of the prostate MR imaging expert compared to the abdominal imaging radiologist (area under ROC 0.88 vs. 0.66, p < 0.001). Based on the prospective reading, a pre-test probability for PCa of 17.4 % as in our study can be reduced to 5 % when obtaining a tumor-negative result in MRI. Conclusion: MR imaging in a multi-reader ambulatory care setting assists in patient selection for re-biopsy. Reducing the post-test probability for PCa to 5 % allows for further follow-up instead of re-biopsy in MR tumor-negative patients. Specific training and experience improve tumor detection in prostate MR imaging. (orig.)

  3. Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules.

    Science.gov (United States)

    Masoodi, Khalid Z; Xu, Yadong; Dar, Javid A; Eisermann, Kurtis; Pascal, Laura E; Parrinello, Erica; Ai, Junkui; Johnston, Paul A; Nelson, Joel B; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120-9. ©2017 AACR . ©2017 American Association for Cancer Research.

  4. Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

    Science.gov (United States)

    Deep, Gagan; Panigrahi, Gati K.

    2017-01-01

    Prostate cancer (PCA) is the leading malignancy in men and the second leading cause of cancer-related deaths. Hypoxia (low O2 condition) is considered an early event in prostate carcinogenesis associated with an aggressive phenotype. In fact, clinically, hypoxia and hypoxia-related biomarkers are associated with treatment failure and disease progression. Hypoxia-inducible factor 1 (HIF-1) is the key factor that is activated under hypoxia, and mediates adaptation of cells to hypoxic conditions through regulating the expression of genes associated with angiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis, survival, proliferation, metabolism, stemness, hormone-refractory progression, and therapeutic resistance. Besides HIF-1, several other signaling pathways including PI3K/Akt/mTOR, NADPH oxidase (NOX), Wnt/β-catenin, and Hedgehog are activated in cancer cells under hypoxic conditions, and also contribute in hypoxia-induced biological effects in HIF-1-dependent and -independent manners. Hypoxic cancer cells cause extensive changes in the tumor microenvironment both local and distant, and recent studies have provided ample evidence supporting the crucial role of nanosized vesicles “exosomes” in mediating hypoxia-induced tumor microenvironment remodeling. Exosomes’ role has been reported in hypoxia-induced angiogenesis, stemness, activation of cancer-associated fibroblasts (CAFs), and EMT. Together, existing literature suggests that hypoxia plays a predominant role in PCA growth and progression, and PCA could be effectively prevented and treated via targeting hypoxia/hypoxia-related signaling pathways. PMID:27279239

  5. Bacterial prostatitis.

    Science.gov (United States)

    Gill, Bradley C; Shoskes, Daniel A

    2016-02-01

    The review provides the infectious disease community with a urologic perspective on bacterial prostatitis. Specifically, the article briefly reviews the categorization of prostatitis by type and provides a distillation of new findings published on bacterial prostatitis over the past year. It also highlights key points from the established literature. Cross-sectional prostate imaging is becoming more common and may lead to more incidental diagnoses of acute bacterial prostatitis. As drug resistance remains problematic in this condition, the reemergence of older antibiotics such as fosfomycin, has proven beneficial. With regard to chronic bacterial prostatitis, no clear clinical risk factors emerged in a large epidemiological study. However, bacterial biofilm formation has been associated with more severe cases. Surgery has a limited role in bacterial prostatitis and should be reserved for draining of a prostatic abscess or the removal of infected prostatic stones. Prostatitis remains a common and bothersome clinical condition. Antibiotic therapy remains the basis of treatment for both acute and chronic bacterial prostatitis. Further research into improving prostatitis treatment is indicated.

  6. Evaluation of Tumor Viability for Primary and Bone Metastases in Metastatic Castration-Resistant Prostate Cancer Using Whole-Body Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Hiromichi Iwamura

    2018-01-01

    Full Text Available In contrast to bone scan and computed tomography (CT, which depend on osteoblastic response to detect bone metastasis, whole-body magnetic resonance imaging (WB-MRI may be able to directly detect viable tumors. A 75-year-old male who had progressive metastatic prostate cancer during primary androgen deprivation therapy was referred to our hospital. Although bone scan and CT showed multiple bone metastases, WB-MRI suggested nonviable bone metastasis and viable tumor of the primary lesion. Prostate needle biopsy demonstrated viable prostate cancer cells from 10 of 12 cores. In contrast, CT-guided needle biopsy from bone metastasis of the lumbar vertebra revealed no malignant cells. Based on these findings, we reasoned that viable tumor cells inducing disease progression may primarily exist in the primary lesions and not in the metastatic lesions, and combined prostate radiotherapy and systemic hormonal therapy resulted in successful clinical response and disease control. The use of WB-MRI to detect viable disease lesions may enable us to design optimal treatment strategies for patients with metastatic castration-resistant prostate cancer.

  7. Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure inhibit prostate tumor growth in TRAMP mice

    Czech Academy of Sciences Publication Activity Database

    Mikyšková, Romana; Indrová, Marie; Štěpánek, Ivan; Kanchev, Ivan; Bieblová, Jana; Vošahlíková, Š.; Moserová, I.; Truxová, I.; Fučíková, J.; Bartunkova, J.; Spisek, R.; Sedláček, Radislav; Reiniš, Milan

    2017-01-01

    Roč. 6, č. 12 (2017), č. článku e1362528. ISSN 2162-402X R&D Projects: GA MŠk(CZ) LM2015040; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk ED2.1.00/19.0395; GA ČR GA15-24769S Institutional support: RVO:68378050 Keywords : dendritic cells * docetaxel * high hydrostatic pressure * immunotherapy * prostate cancer Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Immunology Impact factor: 7.719, year: 2016

  8. PC-3 prostate carcinoma cells release signal substances that influence the migratory activity of cells in the tumor's microenvironment

    Directory of Open Access Journals (Sweden)

    Zänker Kurt S

    2010-07-01

    Full Text Available Abstract Background Tumor cells interact with the cells of the microenvironment not only by cell-cell-contacts but also by the release of signal substances. These substances are known to induce tumor vascularization, especially under hypoxic conditions, but are also supposed to provoke other processes such as tumor innervation and inflammatory conditions. Inflammation is mediated by two organ systems, the neuroendocrine system and the immune system. Therefore, we investigated the influence of substances released by PC-3 human prostate carcinoma cells on SH-SY5Y neuroblastoma cells as well as neutrophil granulocytes and cytotoxic T lymphocytes, especially with regard to their migratory activity. Results PC-3 cells express several cytokines and growth factors including vascular endothelial growth factors, fibroblast growth factors, interleukins and neurotrophic factors. SH-SY5Y cells are impaired in their migratory activity by PC-3 cell culture supernatant, but orientate chemotactically towards the source. Neutrophil granulocytes increase their locomotory activity only in response to cell culture supernantant of hypoxic but not of normoxic PC-3 cells. In contrast, cytotoxic T lymphocytes do not change their migratory activity in response to either culture supernatant, but increase their cytotoxicity, whereas supernatant of normoxic PC-3 cells leads to a stronger increase than that of hypoxic PC-3 cells. Conclusions PC-3 cells release several signal substances that influence the behavior of the cells in the tumor's microenvironment, whereas no clear pattern towards proinflammatory or immunosuppressive conditions can be seen.

  9. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

    OpenAIRE

    Piwen Wang; Walter Solorzano; Tanya Diaz; Clara E. Magyar; Susanne M. Henning; Jaydutt V. Vadgama

    2017-01-01

    The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower dos...

  10. SU-E-J-228: MRI-Based Planning: Dosimetric Feasibility of Dose Painting for ADCDefined Intra-Prostatic Tumor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, X; Dalah, E; Prior, P; Lawton, C; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States)

    2015-06-15

    Purpose: Apparent diffusion coefficient (ADC) map may help to delineate the gross tumor volume (GTV) in prostate gland. Dose painting with external beam radiotherapy for GTV might increase the local tumor control. The purpose of this study is to explore the maximum boosting dose on GTV using VMAT without sacrificing sparing of organs at risk (OARs) in MRI based planning. Methods: VMAT plans for 5 prostate patients were generated following the commonly used dose volume (DV) criteria based on structures contoured on T2 weighted MRI with bulk electron density assignment using electron densities derived from ICRU46. GTV for each patient was manually delineated based on ADC maps and fused to T2-weighted image set for planning study. A research planning system with Monte Carlo dose engine (Monaco, Elekta) was used to generate the VMAT plans with boosting dose on GTV gradually increased from 85Gy to 100Gy. DV parameters, including V(boosting-dose) (volume covered by boosting dose) for GTV, V75.6Gy for PTV, V45Gy, V70Gy, V72Gy and D1cc (Maximum dose to 1cc volume) for rectum and bladder, were used to measure plan quality. Results: All cases achieve at least 99.0% coverage of V(boosting-dose) on GTV and 95% coverage of V75.6Gy to the PTV. All the DV criteria, V45Gy≤50% and V70Gy≤15% for bladder and rectum, D1cc ≤77Gy (Rectum) and ≤80Gy (Bladder), V72Gy≤5% (rectum and bladder) were maintained when boosting GTV to 95Gy for all cases studied. Except for two patients, all the criteria were also met when the boosting dose goes to 100Gy. Conclusion: It is dosimetrically feasible safe to boost the dose to at least 95Gy to ADC defined GTV in prostate cancer using MRI guided VMAT delivery. Conclusion: It is dosimetrically feasible safe to boost the dose to at least 95Gy to ADC defined GTV in prostate cancer using MRI guided VMAT delivery. This research is partially supported by Elekta Inc.

  11. Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors.

    Science.gov (United States)

    Milowsky, Matthew I; Nanus, David M; Kostakoglu, Lale; Sheehan, Christine E; Vallabhajosula, Shankar; Goldsmith, Stanley J; Ross, Jeffrey S; Bander, Neil H

    2007-02-10

    Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response. Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received 111Indium (111ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of 111In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues. Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by 111In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment. Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.

  12. Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models.

    Directory of Open Access Journals (Sweden)

    Lucie Carolle Kenmogne

    Full Text Available In the fight against androgen-sensitive prostate cancer, the enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3 is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17β-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione; rather, the levels of the androgens testosterone (T and dihydrotestosterone (DHT increased within the tumors. In plasma, however, DHT levels increased but T levels did not. In troubleshooting experiments, the non-androgenic potential of RM-532-105 was confirmed by two different assays (LAPC-4 proliferation and androgen receptor transcriptional activity assays. The enzyme 5α-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5α-androstane-3,17-dione and not T. Other 17β-HSDs than 17β-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17β-HSD3 inhibitor RM-532-105 is concentrated inside tumors.

  13. Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

    Science.gov (United States)

    Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

    2017-01-01

    Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  14. In vitro and in vivo studies in Balb-c and nude mice of a new 177Lu-Bombesin analog developed for prostate tumor diagnosis and treatment

    International Nuclear Information System (INIS)

    Pujatti, Priscilla B.; Santos, Josefina S.; Couto, Renata M.; Araujo, Elaine B. de; Mengatti, Jair; Suzuki, Miriam F.

    2009-01-01

    In this work we describe the radiolabeling with 177 Lu and some properties of the novel bombesin analog BBNp6 - DOTA-X-BBN(6-14), where X is a spacer of six aminoacids. Bombesin (BBN) is an analog of human gastrin releasing peptide (GRP) isolated from the skin of the frog Bombina bombina in 1970. Development of radiolabeled BBN derivatives as agents for diagnostic imaging and systemic radiotherapy has increased considerable because of the observation that GRP receptors (GRPr) are over-expressed in a variety of human tumor cells, such as prostate tumor cells. 177 Lu-labeled peptides are attractive due to the excellent radiophysical properties and commercial availability of the radiometal. BBNp6 was labeled with high yield after reacting with 92.5 MBq of 177 LuCl3 at 90 deg C for 30 minutes and this mixture kept stable for more than 96 hours at 4 deg C and 1 hour in human plasma. In vivo studies showed a multicompartimental distribution model with fast blood clearance, mainly performed by renal pathway. In addition, 177 Lu-BBNp6 showed high affinity for PC-3 tumor xenografts, but not for pancreas and intestine (GRP positive tissues), suggesting its specificity and usefulness for prostate tumor treatment. Moreover, scintigraphic images showed that this derivative can also be a tool in this tumor diagnosis. So, BBNp6 is a promising radiopharmaceutical for prostate tumor imaging and treatment. (author)

  15. Development of lutetium-labeled bombesin derivates: relationship between structure and diagnostic-therapeutic activity for prostate tumor

    International Nuclear Information System (INIS)

    Pujatti, Priscilla Brunelli

    2009-01-01

    Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor peptide - have been shown to be massively over expressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel series of bombesin derivatives with lutetium-177 and to evaluate the relationship between their structure and diagnostic-therapeutic activity for prostate tumor. The generic structure of studied peptides is DOTA-Phe-(Gly) n -BBN(6-14), where DOTA is the chelator, n is the number of glycine amino acids of Phe-(Gly) n spacer and BBN(6-14) is the bombesin sequence from the amino acid 6 to the amino acid 14. Preliminary studies were done to establish the ideal labeling conditions for obtaining the highest yield of labeled bombesin derivatives, determined by instant thin layer chromatography (ITLC-SG) and high performance liquid chromatography (HPLC). The stability of the preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C and the partition coefficient was determined in n:octanol:water. In vivo studies were performed in both healthy Balb-c and Nude mice bearing PC-3 xenografts, in order to characterize the biological properties of labeled peptides. In vitro studies involved the evaluation of cold bombesin derivatives effect in PC-3 cells proliferation. Bombesin derivatives were successfully labeled with high yield at optimized conditions and exhibited high stability at 4 degree C. The analysis of the

  16. FTIR spectro-imaging of collagen scaffold formation during glioma tumor development.

    Science.gov (United States)

    Noreen, Razia; Chien, Chia-Chi; Chen, Hsiang-Hsin; Bobroff, Vladimir; Moenner, Michel; Javerzat, Sophie; Hwu, Yeukuang; Petibois, Cyril

    2013-11-01

    Evidence has recently emerged that solid and diffuse tumors produce a specific extracellular matrix (ECM) for division and diffusion, also developing a specific interface with microvasculature. This ECM is mainly composed of collagens and their scaffolding appears to drive tumor growth. Although collagens are not easily analyzable by UV-fluorescence means, FTIR imaging has appeared as a valuable tool to characterize collagen contents in tissues, specially the brain, where ECM is normally devoid of collagen proteins. Here, we used FTIR imaging to characterize collagen content changes in growing glioma tumors. We could determine that C6-derived solid tumors presented high content of triple helix after 8-11 days of growth (typical of collagen fibrils formation; 8/8 tumor samples; 91 % of total variance), and further turned to larger α-helix (days 12-15; 9/10 of tumors; 94 % of variance) and β-turns (day 18-21; 7/8 tumors; 97 % of variance) contents, which suggest the incorporation of non-fibrillar collagen types in ECM, a sign of more and more organized collagen scaffold along tumor progression. The growth of tumors was also associated to the level of collagen produced (P < 0.05). This study thus confirms that collagen scaffolding is a major event accompanying the angiogenic shift and faster tumor growth in solid glioma phenotypes.

  17. Nonvisible tumors on multiparametric magnetic resonance imaging does not predict low-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Seung Hwan Lee

    2015-12-01

    Conclusions: Even though cancer foci were not visualized by postbiopsy MRI, the pathological tumor volumes and extent of GS upgrading were relatively high. Therefore, nonvisible tumors by multiparametric MRI do not appear to be predictive of low-risk PCA.

  18. Assessment of tumor control following definitive radiotherapy in carcinoma of the prostate: A continuing dilemma

    International Nuclear Information System (INIS)

    Pilepich, M.V.

    1987-01-01

    Evaluation of tumor response and tumor control after definitive radiotherapy is a relatively simple task in most malignancies arising at sites amenable to clinical examination (inspection and palpation). The rates of tumor regression following irradiation are quite variable. While some types of cancer regress completely during the radiotherapy course, some may take weeks or months to resolve. Occasionally, residual induration or a residual mass may persist for prolonged periods (many months), prompting the clinician to consider a biopsy for evaluation of the tumor status. In these circumstances histological examination may show necrotic tumor or residual fibrotic tissue. Finding viable-appearing tumor cells beyond the immediate postirradiation period (several weeks to a few months after completion of the radiotherapy course) is generally accepted as an equivalent of failure to eradicate the tumor. However, in a few types of cancer, presence of histologically identifiable and apparently viable tumor cells over protracted periods does not necessarily imply treatment failure

  19. Calculation errors of Set-up in patients with tumor location of prostate. Exploratory study; Calculo de errores de Set-up en pacientes con localizacion tumoral de prostata. Estudio exploratorio

    Energy Technology Data Exchange (ETDEWEB)

    Donis Gil, S.; Robayna Duque, B. E.; Jimenez Sosa, A.; Hernandez Armas, O.; Gonzalez Martin, A. E.; Hernandez Armas, J.

    2013-07-01

    The calculation of SM is done from errors in positioning (set-up). These errors are calculated from movements in 3D of the patient. This paper is an exploratory study of 20 patients with tumor location of prostate in which errors of set-up for two protocols of work are evaluated. (Author)

  20. High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

    Directory of Open Access Journals (Sweden)

    Jehnan Liu

    2015-03-01

    Conclusion: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

  1. Metastatic prostatic adenocarcinoma diagnosed in a bronchoalveolar lavage specimen: An unusual presentation of a common tumor

    Directory of Open Access Journals (Sweden)

    Adrienne E Moul

    2016-01-01

    Full Text Available Metastatic prostatic adenocarcinoma presenting as a primary lung disease is rare. We present a 52-year-old male with a 3-month history of cough, shortness of breath, and weight loss with clinical and radiological findings suggestive of a primary lung disease: Bilateral interstitial and alveolar opacities with blunting of the costophrenic angles, multiple diffuse foci of consolidations and nodules, predominantly subpleural and located in the lower lobes, and diffuse interlobular septal thickening and peribronchial thickening. The patient underwent bronchoscopy and bronchoalveolar lavage (BAL was obtained. Cytospin smears were diagnostic for a low-grade adenocarcinoma. Clinically, the patient had elevated serum prostate-specific antigen (PSA levels greater than 5,000 ng/mL. Because of this, immunocytochemistry for PSA was performed which was positive, confirming the diagnosis of metastatic prostatic adenocarcinoma. This unusual case of metastatic adenocarcinoma of the prostate first diagnosed by BAL highlights the significance of available clinical information and the use of immunocytochemistry for proper diagnosis.

  2. Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

    Science.gov (United States)

    2013-10-01

    methotrexate were from the Cancer Institute of New Jersey pharmacy . Both collagen I, IV and laminin were purchased from BD Biosciences, and athymicnu/nu mice...forming cells from human prostate [31]. We elected to use a strategy of combin- ing phenotypic and time-of-adherence assays to iso - late TICs from PCa

  3. Oligometastatic prostate cancer: shaping the definition with molecular imaging and an improved understanding of tumor biology.

    Science.gov (United States)

    Joice, Gregory A; Rowe, Steven P; Pienta, Kenneth J; Gorin, Michael A

    2017-11-01

    The aim of this review is to discuss how novel imaging modalities and molecular markers are shaping the definition of oligometastatic prostate cancer. To effectively classify a patient as having oligometastatic prostate cancer, diagnostic tests must be sensitive enough to detect subtle sites of metastatic disease. Conventional imaging modalities can readily detect widespread polymetastatic disease but do not have the sensitivity necessary to reliably classify patients as oligometastatic. Molecular imaging using both metabolic- and molecularly-targeted radiotracers has demonstrated great promise in aiding in our ability to define the oligometastatic state. Perhaps the most promising data to date have been generated with radiotracers targeting prostate-specific membrane antigen. In addition, early studies are beginning to define biologic markers in the oligometastatic state that may be indicative of disease with minimal metastatic potential. Recent developments in molecular imaging have allowed for improved detection of metastatic prostate cancer allowing for more accurate staging of patients with oligometastatic disease. Future development of biologic markers may assist in defining the oligometastatic state and determining prognosis.

  4. Efficacy of c-Met inhibitor for advanced prostate cancer

    International Nuclear Information System (INIS)

    Tu, William H; Zhu, Chunfang; Clark, Curtis; Christensen, James G; Sun, Zijie

    2010-01-01

    Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer. We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression. We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration. The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer

  5. Integrated imaging (ultrasound, computed tomography, intravenous urography) in diagnosing renal tumors and tumor-like formations

    International Nuclear Information System (INIS)

    Drudi, F.M.; Capanna, G.; Poggi, R.; Occhiato, R.; Iannicelli, E.; Nardo, R.; di Passariello, R.

    1994-01-01

    This is an assessment of semiologic imaging criteria based on computerised tomography, ultrasound diagnosis and intravenous urography in renal tumors. The purpose is to obtain differential diagnostic data capable to modify the treatment approach. Over the last three years, a total of 570 cases of kidney tumors are observed. In 490 of them (86%) the imaging patterns obtained by either of the three techniques leads to correct diagnosis. In 62 of the remaining 80 patients, the integration of two techniques allows to unveil the neoplastic nature of the disease (27 cases), or the presence of a benign process (35 cases). In 15 of the remaining 18 cases only integration of the three techniques results in diagnosing renal tumors or tumor-like conditions (3 adeno-carcinomas, 5 abscesses, 3 cases of tuberculosis, 2 - pyeloxanthogranulomatosis, 2 dysmorphisms). In the last three cases definite diagnosis is made on the basis of needle biopsy. The radiological diagnosis is confirmed intraoperatively or during clinical follow-up study. The obtained data underscore the clinical relevance of imaging integration in evaluating renal lesions. This is particularly valid whenever the clinical data are nonspecific or misleading. 15 refs., 3 figs., 5 tabs. (orig.)

  6. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1

    Energy Technology Data Exchange (ETDEWEB)

    Sympson, Carolyn J; Bissell, Mina J; Werb, Zena

    1995-06-01

    An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of BM during mammary gland development in vivo, we generated transgenic mice that inappropriately express autoactivating isoforms of the matrix metalloproteinase stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of stromelysin-1 and disruption of the BM may be a key step in the multi-step process of breast cancer.

  7. Pomegranate-Extract Pill in Preventing Tumor Growth in Patients With Localized Prostate Cancer Undergoing Active Surveillance

    Science.gov (United States)

    2018-03-02

    PSA Level Less Than or Equal to Fifteen; PSA Level Less Than Ten; Stage I Prostate Cancer AJCC v7; Stage II Prostate Cancer AJCC v7; Stage IIA Prostate Cancer AJCC v7; Stage IIB Prostate Cancer AJCC v7

  8. Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microRNA-96-mediated downregulation of the tumor suppressor ETV6.

    Science.gov (United States)

    Tsai, Yuan-Chin; Chen, Wei-Yu; Siu, Man Kit; Tsai, Hong-Yuan; Yin, Juan Juan; Huang, Jiaoti; Liu, Yen-Nien

    2017-01-01

    It has been suggested that ETV6 serves as a tumor suppressor; however, its molecular regulation and cellular functions remain unclear. We used prostate cancer as a model system and demonstrated a molecular mechanism in which ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA-96 (miR-96)-mediated downregulation. In addition, EGFR acts as a transcriptional coactivator that binds to the promoter of primary miR-96 and transcriptionally regulates miR-96 levels. We analyzed two sets of clinical prostate cancer samples, confirmed association patterns that were consistent with the EGFR-miR-96-ETV6 signaling model and demonstrated that the reduced ETV6 levels were associated with malignant prostate cancer. Based on results derived from multiple approaches, we identified the biological functions of ETV6 as a tumor suppressor that inhibits proliferation and metastasis in prostate cancer. We present a molecular mechanism in which EGFR activation leads to the induction of miR-96 expression and suppression of ETV6, which contributes to prostate cancer progression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Detachment-induced E-cadherin expression promotes 3D tumor spheroid formation but inhibits tumor formation and metastasis of lung cancer cells.

    Science.gov (United States)

    Powan, Phattrakorn; Luanpitpong, Sudjit; He, Xiaoqing; Rojanasakul, Yon; Chanvorachote, Pithi

    2017-11-01

    The epithelial-to-mesenchymal transition is proposed to be a key mechanism responsible for metastasis-related deaths. Similarly, cancer stem cells (CSCs) have been proposed to be a key driver of tumor metastasis. However, the link between the two events and their control mechanisms is unclear. We used a three-dimensional (3D) tumor spheroid assay and other CSC-indicating assays to investigate the role of E-cadherin in CSC regulation and its association to epithelial-to-mesenchymal transition in lung cancer cells. Ectopic overexpression and knockdown of E-cadherin were found to promote and retard, respectively, the formation of tumor spheroids in vitro but had opposite effects on tumor formation and metastasis in vivo in a xenograft mouse model. We explored the discrepancy between the in vitro and in vivo results and demonstrated, for the first time, that E-cadherin is required as a component of a major survival pathway under detachment conditions. Downregulation of E-cadherin increased the stemness of lung cancer cells but had an adverse effect on their survival, particularly on non-CSCs. Such downregulation also promoted anoikis resistance and invasiveness of lung cancer cells. These results suggest that anoikis assay could be used as an alternative method for in vitro assessment of CSCs that involves dysregulated adhesion proteins. Our data also suggest that agents that restore E-cadherin expression may be used as therapeutic agents for metastatic cancers. Copyright © 2017 the American Physiological Society.

  10. Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening.

    Science.gov (United States)

    Fong, Eliza L S; Martinez, Mariane; Yang, Jun; Mikos, Antonios G; Navone, Nora M; Harrington, Daniel A; Farach-Carson, Mary C

    2014-07-07

    The lack of effective therapies for bone metastatic prostate cancer (PCa) underscores the need for accurate models of the disease to enable the discovery of new therapeutic targets and to test drug sensitivities of individual tumors. To this end, the patient-derived xenograft (PDX) PCa model using immunocompromised mice was established to model the disease with greater fidelity than is possible with currently employed cell lines grown on tissue culture plastic. However, poorly adherent PDX tumor cells exhibit low viability in standard culture, making it difficult to manipulate these cells for subsequent controlled mechanistic studies. To overcome this challenge, we encapsulated PDX tumor cells within a three-dimensional hyaluronan-based hydrogel and demonstrated that the hydrogel maintains PDX cell viability with continued native androgen receptor expression. Furthermore, a differential sensitivity to docetaxel, a chemotherapeutic drug, was observed as compared to a traditional PCa cell line. These findings underscore the potential impact of this novel 3D PDX PCa model as a diagnostic platform for rapid drug evaluation and ultimately push personalized medicine toward clinical reality.

  11. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Liquan; Wang, Dan [Department of Urology, The University of Pittsburgh, 5200 Centre Avenue, Pittsburgh, PA 15216 (United States); Fisher, Alfred L., E-mail: fishera2@uthscsa.edu [Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, UTHSCSA, San Antonio, TX 78229 (United States); Center for Healthy Aging, UTHSCSA, San Antonio, TX 78229 (United States); GRECC, STVAHCS, San Antonio, TX 78229 (United States); Wang, Zhou, E-mail: wangz2@upmc.edu [Department of Urology, The University of Pittsburgh, 5200 Centre Avenue, Pittsburgh, PA 15216 (United States); GRECC, STVAHCS, San Antonio, TX 78229 (United States)

    2014-05-02

    Highlights: • RNAi screen identified genetic enhancers for the C. elegans homolog of EAF2. • EAF2 and RBBP4 proteins physically bind to each other and alter transcription. • Overexpression of EAF2 and RBBP4 induces the cell death in prostate cancer cells. - Abstract: The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in Caenorhabditiselegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to control development and fertility in worms. To identify genetic pathways that interact with eaf-1, we screened RNAi libraries consisting of transcription factors, phosphatases, and chromatin-modifying factors to identify genes which enhance the effects of eaf-1(tm3976) on fertility. From this screen, we identified lin-53, hmg-1.2, pha-4, ruvb-2 and set-6 as hits. LIN-53 is the C. elegans ortholog of human retinoblastoma binding protein 4/7 (RBBP 4/7), which binds to the retinoblastoma protein and inhibits the Ras signaling pathway. We find that lin-53 showed a synthetic interaction with eaf-1(tm3976) where knockdown of lin-53 in an eaf-1(tm3976) mutant resulted in sterile worms. This phenotype may be due to cell death as the treated worms contain degenerated embryos with increased expression of the ced-1:GFP cell death marker. Further we find that the interaction between eaf-1 and lin-53/RBBP4/7 also exists in vertebrates, which is reflected by the formation of a protein complex between EAF2 and RBBP4/7. Finally, overexpression of either human EAF2 or RBBP4 in LNCaP cells induced the cell death while knockdown of EAF2 in LNCaP enhanced cell proliferation, indicating an important role of EAF2 in

  12. Tasquinimod (ABR-215050, a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors

    Directory of Open Access Journals (Sweden)

    Isaacs John T

    2010-05-01

    Full Text Available Abstract Background The orally active quinoline-3-carboxamide tasquinimod [ABR-215050; CAS number 254964-60-8, which currently is in a phase II-clinical trial in patients against metastatic prostate cancer, exhibits anti-tumor activity via inhibition of tumor angiogenesis in human and rodent tumors. To further explore the mode of action of tasquinimod, in vitro and in vivo experiments with gene microarray analysis were performed using LNCaP prostate tumor cells. The array data were validated by real-time semiquantitative reversed transcriptase polymerase chain reaction (sqRT-PCR and protein expression techniques. Results One of the most significant differentially expressed genes both in vitro and in vivo after exposure to tasquinimod, was thrombospondin-1 (TSP1. The up-regulation of TSP1 mRNA in LNCaP tumor cells both in vitro and in vivo correlated with an increased expression and extra cellular secretion of TSP1 protein. When nude mice bearing CWR-22RH human prostate tumors were treated with oral tasquinimod, there was a profound growth inhibition, associated with an up-regulation of TSP1 and a down- regulation of HIF-1 alpha protein, androgen receptor protein (AR and glucose transporter-1 protein within the tumor tissue. Changes in TSP1 expression were paralleled by an anti-angiogenic response, as documented by decreased or unchanged tumor tissue levels of VEGF (a HIF-1 alpha down stream target in the tumors from tasquinimod treated mice. Conclusions We conclude that tasquinimod-induced up-regulation of TSP1 is part of a mechanism involving down-regulation of HIF1α and VEGF, which in turn leads to reduced angiogenesis via inhibition of the "angiogenic switch", that could explain tasquinimods therapeutic potential.

  13. Clinically Significant Prostate Cancer Local Recurrence After Radiation Therapy Occurs at the Site of Primary Tumor: Magnetic Resonance Imaging and Step-Section Pathology Evidence

    International Nuclear Information System (INIS)

    Pucar, Darko; Hricak, Hedvig; Shukla-Dave, Amita; Kuroiwa, Kentaro; Drobnjak, Marija; Eastham, James; Scardino, Peter T.; Zelefsky, Michael J.

    2007-01-01

    Purpose: To determine whether prostate cancer local recurrence after radiation therapy (RT) occurs at the site of primary tumor by retrospectively comparing the tumor location on pre-RT and post-RT magnetic resonance imaging (MRI) and using step-section pathology after salvage radical prostatectomy (SRP) as the reference standard. Methods and Materials: Nine patients with localized prostate cancer were treated with intensity modulated RT (69-86.4 Gy), and had pre-RT and post-RT prostate MRI, biopsy-proven local recurrence, and SRP. The location and volume of lesions on pre-RT and post-RT MRI were correlated with step-section pathology findings. Tumor foci >0.2 cm 3 and/or resulting in extraprostatic disease on pathology were considered clinically significant. Results: All nine significant tumor foci (one in each patient; volume range, 0.22-8.63 cm 3 ) were detected both on pre-RT and post-RT MRI and displayed strikingly similar appearances on pre-RT and post-RT MRI and step-section pathology. Two clinically insignificant tumor foci (≤0.06 cm 3 ) were not detected on imaging. The ratios between tumor volumes on pathology and on post-RT MRI ranged from 0.52 to 2.80. Conclusions: Our study provides a direct visual confirmation that clinically significant post-RT local recurrence occurs at the site of primary tumor. Our results are in agreement with reported clinical and pathologic results and support the current practice of boosting the radiation dose within the primary tumor using imaging guidance. They also suggest that monitoring of primary tumor with pre-RT and post-RT MRI could lead to early detection of local recurrence amenable to salvage treatment

  14. Imaging of bioluminescent LNCaP-luc-M6 tumors: a new animal model for the study of metastatic human prostate cancer.

    Science.gov (United States)

    Scatena, Caroline D; Hepner, Mischa A; Oei, Yoko A; Dusich, Joan M; Yu, Shang-Fan; Purchio, Tony; Contag, Pamela R; Jenkins, Darlene E

    2004-05-15

    Animal experiments examining hormone-sensitive metastatic prostate cancer using the human LNCaP cell line have been limited to endpoint analyses. To permit longitudinal studies, we generated a luciferase-expressing cell line and used bioluminescent imaging (BLI) to non-invasively monitor the in vivo growth of primary LNCaP tumors and metastasis. LNCaP.FGC cells were transfected to constitutively express firefly luciferase. LNCaP-luc-M6 cells were tested for bioluminescent signal intensity and hormone responsiveness in vitro. The cells were implanted in subcutaneous and orthotopic sites in SCID-bg mice and imaged over time. The LNCaP-luc-M6 cells formed subcutaneous and orthotopic tumors in SCID-bg mice, and nearly all tumor-bearing animals developed pulmonary metastases. Early detection and temporal growth of primary tumors and metastatic lesions was successfully monitored by BLI. The LNCaP-luc-M6 cell line is a bioluminescent, hormone-sensitive prostate cancer cell line applicable for BLI studies to non-invasively monitor subcutaneous and orthotopic prostate tumor growth and metastasis in vivo. Copyright 2004 Wiley-Liss, Inc.

  15. Use of 99mTc-HYNIC-βAla-Bombesina(7-14) peptide for the identification of prostate tumor, LNCaP line, in an experimental model

    International Nuclear Information System (INIS)

    Fuscaldi, Leonardo Lima

    2012-01-01

    Prostate cancer is one of the most prevalent tumors in men, showing high mortality rates. Current diagnostic methods are not able to identify early prostate carcinoma, often resulting in a late diagnosis with established metastasis. Thus, there is by the scientific community an incessant search for diagnostic methods for early assessment of prostate cancer, facilitating the treatment and increasing the chances of cure. In this context, nuclear medicine provides a diagnostic method which can detect tumors at an early stage, because it is based on biochemical and physiological changes of the tissue, such as overexpression of gastrin releasing peptide receptors (GRPr's) by prostate cancer cells. Bombesin, a tetradecapeptide isolated from the frog Bombina bombina, has a high affinity for the GRPr's, since it is analogous to gastrin releasing peptide. Therefore, this study aims to prepare the complex 99m Tc-HYNIC-βAla-Bombesina (7-14) and use it for the identification of prostate tumor, LNCaP line, in an experimental model. For in vitro assays, aliquots of 0.026 MBq of the radiopeptide were incubated with 2x10 6 LNCaP cells in a water bath at 37 deg C, for 1 and 4 hours, with and without prior addition of cold peptide (n=3). Prostate tumors were induced into the upper right flank of male BALB/c nude mice by subcutaneous injection of 5x106 LNCaP cells resuspended in 150 μL of Matrigel:RPMI-1640 medium (1:1). Biodistribution profile (n=5) and scintigraphic images (n=3) were obtained at 1 and 4 hours after intravenous injection of 7.4 MBq of 99m Tc-HYNIC-βAla-Bombesina (7-14) . To assess this, healthy male BALB/c mice and tumor-bearing male BALB/c nude mice with 15, 20 and 25 days of tumor development were used. In vitro study results showed that the fraction of the radiopeptide which bound to LNCaP cells was 2.08 +- 0.30% (1 hour) and 2.44 +- 0.18% (4 hours). From the percentage which was bound, the internalized fractions were 25.64 +- 3.14% (1 hour) and 25.27 +- 2

  16. Novel PCA-VIP scheme for ranking MRI protocols and identifying computer-extracted MRI measurements associated with central gland and peripheral zone prostate tumors.

    Science.gov (United States)

    Ginsburg, Shoshana B; Viswanath, Satish E; Bloch, B Nicolas; Rofsky, Neil M; Genega, Elizabeth M; Lenkinski, Robert E; Madabhushi, Anant

    2015-05-01

    To identify computer-extracted features for central gland and peripheral zone prostate cancer localization on multiparametric magnetic resonance imaging (MRI). Preoperative T2-weighted (T2w), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) MRI were acquired from 23 men with confirmed prostate cancer. Following radical prostatectomy, the cancer extent was delineated by a pathologist on ex vivo histology and mapped to MRI by nonlinear registration of histology and corresponding MRI slices. In all, 244 computer-extracted features were extracted from MRI, and principal component analysis (PCA) was employed to reduce the data dimensionality so that a generalizable classifier could be constructed. A novel variable importance on projection (VIP) measure for PCA (PCA-VIP) was leveraged to identify computer-extracted MRI features that discriminate between cancer and normal prostate, and these features were used to construct classifiers for cancer localization. Classifiers using features selected by PCA-VIP yielded an area under the curve (AUC) of 0.79 and 0.85 for peripheral zone and central gland tumors, respectively. For tumor localization in the central gland, T2w, DCE, and DWI MRI features contributed 71.6%, 18.1%, and 10.2%, respectively; for peripheral zone tumors T2w, DCE, and DWI MRI contributed 29.6%, 21.7%, and 48.7%, respectively. PCA-VIP identified relatively stable subsets of MRI features that performed well in localizing prostate cancer on MRI. © 2014 Wiley Periodicals, Inc.

  17. Tumor suppressor function of PGP9.5 is associated with epigenetic regulation in prostate cancer--novel predictor of biochemical recurrence after radical surgery.

    Science.gov (United States)

    Mitsui, Yozo; Shiina, Hiroaki; Hiraki, Miho; Arichi, Naoko; Hiraoka, Takeo; Sumura, Masahiro; Honda, Satoshi; Yasumoto, Hiroaki; Igawa, Mikio

    2012-03-01

    The expression level of protein G product 9.5 (PGP9.5) is downregulated because of promoter CpG hypermethylation in several tumors. We speculated that impaired regulation of PGP9.5 through epigenetic pathways is associated with the pathogenesis of prostate cancer. CpG methylation of the PGP9.5 gene was analyzed in cultured prostate cancer cell lines, 226 localized prostate cancer samples from radical prostatectomy cases, and 80 benign prostate hyperplasia (BPH) tissues. Following 5-aza-2'-deoxycytidune treatment, increased PGP9.5 mRNA transcript expression was found in the LNCaP and PC3 cell lines. With bisulfite DNA sequencing, partial methylation of the PGP9.5 promoter was shown in LNCaP whereas complete methylation was found in PC3 cells. After transfection of PGP9.5 siRNA, cell viability was significantly accelerated in LNCaP but not in PC3 cells as compared with control siRNA transfection. Promoter methylation of PGP9.5 was extremely low in only one of 80 BPH tissues, whereas it was found in 37 of 226 prostate cancer tissues. Expression of the mRNA transcript of PGP9.5 was significantly lower in methylation (+) than methylation (-) prostate cancer tissues. Multivariate analysis of biochemical recurrence (BCR) after an radical prostatectomy revealed pT category and PGP9.5 methylation as prognostically relevant. Further stratification with the pT category in addition to methylation status identified a stepwise reduction of BCR-free probability. This is the first clinical and comprehensive study of inactivation of the PGP9.5 gene via epigenetic pathways in primary prostate cancer. CpG methylation of PGP9.5 in primary prostate cancer might become useful as a molecular marker for early clinical prediction of BCR after radical prostatectomy. ©2012 AACR.

  18. PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer.

    Science.gov (United States)

    Rogers, Oliver C; Anthony, Lizamma; Rosen, D Marc; Brennen, W Nathaniel; Denmeade, Samuel R

    2018-04-27

    Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death in American men. While localized therapy is highly curative, treatments for metastatic prostate cancer are largely palliative. Thus, new innovative therapies are needed to target metastatic tumors. Prostate-Specific Antigen (PSA) is a chymotrypsin-like protease with a unique substrate specificity that is secreted by both normal and malignant prostate epithelial cells. Previous studies demonstrated the presence of high levels (μM-mM) of enzymatically active PSA is present in the extracellular fluid of the prostate cancer microenvironment. Because of this, PSA is an attractive target for a protease activated pro-toxin therapeutic strategy. Because prostate cancers typically grow very slowly, a strategy employing a proliferation-independent cytotoxic payload is preferred. Recently, it was shown that the human protease Granzyme B (GZMB), at low micromolar concentrations in the extracellular space, can cleave an array of extracellular matrix (ECM) proteins thus perturbing cell growth, signaling, motility, and integrity. It is also well established that other human proteases such as trypsin can induce similar effects. Because both enzymes require N-terminal proteolytic activation, we propose to convert these proteins into PSA-activated cytotoxins. In this study, we examine the enzymatic and cell targeting parameters of these PSA-activated cytotoxic serine proteases. These pro-enzymes were activated robustly by PSA and induced ECM damage that led to the death of prostate cancer cells in vitro thus supporting the potential use of this strategy as means to target metastatic prostate cancers.

  19. Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

    Science.gov (United States)

    2016-07-01

    group B) (P=0.025), which was absent in CTCs with high GR expression (P=0.34) (Appendix, Fig. 3B and Fig. S6D). Thus, these two AR-independent drug ...presentations, and manuscripts. This Research Project has thus far resulted in published manuscripts in Cancer Discovery (4), Science Translational Medicine...investigator in translational prostate cancer research, I have been promoted to the position of Assistant Professor of Radiation Oncology at

  20. Do Prostate Cancer Exosomes Generate a Field Effect Leading to Tumor Multifocality

    Science.gov (United States)

    2016-04-01

    Undergraduate Research program (to K. Gabriel and E. Frisch), and a generous gift from Melinda and Edward Subia of Orange County CA. Abstract Field effect or...kind gift of Dr. W. Xiao, University of Science and Technology of China, Hefei, China. pLKO.1 control and pLKO.1/EGR-1 shRNA plasmids were from...Pathology and Hospital: Trisha Fleet for procuring prostate tissues through patient consent; Myra Zucker, Cathy Martinez, and Kari Rigg for skillfully

  1. Food-grade titanium dioxide exposure exacerbates tumor formation in colitis associated cancer model.

    Science.gov (United States)

    Urrutia-Ortega, Ismael M; Garduño-Balderas, Luis G; Delgado-Buenrostro, Norma L; Freyre-Fonseca, Verónica; Flores-Flores, José O; González-Robles, Arturo; Pedraza-Chaverri, José; Hernández-Pando, Rogelio; Rodríguez-Sosa, Miriam; León-Cabrera, Sonia; Terrazas, Luis I; van Loveren, Henk; Chirino, Yolanda I

    2016-07-01

    Colorectal cancer is the fourth worldwide cause of death and even if some dietary habits are consider risk factors, the contribution of food additives including foodgrade titanium dioxide (TiO2), designated as E171, has been poorly investigated. We hypothesized that oral E171 intake could have impact on the enhancement of colorectal tumor formation and we aimed to investigate if E171 administration could enhance tumor formation in a colitis associated cancer (CAC) model. BALB/c male mice were grouped as follows: a) control, b) E171, c) CAC and d) CAC + E171 group (n = 6). E171 used in this study formed agglomerates of 300 nm in water. E171 intragastric administration (5 mg/kg body weight/5 days/10 weeks) was unable to induce tumor formation but dysplastic alterations were observed in the distal colon but enhanced the tumor formation in distal colon (CAC + E171 group) measured by tumor progression markers. Some E171 particles were internalized in colonic cells of the E171 and CAC + E171 groups and both groups showed a decrease in goblet cells in the distal colon. However the CAC + E171 group showed a higher decrease of these cells that act as protection barrier in colon. These results suggest that E171 could worsen pre-existent intestinal diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Clinical use and primary evaluation of tumor marker-free prostate specific antigen

    International Nuclear Information System (INIS)

    Wu Junyuan; Gao Xiuying; Kong Linghua; Su Ping; Guo Xinrong

    2002-01-01

    Free-prostate specific antigen (fPSA)/total prostate specific antigen (tPSA) ratio was evaluated in clinical utility. Serum tPSA and fPSA level were measured by electro-chemo-luminescence (ECL) immunoassay and fPSA/tPSA ratio was calculated. Samples were drawn from 38 patients with Pca, 68 patients with BPH and 43 health men. Results showed serum tPSA > 4.0 μg/L as only cut off for diagnosis Pca, sensitivity and specificity of fPSA/tPSA ratio were 84.2%, 75.0% respectively. But fPSA/tPSA ratio 20.0 μg/L; they were 93.6%, 89.9% when serum tPSA was 2-20 μg/L. fPSA/tPSA ratio may greatly raised accurate rate for diagnosis prostate cancer when tPSA level between 2-20 μg/L and no value to other patients

  3. Differential oxygen dynamics in two diverse Dunning prostate R3327 rat tumor sublines (MAT-Lu and HI) with respect to growth and respiratory challenge

    International Nuclear Information System (INIS)

    Zhao Dawen; Constantinescu, Anca; Hahn, Eric W.; Mason, Ralph P.

    2002-01-01

    Purpose: Since hypoxia may influence tumor response to therapy and prognosis, we have compared oxygenation of tumors known to exhibit differential growth rate and tissue differentiation. Methods and Materials: Regional tumor oxygen tension was measured using 19 F nuclear magnetic resonance echo planar imaging relaxometry of hexafluorobenzene, which provided dynamic maps with respect to respiratory intervention. Investigations used two Dunning prostate R3327 rat tumor sublines: the fast growing, highly metastatic MAT-Lu and the moderately well-differentiated, slower growing HI. Results: Both sublines showed significantly higher oxygen tension in smaller tumors ( 3 ) than in larger tumors (>3.5 cm 3 ). Pooled data showed that MAT-Lu tumors exhibited greater hypoxia compared with the size-matched HI tumors (p 2 for tumors of both sublines (p 2 , while those in the MAT-Lu tumors showed little response to respiratory intervention. Conclusions: These results concur with hypotheses that hypoxia is related to tumor growth rate and degree of differentiation. Under baseline conditions, the differences were subtle. However, response to respiratory intervention revealed highly significant differences, which, if held valid in the clinic, could have prognostic value

  4. Serum PSA and cure perspective for prostate cancer in males with nonpalpable tumor

    Directory of Open Access Journals (Sweden)

    Marcos F. Dall'Oglio

    2005-10-01

    Full Text Available INTRODUCTION: Many studies have shown the association between PSA levels and the subsequent detection of prostate cancer. In the present trial, we have studied the relationship between preoperative PSA levels and clinical outcome following radical prostatectomy in men with clinical stage T1c. MATERIALS AND METHODS: 257 individuals with clinical stage T1c undergoing retropubic radical prostatectomy were selected in the period from 1991 to 2000. Following surgery, biochemical recurrence-free survival curves were constructed according to PSA levels between 0-4; 4.1-10; 10.1-20 and > 20 ng/mL. RESULTS: Of the total of 257 selected patients, 206 (80% had Gleason scores from 2 to 6 and 51 (20%, presented Gleason scores 7 and 8, as defined by the pathological report from prostate biopsy. There was no biochemical recurrence of disease when the PSA was lower than 4, regardless of Gleason score. Biochemical recurrence-free survival according to PSA between 0-4; 4.1-10; 10.1-20 and > 20 was 100%, 87.6%, 79% and 68.8% for Gleason scores 2-6 and 100%; 79.4%; 40% and 100% for Gleason scores 7-8 respectively. When all individuals were grouped, regardless of their Gleason scores, the probability of biochemical recurrence-free survival was 100%, 65.1%, 53.4% and 72.2% according to PSA between 0-4; 4.1-10; 10.1-20 and > 20 ng/mL respectively. CONCLUSION: Non-palpable prostate cancer presents higher chances of cure when the PSA is inferior to 4 ng/mL.

  5. Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.

    Science.gov (United States)

    Liu, Bigang; Gong, Shuai; Li, Qiuhui; Chen, Xin; Moore, John; Suraneni, Mahipal V; Badeaux, Mark D; Jeter, Collene R; Shen, Jianjun; Mehmood, Rashid; Fan, Qingxia; Tang, Dean G

    2017-08-08

    This project was undertaken to address a critical cancer biology question: Is overexpression of the pluripotency molecule Nanog sufficient to initiate tumor development in a somatic tissue? Nanog1 is critical for the self-renewal and pluripotency of ES cells, and its retrotransposed homolog, NanogP8 is preferentially expressed in somatic cancer cells. Our work has shown that shRNA-mediated knockdown of NanogP8 in prostate, breast, and colon cancer cells inhibits tumor regeneration whereas inducible overexpression of NanogP8 promotes cancer stem cell phenotypes and properties. To address the key unanswered question whether tissue-specific overexpression of NanogP8 is sufficient to promote tumor development in vivo , we generated a NanogP8 transgenic mouse model, in which the ARR 2 PB promoter was used to drive NanogP8 cDNA. Surprisingly, the ARR 2 PB-NanogP8 transgenic mice were viable, developed normally, and did not form spontaneous tumors in >2 years. Also, both wild type and ARR 2 PB-NanogP8 transgenic mice responded similarly to castration and regeneration and castrated ARR 2 PB-NanogP8 transgenic mice also did not develop tumors. By crossing the ARR 2 PB-NanogP8 transgenic mice with ARR 2 PB-Myc (i.e., Hi-Myc) mice, we found that the double transgenic (i.e., ARR 2 PB-NanogP8; Hi-Myc) mice showed similar tumor incidence and histology to the Hi-Myc mice. Interestingly, however, we observed white dots in the ventral lobes of the double transgenic prostates, which were characterized as overgrown ductules/buds featured by crowded atypical Nanog-expressing luminal cells. Taken together, our present work demonstrates that transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.

  6. MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells

    Directory of Open Access Journals (Sweden)

    Migneault Martine

    2010-01-01

    Full Text Available Abstract Background Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition. Results Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL, which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16low targets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors. Conclusion MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in

  7. USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

    Directory of Open Access Journals (Sweden)

    Zhenghong Lin

    2013-12-01

    Full Text Available The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell-cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell-cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.

  8. Functional roles for Rad9 in prostate cancer

    International Nuclear Information System (INIS)

    Lieberman, H.B.; Broustas, C.G.

    2012-01-01

    The goal of this work is to understand the mechanistic relationship between high levels of Rad9 protein and prostate cancer. The study is based on several findings suggesting a role for Rad9 in this disease. Rad9 has all the hallmark features of an oncogene or tumor suppressor. It regulates genomic stability, multiple cell cycle checkpoints, apoptosis and DNA repair. In addition, it can transactivate downstream target genes via direct interaction with promoter DNA sequences. We found Rad9 protein levels were very high in prostate cancer cell lines. Furthermore, we examined 52 primary normal prostate and 339 prostate cancer specimens for Rad9 protein by immunohistochemical staining. Statistical significance for Rad9 positive staining versus cancer, and stain intensity versus Stage were tested. We get a p-value of <0.001 when comparing percentage positive by cancer Stage, or stain intensity by cancer Stage. Based on these data, we sought to define the nature of the relationship between Rad9 and prostate cancer. We demonstrate that Rad9 acts as an oncogene in prostate cancer by playing a critical role in tumor formation in a mouse xenograph model. We also show that Rad9 is important for cellular phenotypes essential for metastasis, including tumor cell migration, invasion and resistance to programmed cell death after detachment from extracellular matrix. Therefore, Rad9 is critical for several aspects of prostate tumor progression, and could serve as a novel target for anti-cancer therapy

  9. Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

    Science.gov (United States)

    Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

    2012-01-01

    The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

  10. The Androgen-Regulated Calcium-Activated Nucleotidase 1 (CANT1) Is Commonly Overexpressed in Prostate Cancer and Is Tumor-Biologically Relevant in Vitro

    Science.gov (United States)

    Gerhardt, Josefine; Steinbrech, Corinna; Büchi, Oralea; Behnke, Silvia; Bohnert, Annette; Fritzsche, Florian; Liewen, Heike; Stenner, Frank; Wild, Peter; Hermanns, Thomas; Müntener, Michael; Dietel, Manfred; Jung, Klaus; Stephan, Carsten; Kristiansen, Glen

    2011-01-01

    Previously, we identified the calcium-activated nucleotidase 1 (CANT1) transcript as up-regulated in prostate cancer. Now, we studied CANT1 protein expression in a large cohort of nearly 1000 prostatic tissue samples including normal tissue, prostatic intraepithelial neoplasia (PIN), primary carcinomas, metastases, and castrate-resistant carcinomas, and further investigated its functional relevance. CANT1 displayed predominantly a Golgi-type immunoreactivity with additional and variable cytoplasmic staining. In comparison to normal tissues, the staining intensity was significantly increased in PIN lesions and cancer. In cancer, high CANT1 levels were associated with a better prognosis, and castrate-resistant carcinomas commonly showed lower CANT1 levels than primary carcinomas. The functional role of CANT1 was investigated using RNA interference in two prostate cancer cell lines with abundant endogenous CANT1 protein. On CANT1 knockdown, a significantly diminished cell number and DNA synthesis rate, a cell cycle arrest in G1 phase, and a strong decrease of cell transmigration rate and wound healing capacity of CANT1 knockdown cells was found. However, on forced CANT1 overexpression, cell proliferation and migration remained unchanged. In summary, CANT1 is commonly overexpressed in the vast majority of primary prostate carcinomas and in the precursor lesion PIN and may represent a novel prognostic biomarker. Moreover, this is the first study to demonstrate a functional involvement of CANT1 in tumor biology. PMID:21435463

  11. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    Directory of Open Access Journals (Sweden)

    John C. Leach

    2016-03-01

    Full Text Available The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA, was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

  12. Spatial distribution of elements in the spheroids by prostate tumor cells using synchrotron radiation x-ray fluorescence

    Energy Technology Data Exchange (ETDEWEB)

    Leitao, Roberta G.; Santos, Carlos Antonio N.; Junior, Antonio Palumbo; Souza, Pedro A. V. R.; Canellas, Catarine G. L.; Anjos, Marcelino J.; Nasciutti, Luiz E.; Lopes, Ricardo T. [Laboratorio de Instrumentacao Nuclear, PEN/COPPE, Universidade Federal do Rio de Janeiro, Ilha do Fundao, 21941-972, Rio de Janeiro, RJ (Brazil); Laboratorio de Biotecnologia - Bioengenharia - DIPRO, Instituto Nacional de Metrologia, Normalizacao e Qualidade Industrial, Xerem. 25250-020, Duque de Caxias, RJ (Brazil); Laboratorio de Interacoes Celulares, ICB-CCS, Universidade Federal do Rio de Janeiro, Ilha do Fundao, 21941- 590, Rio de Janeiro, RJ (Brazil); Laboratorio de Instrumentacao Nuclear, PEN/COPPE, Universidade Federal do Rio de Janeiro, Ilha do Fundao, 21941-972, Rio de Janeiro, RJ (Brazil); Laboratorio de Interacoes Celulares, ICB-CCS, Universidade Federal do Rio de Janeiro, Ilha do Fundao, 21941- 590, Rio de Janeiro, RJ (Brazil); Laboratorio de Instrumentacao Nuclear, PEN/COPPE, Universidade Federal do Rio de Janeiro, Ilha do Fundao, 21941-972, Rio de Janeiro, RJ (Brazil)

    2012-05-17

    The formation of three-dimensional cell microspheres such as spheroids has attracted attention as a useful culture technique. In this study, we investigated the trace elemental distribution (mapping) in spheroids derived from tissue prostate cancer (PCa). The measurements were performed in standard geometry of 45 deg. incidence, exciting with a white beam and using an optical capillary with 20 {mu}m diameter collimation in the XRF beam line at the Synchrotron Light National Laboratory (Campinas, Brazil). The results showed that most elements analyzed presented non-uniform distribution. P, S and Cl showed similar elemental distribution in all the samples analyzed. K, Ca, Fe, and Cu showed different elemental distribution for the spheroids analyzed. Zinc presented more intense distributions in the spheroid central region for all spheroids analyzed.

  13. Spatial distribution of elements in the spheroids by prostate tumor cells using synchrotron radiation X-ray fluorescence

    International Nuclear Information System (INIS)

    Leitao, Roberta G.; Canellas, Catarine G.L.; Anjos, Marcelino J.; Lopes, Ricardo T.; Santos, Carlos Antonio N.; Palumbo Junior, Antonio; Souza, Pedro A.V.R.; Nasciutti, Luiz E.

    2011-01-01

    The formation of three-dimensional cell microspheres such as spheroids has attracted attention as a useful culture technique. In this study, we investigated the trace elemental distribution (mapping) in spheroids derived from tissue prostate cancer (PCa). The measurements were performed in standard geometry of 45 deg incidence, exciting with a white beam and using an optical capillary with 20 μm diameter collimation in the XRF beam line at the Synchrotron Light National Laboratory (Campinas, Brazil). The results showed that most elements analyzed presented non-uniform distribution. P, S and Cl showed similar elemental distribution in all the samples analyzed. K, Ca, Fe, and Cu showed different elemental distribution for the spheroids analyzed. Zinc presented more intense distributions in the spheroid central region for all spheroids analyzed. (author)

  14. Spatial distribution of elements in the spheroids by prostate tumor cells using synchrotron radiation x-ray fluorescence

    International Nuclear Information System (INIS)

    Leitao, Roberta G.; Santos, Carlos Antonio N.; Junior, Antonio Palumbo; Souza, Pedro A. V. R.; Canellas, Catarine G. L.; Anjos, Marcelino J.; Nasciutti, Luiz E.; Lopes, Ricardo T.

    2012-01-01

    The formation of three-dimensional cell microspheres such as spheroids has attracted attention as a useful culture technique. In this study, we investigated the trace elemental distribution (mapping) in spheroids derived from tissue prostate cancer (PCa). The measurements were performed in standard geometry of 45 deg. incidence, exciting with a white beam and using an optical capillary with 20 μm diameter collimation in the XRF beam line at the Synchrotron Light National Laboratory (Campinas, Brazil). The results showed that most elements analyzed presented non-uniform distribution. P, S and Cl showed similar elemental distribution in all the samples analyzed. K, Ca, Fe, and Cu showed different elemental distribution for the spheroids analyzed. Zinc presented more intense distributions in the spheroid central region for all spheroids analyzed.

  15. Spatial distribution of elements in the spheroids by prostate tumor cells using synchrotron radiation X-ray fluorescence

    Energy Technology Data Exchange (ETDEWEB)

    Leitao, Roberta G.; Canellas, Catarine G.L.; Anjos, Marcelino J.; Lopes, Ricardo T. [Universidade Federal do Rio de Janeiro (PEN/COPPE/UFRJ), RJ (Brazil). Coordenacao dos Programas de Pos-Graduacao de Engenharia. Programa de Energia Nuclear; Santos, Carlos Antonio N. [Instituto Nacional de Metrologia, Normalizacao e Qualidade Industrial (INMETRO), Duque de Caxias, RJ (Brazil). Lab. de Biotecnologia - Bioengenharia; Palumbo Junior, Antonio; Souza, Pedro A.V.R.; Nasciutti, Luiz E., E-mail: nasciutt@ufrj.b [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Lab. de Interacoes Celulares

    2011-07-01

    The formation of three-dimensional cell microspheres such as spheroids has attracted attention as a useful culture technique. In this study, we investigated the trace elemental distribution (mapping) in spheroids derived from tissue prostate cancer (PCa). The measurements were performed in standard geometry of 45 deg incidence, exciting with a white beam and using an optical capillary with 20 {mu}m diameter collimation in the XRF beam line at the Synchrotron Light National Laboratory (Campinas, Brazil). The results showed that most elements analyzed presented non-uniform distribution. P, S and Cl showed similar elemental distribution in all the samples analyzed. K, Ca, Fe, and Cu showed different elemental distribution for the spheroids analyzed. Zinc presented more intense distributions in the spheroid central region for all spheroids analyzed. (author)

  16. TU-F-CAMPUS-T-05: Dose Escalation to Biological Tumor Volumes of Prostate Cancer Patients Using Gold Nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Jermoumi, M; Ngwa, W [Department of Physics and Applied Physics, Medical Physics Program, University of Massachusetts Lowell (United States); Department of Radiation Oncology, Dana Farber Cancer Insitute, Brigham and Women’s Hospital, Harvard Medical, Boston, MA (United States); Sajo, E [Department of Physics and Applied Physics, Medical Physics Program, University of Massachusetts Lowell (United States); Houari, K [Department of Radiation Oncology, Dana Farber Cancer Insitute, Brigham and Women’s Hospital, Harvard Medical, Boston, MA (United States)

    2015-06-15

    Purpose: Studies have shown that radiation boosting could help reduce prostate cancer (PCa) recurrence. Biological tumor volumes (BTV) are a high priority for such radiation boosting. The purpose of this study is to investigate the potential of radiation boosting of real patient BTVs using gold nanoparticles (GNP) released from gold-loaded brachytherapy spacers (GBS) during brachytherapy. Methods: The BTVs of 12 patients having prostate adenocarcinoma identified with positron emission tomography (PET) and CT scanner using C-11 labeled tracer [11C]acetate were investigated. The initial GNP concentration and time to achieve a dose enhancement effect (DEF) of 2 was simulated using the freely downloadable software RAID APP. The investigations were carried out for low dose rate (LDR) brachytherapy sources (BTS) described in AAPM Task Group report 43: Cs-131, I-125, and Pd-103. In first case, we used 7 mg/g and 18 mg/g of GNP initial concentrations to estimate the time needed for released GNP to achieve a DEF of 2 for the different BTS, and compare with clinically relevant treatment times. In second case, we calculated the initial concentration of GNPs needed to achieve a DEF of 2 during the time the BTS would typically deliver 50%, 70% and 90% of the total dose. Results: For an initial concentration of 18 mg/g, when using Cs-131, and Pd-103, a DEF of 2 could only be achieved for BTV of 3.3 cm3 and 1 cm3 respectively. Meanwhile a DEF of 2 could be achieved for all 12 BTVs when using I-125. To achieve a DEF of 2 for all patients using Cs-131 and Pd-103, much higher initial concentrations would have to be used than have been typically employed in pre-clinical studies. Conclusion: The I-125 is the most viable BTS that can be employed with GBS to guide dose painting treatment planning for localized PCa.

  17. Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer

    Science.gov (United States)

    2018-05-15

    Adult Solid Neoplasm; Hormone-Resistant Prostate Carcinoma; Recurrent Melanoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Prostate Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7

  18. Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities

    Science.gov (United States)

    2015-10-01

    Anatomy and Regen- erativeBiology,TheGeorgeWashingtonUniversitySchoolofMedicine and Health Sciences,Washington, District of Columbia. 7Department of...types of cancers, including prostate, head and neck, renal , lung, breast, colon, ovarian, glioma, pan- creas, and bladder cancers (22, 23). In terms of...triphosphate receptor type 2 (ITPR2) gene as a novel risk locus for renal cell carcinoma (47, 48).MiR-145 has been implicated as a tumor-suppressive miRNA

  19. An HTS-compatible 3D colony formation assay to identify tumor-specific chemotherapeutics.

    Science.gov (United States)

    Horman, Shane R; To, Jeremy; Orth, Anthony P

    2013-12-01

    There has been increasing interest in the development of cellular behavior models that take advantage of three-dimensional (3D) cell culture. To enable assessment of differential perturbagen impacts on cell growth in 2D and 3D, we have miniaturized and adapted for high-throughput screening (HTS) the soft agar colony formation assay, employing a laser-scanning cytometer to image and quantify multiple cell types simultaneously. The assay is HTS compatible, providing high-quality, image-based, replicable data for multiple, co-cultured cell types. As proof of concept, we subjected colorectal carcinoma colonies in 3D soft agar to a mini screen of 1528 natural product compounds. Hit compounds from the primary screen were rescreened in an HTS 3D co-culture matrix containing colon stromal cells and cancer cells. By combining tumor cells and normal, nontransformed colon epithelial cells in one primary screening assay, we were able to obtain differential IC50 data, thereby distinguishing tumor-specific compounds from general cytotoxic compounds. Moreover, we were able to identify compounds that antagonized tumor colony formation in 3D only, highlighting the importance of this assay in identifying agents that interfere with 3D tumor structural growth. This screening platform provides a fast, simple, and robust method for identification of tumor-specific agents in a biologically relevant microenvironment.

  20. Dynamic contrast-enhanced case-control analysis in 3T MRI of prostate cancer can help to characterize tumor aggressiveness

    Energy Technology Data Exchange (ETDEWEB)

    Sanz-Requena, Roberto, E-mail: roberto.sanz@quironsalud.es [Biomedical Engineering, Hospital Quirónsalud Valencia, Valencia (Spain); Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); GIBI230, Instituto de Investigación Sanitaria y Hospital Universitari i Politècnic La Fe, Valencia (Spain); Martí-Bonmatí, Luis [Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); GIBI230, Instituto de Investigación Sanitaria y Hospital Universitari i Politècnic La Fe, Valencia (Spain); Pérez-Martínez, Rosario [Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); García-Martí, Gracián [Biomedical Engineering, Hospital Quirónsalud Valencia, Valencia (Spain); Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); GIBI230, Instituto de Investigación Sanitaria y Hospital Universitari i Politècnic La Fe, Valencia (Spain); CIBER-SAM, Instituto de Salud Carlos III, Madrid (Spain)

    2016-11-15

    Highlights: • Curve types showed no statistical association with healthy/tumor peripheral areas. • K{sup trans}, v{sub e}, upslope and AUC showed significant differences in controls vs. tumors. • The global diagnostic performance of standard MRI perfusion parameters is poor. • Normalized K{sup trans}, upslope and AUC had good diagnostic accuracy for tumor grading. - Abstract: Purpose: The aim of this work is to establish normality and tumor tissue ranges for perfusion parameters from dynamic contrast-enhanced (DCE) MR of the peripheral prostate at 3T and to compare the diagnostic performance of quantitative and semi-quantitative parameters. Materials and methods: Thirty-six patients with prostate carcinomas (18 Gleason-6, 15 Gleason-7, and 3 Gleason-8) and 33 healthy subjects were included. Image analysis workflow comprised four steps: manual segmentation of whole prostate and lesions, series registration, voxelwise T1 mapping and calculation of pharmacokinetic and semi-quantitative parameters. Results: K{sup trans}, v{sub e}, upslope and AUC60 showed statistically significant differences between healthy peripheral areas and tumors. Curve type showed no association with healthy/tumor peripheral areas (chi-square = 0.702). Areas under the ROC curves were 0.64 (95% CI: 0.54–0.75), 0.70 (0.60–0.80), 0.62 (0.51–0.72) and 0.63 (0.52–0.74) for K{sup trans}, v{sub e}, upslope and AUC60, respectively. The optimal cutoff values were: K{sup trans} = 0.21 min{sup −1} (sensitivity = 0.61, specificity = 0.64), v{sub e} = 0.36 (0.63, 0.71), upslope = 0.59 (0.59, 0.59) and AUC60 = 2.4 (0.63, 0.64). Significant differences were found between Gleason scores 6 and 7 for normalized K{sup trans}, upslope and AUC60, with good diagnostic accuracy (area under ROC curve 0.80, 95% CI: 0.60–1.00). Conclusion: Quantitative (K{sup trans} and v{sub e}) and semi-quantitative (upslope and AUC60) perfusion parameters showed significant differences between tumors and control

  1. Free Base Lysine Increases Survival and Reduces Metastasis in Prostate Cancer Model.

    Science.gov (United States)

    Ibrahim-Hashim, Arig; Wojtkowiak, Jonathan W; de Lourdes Coelho Ribeiro, Maria; Estrella, Veronica; Bailey, Kate M; Cornnell, Heather H; Gatenby, Robert A; Gillies, Robert J

    2011-11-19

    Malignant tumor cells typically metabolize glucose anaerobically to lactic acid even under normal oxygen tension, a phenomenon called aerobic glycolysis or the Warburg effect. This results in increased acid production and the acidification of the extracellular microenvironment in solid tumors. H + ions tend to flow along concentration gradients into peritumoral normal tissue causing extracellular matrix degradation and increased tumor cell motility thus promoting invasion and metastasis. We have shown that reducing this acidity with sodium bicarbonate buffer decreases the metastatic fitness of circulating tumor cells in prostate cancer and other cancer models. Mathematical models of the tumor-host dynamics predicted that buffers with a pka around 7 will be more effective in reducing intra- and peri-tumoral acidosis and, thus, and possibly more effective in inhibiting tumor metastasis than sodium bicarbonate which has a pKa around 6. Here we test this prediction the efficacy of free base lysine; a non-bicarbonate/non-volatile buffer with a higher pKa (~10), on prostate tumor metastases model. Oxygen consumption and acid production rate of PC3M prostate cancer cells and normal prostate cells were determined using the Seahorse Extracellular Flux (XF-96) analyzer. In vivo effect of 200 mM lysine started four days prior to inoculation on inhibition of metastasis was examined in PC3M-LUC-C6 prostate cancer model using SCID mice. Metastases were followed by bioluminescence imaging. PC3M prostate cancer cells are highly acidic in comparison to a normal prostate cell line indicating that reduction of intra- and perit-tumoral acidosis should inhibit metastases formation. In vivo administration of 200 mM free base lysine increased survival and reduced metastasis. PC3M prostate cancer cells are highly glycolytic and produce large amounts of acid when compared to normal prostate cells. Administration of non-volatile buffer decreased growth of metastases and improved survival

  2. Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Teresa D. Elo

    2010-11-01

    Full Text Available Expression of fibroblast growth factor 8 (FGF-8 is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelialmorphology progressing fromatypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.

  3. Analysis of biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer using dose-distribution variables and tumor control probability models

    International Nuclear Information System (INIS)

    Levegruen, Sabine; Jackson, Andrew; Zelefsky, Michael J.; Venkatraman, Ennapadam S.; Skwarchuk, Mark W.; Schlegel, Wolfgang; Fuks, Zvi; Leibel, Steven A.; Ling, C. Clifton

    2000-01-01

    Purpose: To investigate tumor control following three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer and to identify dose-distribution variables that correlate with local control assessed through posttreatment prostate biopsies. Methods and Material: Data from 132 patients, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), who had a prostate biopsy 2.5 years or more after 3D-CRT for T1c-T3 prostate cancer with prescription doses of 64.8-81 Gy were analyzed. Variables derived from the dose distribution in the PTV included: minimum dose (Dmin), maximum dose (Dmax), mean dose (Dmean), dose to n% of the PTV (Dn), where n = 1%, ..., 99%. The concept of the equivalent uniform dose (EUD) was evaluated for different values of the surviving fraction at 2 Gy (SF 2 ). Four tumor control probability (TCP) models (one phenomenologic model using a logistic function and three Poisson cell kill models) were investigated using two sets of input parameters, one for low and one for high T-stage tumors. Application of both sets to all patients was also investigated. In addition, several tumor-related prognostic variables were examined (including T-stage, Gleason score). Univariate and multivariate logistic regression analyses were performed. The ability of the logistic regression models (univariate and multivariate) to predict the biopsy result correctly was tested by performing cross-validation analyses and evaluating the results in terms of receiver operating characteristic (ROC) curves. Results: In univariate analysis, prescription dose (Dprescr), Dmax, Dmean, dose to n% of the PTV with n of 70% or less correlate with outcome (p 2 : EUD correlates significantly with outcome for SF 2 of 0.4 or more, but not for lower SF 2 values. Using either of the two input parameters sets, all TCP models correlate with outcome (p 2 , is limited because the low dose region may not coincide with the tumor location. Instead, for MSKCC prostate cancer patients with their

  4. Cytotoxic effects of 125I-labeled PBZr ligand PK 11195 in prostatic tumor cells: therapeutic implications

    International Nuclear Information System (INIS)

    Alenfall, J.; Kant, R.; Batra, S.

    1998-01-01

    The effect of [ 125 I]PK 11195 was examined in human prostatic tumor cells (DU 145) in culture and compared with Na[ 125 I] and non-radioactive PK 11195. [ 125 I]PK 11195 was clearly cytocidal. The data for dose-related cell survival with [ 125 I]PK 11195 showed a linear relationship. Na[ 125 I] or non-labeled PK 11195 at similar concentrations did not lead to any cell killing. The uptake of [ 125 I]PK 11195 and [ 3 H]PK 11195 in cells was very similar. Fragmentation of DNA measured by agarose gel electrophoresis showed that exposure of DU 145 cells to [ 125 I]PK 11195 for 1, 4 or 24 h caused no fragmentation. These results indicate that nuclear DNA is not the prime binding site for [ 125 I]PK 11195, which is consistent with the presence of specific peripheral benzodiazepine receptors (PBZr) in the mitochondria. The cell killing effect of [ 125 I]PK 11195 suggests the use of PBZr ligand for radiotherapy

  5. Is Serum Prostate-specific Antigen a Diagnostic Marker for Benign and Malignant Breast Tumors in Women.

    Science.gov (United States)

    Razavi, Seyed Hasan Emami; Ghajarzadeh, Mahsa; Abdollahi, Alireza; Taran, Ludmila; Shoar, Saeed; Omranipour, Ramesh

    2015-06-01

    Breast cancer is the most common cancer in women. Prostrate-specific antigen (PSA) is a marker of prostate gland malignancy which has been considered in cases with breast cancer in recent years. The goal of this study was to determine total and free PSA levels in cases with malignant and benign breast lesions. Ninety women with histological proved malignant breast masses and 90 with benign breast masses were enrolled. Total and free PSA levels along with histological grade and conditions of vascular and perinural invasion, status of hormonal tumor receptors, immune-histo-chemistry markers recorded for all cases. Total and free PSA levels were assessed after treatment in cases with malignant masses. Total and free PSA levels were significantly higher in cases with malignant masses. The best cut off point for total PSA to differentiate benign and malignant masses was 0.31 and the best cut off point for free PSA to differentiate benign and malignant masses was 0.19. After treatment, mean free PSA level was significantly lower than free PSA before treatment (0.23 vs 0.3, pbenign and malignant breast masses.

  6. Imaging of Gastrin-Releasing Peptide Receptor-Expressing Prostate Tumor using a {sup 68}Ga-Labeled Bombesin Analog

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jae Cheong; Dho, So Hee; Cho, Eun Ha; Lee, So Young; Kim, Soo Yong [KAERI, Daejeon (Korea, Republic of)

    2016-05-15

    Although the transmissivity of cold neutrons are low comparing that of thermal neutrons, the slower neutrons are more apt to be absorbed in a target, and can increase the prompt gamma emission rate. Also the flux of both thermal and cold neutron beam is high enough to activate thick target. If the neutron beam is irradiated on the front and the reverse side of gold bar, all insides of it can be detected. The imaging efficacy of {sup 68}Ga-DOTA-gluBBN was evaluated in the PC-3- peritoneal metastasized model. These results suggest that {sup 68}Ga-labeled bombesin derivative has promising characteristics as a novel nuclear medicine, especially for the imaging of GRPR over-expressing prostate tumors. A target for irradiation was produced using 99% Ni-62 metal power concentrate. Ni-62 target of 1 g was irradiated in MARIA reactor operated in Poland for 470 hours at neutron flux of 2.5 x 10{sup 14}n/cm{sup 2}s, and estimated production of Ni-63 was calculated. Irradiated Ni-63 pellets were dissolved in HCl solution, and Ni-63 coatings were deposited by DC electroplating at current density of 20 mA/cm{sup 2}.

  7. The Mechanosensitive Ca2+ Channel as a Central Regular of Prostate Tumor Cell Migration and Invasiveness

    Science.gov (United States)

    2011-04-01

    sion [83], glioma [123], glaucoma [78] atherosclerosis [22, 134], Duchenne muscular dystrophy [44, 45], and tumor- igenesis [128]. Furthermore...healing [137] and promote neuronal regeneration [76]. Of particular note is Duchenne muscular dystrophy (DMD), a devastating X-linked genetic disease...channels in stretch-induced muscle damage: role in muscular dystrophy . Clin Exp Pharmacol Physiol 31:551–556 181. Zampighi GA, Kreman M, Boorer KJ, Loo DDF

  8. Therapeutic Roles of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

    Science.gov (United States)

    2013-10-01

    ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER New Jersey, University of Medicine and Dentistry ...classified according to postoperative Gleason score or clinical stage (TNM system ). Histological categories divided tumors with Gleason scores...On the basis of rapid adhesion on collagen, PCa cells were plated on a collagen-I dish for 5 min (5’=rapidly adherent) (3-5% of cells) were

  9. TREATMENT OF ERECTILE DYSFUNCTION IN PATIENTS WITH PROSTATE TUMOR AFTER RADICAL PROSTATECTOMY

    Directory of Open Access Journals (Sweden)

    A. V. Babintsev

    2017-01-01

    Full Text Available Prostate cancer (PC treatment is a pressing problem both inRussiaand worldwide. According to data for Saint-Petersburg, from 1990 to 2002 morbidity increase rate for PC was 141.3 %. Even after nerve-sparing radical prostatectomy (RP erectile dysfunction of some level is observed in 65–75 % of patients. During follow-up examination, data on sexual history were gathered including information on past and current sexual contacts. A questionnaire based on the International Index of Erectile Function was used which allows to evaluate different parameters of sexual function (sexual drive, erection, orgasm, ejaculation, sexual act, and satisfaction with sexual relationships, as well as determine treatment effectiveness. We performed combined two-stage treatment of erectile dysfunction in patients with PC after RP. At the first stage, phosphodiesterase type 5 inhibitors (sildenafil 100 mg were used. If the drug was ineffective, the second stage was initiated (intracavernosal alprostadil injections. Drug effectiveness, complications, patient compliancy were evaluated.

  10. 99mTc-labeled PSMA inhibitor: Biokinetics and radiation dosimetry in healthy subjects and imaging of prostate cancer tumors in patients.

    Science.gov (United States)

    Santos-Cuevas, Clara; Davanzo, Jenny; Ferro-Flores, Guillermina; García-Pérez, Francisco O; Ocampo-García, Blanca; Ignacio-Alvarez, Eleazar; Gómez-Argumosa, Edgar; Pedraza-López, Martha

    2017-09-01

    The prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate and highly overexpressed in 95% of advanced prostate cancers. The aims of this study was to estimate the biokinetics and dosimetry of 99m Tc-EDDA/HYNIC-iPSMA ( 99m Tc-labeled PSMA inhibitor) in eight healthy subjects and evaluate its usefulness as a tumor-imaging agent in eight prostate cancer patients. 99m Tc-EDDA/HYNIC-iPSMA was obtained from a lyophilized formulation with radiochemical purities >98%, determined by reversed-phase HPLC and ITLC-SG analyses. Whole-body images from eight healthy subjects were acquired at 20min, and at 2, 6 and 24h after 99m Tc-EDDA/HYNIC-iPSMA administration. Regions of interest (ROIs) were drawn around the source organs on each time frame. Each ROI was corrected by background, attenuation, scattered radiation and physical decay. The image sequence was used to extrapolate the 99m Tc-EDDA/HYNIC-iPSMA time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. In eight prostate cancer patients with histologically confirmed cancer, whole-body SPECT/CT images were obtained at 3h. The blood activity showed a half-life value of 4.98min for the fast component (T 1/2 α=ln2/8.34), 2.49h for the first slow component (T 1/2 β=ln2/0.278), and 9.24h for the second slow component (T 1/2 γ=ln2/0.076). Images from patients showed an average tumor/background ratio of 8.99±3.27 at 3h. The average equivalent doses calculated for a study using 740MBq were 3.80, 7.06, 9.69, 10.70, and 28.80mSv for the breast, spleen, salivary glands, liver, and kidneys respectively, with an effective dose of 3.42±0.78mSv. All the absorbed doses were comparable to those known for most of the 99m Tc studies. 99m Tc-EDDA/HYNIC-iPSMA obtained from kit formulations showed high tumor uptake in

  11. Shape anisotropy enhanced optomagnetic measurement for prostate-specific antigen detection via magnetic chain formation

    DEFF Research Database (Denmark)

    Tian, Bo; Wetterskog, Erik; Qiu, Zhen

    2017-01-01

    anisotropy), and directly increasing the optomagnetic signal (via optical shape anisotropy). We achieve a limit of detection (LOD) of 5.5 pM (0.82 ng/mL) for the detection of a model multivalent molecule, biotinylated anti-streptavidin, in PBS. For the measurements of prostate-specific antigen (PSA) in 50...

  12. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice.

    Science.gov (United States)

    Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew; Phan, Ngoc; Marcogliese, Andrea N; Li, Hui; Al-Dhalimy, Muhsen; Major, Angela; Olson, Susan; Monnat, Raymond J; Grompe, Markus

    2016-12-15

    Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 -/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 -/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 -/- Trp53 +/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. © 2016 by The American Society of Hematology.

  13. Quantitative phase imaging characterization of tumor-associated blood vessel formation on a chip

    Science.gov (United States)

    Guo, Peng; Huang, Jing; Moses, Marsha A.

    2018-02-01

    Angiogenesis, the formation of new blood vessels from existing ones, is a biological process that has an essential role in solid tumor growth, development, and progression. Recent advances in Lab-on-a-Chip technology has created an opportunity for scientists to observe endothelial cell (EC) behaviors during the dynamic process of angiogenesis using a simple and economical in vitro platform that recapitulates in vivo blood vessel formation. Here, we use quantitative phase imaging (QPI) microscopy to continuously and non-invasively characterize the dynamic process of tumor cell-induced angiogenic sprout formation on a microfluidic chip. The live tumor cell-induced angiogenic sprouts are generated by multicellular endothelial sprouting into 3 dimensional (3D) Matrigel using human umbilical vein endothelial cells (HUVECs). By using QPI, we quantitatively measure a panel of cellular morphological and behavioral parameters of each individual EC participating in this sprouting. In this proof-of-principle study, we demonstrate that QPI is a powerful tool that can provide real-time quantitative analysis of biological processes in in vitro 3D biomimetic devices, which, in turn, can improve our understanding of the biology underlying functional tissue engineering.

  14. A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy.

    Science.gov (United States)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2014-10-01

    Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules.

  15. Monoclonal carcinoembryonic antigen radioimmunoassay in prostatic cancer: Validation of the method and comparison to some other tumor-associated markers

    International Nuclear Information System (INIS)

    Stefanovic, V.; Ignjatovic, M.; Milosavljevic, B.; Dinic, A.; Nis Univ.

    1987-01-01

    The use of a monoclonal CEA RIA and of some other biological markers for a diagnosis of prostatic cancer was investigated. The increased level of serum CEA was found in both prostatic cancer and in non-malignant disease. The low sensitivity of the CEA monoclonal assay precludes its use for a clinical diagnosis of prostatic cancer. The simultaneous use of some other biological markers (PAP, TPA, β2-microglobulin and ferritin) did increase sensitivity. However, further studies should be directed to a much more specific and sensitive marker of the human prostatic adenocarcinoma. (orig.) [de

  16. Monoclonal carcinoembryonic antigen radioimmunoassay in prostatic cancer: Validation of the method and comparison to some other tumor-associated markers

    Energy Technology Data Exchange (ETDEWEB)

    Stefanovic, V; Ignjatovic, M; Milosavljevic, B; Dinic, A

    1987-04-01

    The use of a monoclonal CEA RIA and of some other biological markers for a diagnosis of prostatic cancer was investigated. The increased level of serum CEA was found in both prostatic cancer and in non-malignant disease. The low sensitivity of the CEA monoclonal assay precludes its use for a clinical diagnosis of prostatic cancer. The simultaneous use of some other biological markers (PAP, TPA, ..beta..2-microglobulin and ferritin) did increase sensitivity. However, further studies should be directed to a much more specific and sensitive marker of the human prostatic adenocarcinoma.

  17. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    International Nuclear Information System (INIS)

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen

    2015-01-01

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice

  18. miRNA let-7b modulates macrophage polarization and enhances tumor-associated macrophages to promote angiogenesis and mobility in prostate cancer.

    Science.gov (United States)

    Wang, Zhigang; Xu, Lu; Hu, Yinying; Huang, Yanqin; Zhang, Yujuan; Zheng, Xiufen; Wang, Shanshan; Wang, Yifan; Yu, Yanrong; Zhang, Meng; Yuan, Keng; Min, Weiping

    2016-05-09

    Macrophage polarization is a highly plastic physiological process that responds to a variety of environmental factors by changing macrophage phenotype and function. Tumor-associated macrophages (TAMs) are generally recognized as promoting tumor progression. As universal regulators, microRNAs (miRNAs) are functionally involved in numerous critical cellular processes including macrophage polarization. Let-7b, a miRNA, has differential expression patterns in inflamed tissues compared with healthy controls. However, whether and how miRNA let-7b regulates macrophage phenotype and function is unclear. In this report, we find that up-regulation of let-7b is characteristic of prostatic TAMs, and down-regulation of let-7b in TAMs leads to changes in expression profiles of inflammatory cytokines, such as IL-12, IL-23, IL-10 and TNF-α. As a result, TAMs treated with let-7b inhibitors reduce angiogenesis and prostate carcinoma (PCa) cell mobility. Let-7b may play a vital role in regulating macrophage polarization, thus modulating the prognosis of prostate cancer.

  19. On complexity and homogeneity measures in predicting biological aggressiveness of prostate cancer; Implication of the cellular automata model of tumor growth.

    Science.gov (United States)

    Tanase, Mihai; Waliszewski, Przemyslaw

    2015-12-01

    We propose a novel approach for the quantitative evaluation of aggressiveness in prostate carcinomas. The spatial distribution of cancer cell nuclei was characterized by the global spatial fractal dimensions D0, D1, and D2. Two hundred eighteen prostate carcinomas were stratified into the classes of equivalence using results of ROC analysis. A simulation of the cellular automata mix defined a theoretical frame for a specific geometric representation of the cell nuclei distribution called a local structure correlation diagram (LSCD). The LSCD and dispersion Hd were computed for each carcinoma. Data mining generated some quantitative criteria describing tumor aggressiveness. Alterations in tumor architecture along progression were associated with some changes in both shape and the quantitative characteristics of the LSCD consistent with those in the automata mix model. Low-grade prostate carcinomas with low complexity and very low biological aggressiveness are defined by the condition D0 1.764 and Hd < 38. The novel homogeneity measure Hd identifies carcinomas with very low aggressiveness within the class of complexity C1 or carcinomas with very high aggressiveness in the class C7. © 2015 Wiley Periodicals, Inc.

  20. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen, E-mail: srrshurology@163.com

    2015-08-14

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

  1. Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

    Science.gov (United States)

    2008-11-01

    H. (2006) Cancer Sci. 97, 1211–1216 34. Yao, V. J., Ozawa, M. G., Trepel, M., Arap, W., McDonald, D. M., and Pasqualini , R. (2005) Am. J. Pathol...and Lemay, S. (2006) Am. J. Physiol. 291, F960–F971 72. Ogawa, K., Pasqualini , R., Lindberg, R. A., Kain, R., Freeman, A. L., and Pasquale, E. B...Science 117: 2037-2049. 21. Ogawa K Pasqualini R Lindberg RA et al. (2000) The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor

  2. Vatuximab(Trademark): Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

    Science.gov (United States)

    2010-01-01

    159: 621-631, 2003. 37. Bourke , V. A., Zhao, D., Gilio, J., Chang, C.-H., Jiang, L., Hahn, E. W., and Mason, R. P. Correlation of Radiation...probe: comparison with a paired survival assay. Radiat Res, 158, 167-73 (2002) 27. Gu, Y. Q., V. A. Bourke , J. G. Kim, A. Constantinescu, R. P. Mason...Res. 1998; 150: 549–556. 10. Bourke VA, Zhao D, Gilio J, Chang C-H, Jiang L, Hahn EW, Mason RP. Correlation of radiation response with tumor oxygen

  3. Registration accuracy and possible migration of internal fiducial gold marker implanted in prostate and liver treated with real-time tumor-tracking radiation therapy (RTRT)

    International Nuclear Information System (INIS)

    Kitamura, Kei; Shirato, Hiroki; Shimizu, Shinichi; Shinohara, Nobuo; Harabayashi, Toru; Shimizu, Tadashi; Kodama, Yoshihisa; Endo, Hideho; Onimaru, Rikiya; Nishioka, Seiko; Aoyama, Hidefumi; Tsuchiya, Kazuhiko; Miyasaka, Kazuo

    2002-01-01

    Background and purpose: We have developed a linear accelerator synchronized with a fluoroscopic real-time tumor-tracking system to reduce errors due to setup and organ motion. In the real-time tumor-tracking radiation therapy (RTRT) system, the accuracy of tumor tracking depends on the registration of the marker's coordinates. The registration accuracy and possible migration of the internal fiducial gold marker implanted into prostate and liver was investigated. Materials and methods: Internal fiducial gold markers were implanted in 14 patients with prostate cancer and four patients with liver tumors. Computed tomography (CT) was carried out as a part of treatment planning in the 18 patients. A total of 72 follow-up CT scans were taken. We calculated the relative relationship between the coordinates of the center of mass (CM) of the organs and those of the marker. The discrepancy in the CM coordinates during a follow-up CT compared to those recorded during the planning CT was used to study possible marker migration. Results: The standard deviation (SD) of interobserver variations in the CM coordinates was within 2.0 and 0.4 mm for the organ and the marker, respectively, in seven observers. Assuming that organs do not shrink, grow, or rotate, the maximum SD of migration error in each direction was estimated to be less than 2.5 and 2.0 mm for liver and prostate, respectively. There was no correlation between the marker position and the time after implantation. Conclusion: The degree of possible migration of the internal fiducial marker was within the limits of accuracy of the CT measurement. Most of the marker movement can be attributed to the measurement uncertainty, which also influences registration in actual treatment planning. Thus, even with the gold marker and RTRT system, a planning target volume margin should be used to account for registration uncertainty

  4. Urogenital tumors

    Energy Technology Data Exchange (ETDEWEB)

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  5. Pilot study of a novel tool for input-free automated identification of transition zone prostate tumors using T2- and diffusion-weighted signal and textural features.

    Science.gov (United States)

    Stember, Joseph N; Deng, Fang-Ming; Taneja, Samir S; Rosenkrantz, Andrew B

    2014-08-01

    To present results of a pilot study to develop software that identifies regions suspicious for prostate transition zone (TZ) tumor, free of user input. Eight patients with TZ tumors were used to develop the model by training a Naïve Bayes classifier to detect tumors based on selection of most accurate predictors among various signal and textural features on T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) maps. Features tested as inputs were: average signal, signal standard deviation, energy, contrast, correlation, homogeneity and entropy (all defined on T2WI); and average ADC. A forward selection scheme was used on the remaining 20% of training set supervoxels to identify important inputs. The trained model was tested on a different set of ten patients, half with TZ tumors. In training cases, the software tiled the TZ with 4 × 4-voxel "supervoxels," 80% of which were used to train the classifier. Each of 100 iterations selected T2WI energy and average ADC, which therefore were deemed the optimal model input. The two-feature model was applied blindly to the separate set of test patients, again without operator input of suspicious foci. The software correctly predicted presence or absence of TZ tumor in all test patients. Furthermore, locations of predicted tumors corresponded spatially with locations of biopsies that had confirmed their presence. Preliminary findings suggest that this tool has potential to accurately predict TZ tumor presence and location, without operator input. © 2013 Wiley Periodicals, Inc.

  6. Development of the Meharry Medical College Prostate Cancer Research Program

    National Research Council Canada - National Science Library

    Ukoli, Flora A. M

    2006-01-01

    African Americans (AA) are disproportionately affected by prostate cancer (PCa) for reasons including, biologic tumor differences, genetic predisposition, differential exposures, lack of access to prostate specific antigen (PSA...

  7. Prevention of Human Lymphoproliferative Tumor Formation in Ovarian Cancer Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Kristina A. Butler

    2017-08-01

    Full Text Available Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID mice from Epstein-Barr virus (EBV–infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice. A subset of PDX models demonstrated atypical patterns of dissemination with mediastinal masses, hepatosplenomegaly, and CD45-positive lymphoblastic atypia without ovarian tumor engraftment. Expression of human CD20 but not CD3 supported a B-cell lineage, and EBV genomes were detected in all lymphoproliferative tumors. Immunophenotyping confirmed monoclonal gene rearrangements consistent with B-cell lymphoma, and global gene expression patterns correlated well with other human lymphomas. The ability of rituximab, an anti-CD20 antibody, to suppress human lymphoproliferation from a patient's ovarian tumor in SCID mice and prevent growth of an established lymphoma led to a practice change with a goal to reduce the incidence of lymphomas. A single dose of rituximab during the primary tumor heterotransplantation process reduced the incidence of CD45-positive cells in subsequent PDX lines from 86.3% (n = 117 without rituximab to 5.6% (n = 160 with rituximab, and the lymphoma rate declined from 11.1% to 1.88%. Taken together, investigators utilizing PDX models for research should routinely monitor for lymphoproliferative tumors and consider implementing methods to suppress their growth.

  8. [Active surveillance for prostate cancer: usefulness of endorectal MR at 1.5 Tesla with pelvic phased array coil in detecting significant tumors].

    Science.gov (United States)

    Luyckx, F; Hallouin, P; Barré, C; Aillet, G; Chauveau, P; Hétet, J-F; Bouchot, O; Rigaud, J

    2011-02-01

    To describe and assess MRI signs of significant tumor in a series of patients who all underwent radical prostatectomy and also fulfilled criteria to choose active surveillance according to French "SurAcaP" protocol. The clinical reports of 681 consecutive patients operated on for prostate cancer between 2002 and 2007 were reviewed retrospectively. All patients had endorectal MR (1.5 Tesla) with pelvic phased array coil. (1.5 T erMR PPA). Sixty-one patients (8.9%) fulfilled "SurAcaP" protocol criteria. Preoperative data (MR+core biopsy) were assessed by comparison to whole-mount step section pathology. 85.3% of the 61 patients entering SurAcaP protocol had significant tumor at pathology. (Non Organ Confined Disease (Non OCD)=8.2%, Gleason sum score>6=39.2%). A new exclusion criterion has been assessed: T3MRI±NPS>1 as a predictor tool of significant tumor. ("T3MRI±NPS>1"=Non OCD at MR±number of positive sextants involved in tumor at MR and/or Core Biopsy > to 1). Sensitivity, specificity, PPV, NPV of the criterion "T3MRI±NPS>1" in predicting significant tumor were, respectively: 77%, 33%, 86%, 20%. Adding this criterion to other criteria of the "SurAcaP" protocol could allow the exclusion of all Non OCD, and a decrease in Gleason sum Score>6 rates (20%). Endorectal MR at 1.5 Tesla with pelvic-phased array coil should be considered when selecting patients for active surveillance in the management of prostate cancer. A criterion based upon MR and core biopsy findings, called "T3MR±NSP>1" may represent an exclusion citeria due to its ability to predict significant tumor. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  9. Pretreatment Endorectal Coil Magnetic Resonance Imaging Findings Predict Biochemical Tumor Control in Prostate Cancer Patients Treated With Combination Brachytherapy and External-Beam Radiotherapy

    International Nuclear Information System (INIS)

    Riaz, Nadeem; Afaq, Asim; Akin, Oguz; Pei Xin; Kollmeier, Marisa A.; Cox, Brett; Hricak, Hedvig; Zelefsky, Michael J.

    2012-01-01

    Purpose: To investigate the utility of endorectal coil magenetic resonance imaging (eMRI) in predicting biochemical relapse in prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Methods and Materials: Between 2000 and 2008, 279 men with intermediate- or high-risk prostate cancer underwent eMRI of their prostate before receiving brachytherapy and supplemental intensity-modulated radiotherapy. Endorectal coil MRI was performed before treatment and retrospectively reviewed by two radiologists experienced in genitourinary MRI. Image-based variables, including tumor diameter, location, number of sextants involved, and the presence of extracapsular extension (ECE), were incorporated with other established clinical variables to predict biochemical control outcomes. The median follow-up was 49 months (range, 1–13 years). Results: The 5-year biochemical relapse-free survival for the cohort was 92%. Clinical findings predicting recurrence on univariate analysis included Gleason score (hazard ratio [HR] 3.6, p = 0.001), PSA (HR 1.04, p = 0.005), and National Comprehensive Cancer Network risk group (HR 4.1, p = 0.002). Clinical T stage and the use of androgen deprivation therapy were not correlated with biochemical failure. Imaging findings on univariate analysis associated with relapse included ECE on MRI (HR 3.79, p = 0.003), tumor size (HR 2.58, p = 0.04), and T stage (HR 1.71, p = 0.004). On multivariate analysis incorporating both clinical and imaging findings, only ECE on MRI and Gleason score were independent predictors of recurrence. Conclusions: Pretreatment eMRI findings predict for biochemical recurrence in intermediate- and high-risk prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Gleason score and the presence of ECE on MRI were the only significant predictors of biochemical relapse in this group of patients.

  10. Fluorescent biopsy of biological tissues in differentiation of benign and malignant tumors of prostate

    Science.gov (United States)

    Trifoniuk, L. I.; Ushenko, Yu. A.; Sidor, M. I.; Minzer, O. P.; Gritsyuk, M. V.; Novakovskaya, O. Y.

    2014-08-01

    The work consists of investigation results of diagnostic efficiency of a new azimuthally stable Mueller-matrix method of analysis of laser autofluorescence coordinate distributions of biological tissues histological sections. A new model of generalized optical anisotropy of biological tissues protein networks is proposed in order to define the processes of laser autofluorescence. The influence of complex mechanisms of both phase anisotropy (linear birefringence and optical activity) and linear (circular) dichroism is taken into account. The interconnections between the azimuthally stable Mueller-matrix elements characterizing laser autofluorescence and different mechanisms of optical anisotropy are determined. The statistic analysis of coordinate distributions of such Mueller-matrix rotation invariants is proposed. Thereupon the quantitative criteria (statistic moments of the 1st to the 4th order) of differentiation of histological sections of uterus wall tumor - group 1 (dysplasia) and group 2 (adenocarcinoma) are estimated.

  11. Three-dimensional intrafractional movement of prostate measured during real-time tumor-tracking radiotherapy in supine and prone treatment positions

    International Nuclear Information System (INIS)

    Kitamura, Kei; Shirato, Hiroki; Seppenwoolde, Yvette; Onimaru, Rikiya; Oda, Makoto; Fujita, Katsuhisa; Shimizu, Shinichi; Shinohara, Nobuo; Harabayashi, Toru; Miyasaka, Kazuo

    2002-01-01

    Purpose: To quantify three-dimensional (3D) movement of the prostate gland with the patient in the supine and prone positions and to analyze the movement frequency for each treatment position. Methods and Materials: The real-time tumor-tracking radiotherapy (RTRT) system was developed to identify the 3D position of a 2-mm gold marker implanted in the prostate 30 times/s using two sets of fluoroscopic images. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within the region of the planned coordinates relative to the isocenter. Ten patients with prostate cancer treated with RTRT were the subjects of this study. The coordinates of the gold marker were recorded every 0.033 s during RTRT in the supine treatment position for 2 min. The patient was then moved to the prone position, and the marker was tracked for 2 min to acquire data regarding movement in this position. Measurements were taken 5 times for each patient (once a week); a total of 50 sets for the 10 patients was analyzed. The raw data from the RTRT system were filtered to reduce system noise, and the amplitude of movement was then calculated. The discrete Fourier transform of the unfiltered data was performed for the frequency analysis of prostate movement. Results: No apparent difference in movement was found among individuals. The amplitude of 3D movement was 0.1-2.7 mm in the supine and 0.4-24 mm in the prone positions. The amplitude in the supine position was statistically smaller in all directions than that in the prone position (p < 0.0001). The amplitude in the craniocaudal and AP directions was larger than in the left-right direction in the prone position (p < 0.0001). No characteristic movement frequency was detected in the supine position. The respiratory frequency was detected for all patients regarding movement in the craniocaudal and AP directions in the prone position. The results of the frequency analysis suggest that prostate movement is

  12. Role of stem cells in tumor initiation, metastasis formation and their use in cancer therapy

    International Nuclear Information System (INIS)

    Altaner, C.; Altanerova, V.

    2010-01-01

    This review considers recent advances in the stem cell field focusing on the challenges and opportunities for their use in clinical practice. Various kinds of stem cells and their roles in the human organism are in the review described. Attention is given to the role of mesenchymal stem cells as a potential tool in regenerative medicine. The origin and consequences of existence of tumor-initiating cells known as cancer stem cells is discussed also in context of metastasis formation. It seems that tumor-initiating cells might be responsible for resistance to many conventional cancer therapies, which might explain the limitations of these therapeutic modalities. Furthermore, the review focuses to tumor homing property of adult mesenchymal (stromal) stem cells. The feasibility of mesenchymal stem cells isolation from human adipose tissue, their genetic modifications with suicide genes together with ability to find tumor in the organism make them an attractive vehicle for cancer therapy without systemic toxicity. Published achievements from our laboratory in stem cell-based gene cancer therapy are shortly summarized. Generally, it is believed that the stem cell therapies might be ideal future treatment modality for inherited, degenerative diseases and in curing human malignancies as well. (author)

  13. The need for central pathology tumor grading in prostate cancer using radiation therapy oncology group(RTOG)8531

    International Nuclear Information System (INIS)

    Winter, K.; Grignon, D.; Pajak, T.F.; Pilepich, M.; Byhardt, R.; Lawton, C.; Gallagher, M.; Mesic, J.; Roach, M.; Hanks, G.; Coughlin, C.; Porter, A.

    1997-01-01

    Purpose/Objective: Inconsistent reproducibility among pathologists when grading the tumor with the Gleason system is well known. Its impact on results and conclusions of clinical trials will be investigated. Materials and Methods: RTOG 8531 was a Phase III trial that tested the timing of hormones with radiotherapy in patients with prostate cancer. There were 977 patients were entered into RTOG 8531, of which 760 had both an institutional and a centrally reviewed Gleason Score(GS). The centrally reviewed GS were performed by a single pathologist and institutional GS came from over 70 different participating institutions. Results: The concordance rate between the grouping of the two scores was 36% (GS 2-5), 70% (GS 6-7) and 73% (GS 8-10) with the discrepancies occurring in both directions. Using patients from the delayed hormone arm, there was a highly significant survival difference between the centrally reviewed GS groups (p = .0001). When the institutional GS groups were used, there was no significant survival difference (p=.19). Another survival analysis compared the treatment arms for GS 8-10 patients. When the centrally reviewed GS were used, there was a significant difference(p = .02), but when the institutional GS were used there was no significant difference in survival between the treatments (p=.48). Conclusions: The lack of reproducibility of Gleason scores among pathologists can lead to very different results and conclusions from clinical trials depending on whether the centrally reviewed or institutional Gleason scores are used. Whenever results are being reported by Gleason score, it is necessary to also report how many pathologists were involved in the grading. If Gleason scores are going to be used in the analysis of treatment, a central review of the Gleason scores is crucial

  14. Disseminated Tumor Cells in Prostate Cancer Patients after Radical Prostatectomy and without Evidence of Disease Predicts Biochemical Recurrence

    Science.gov (United States)

    Morgan, Todd M.; Lange, Paul H.; Porter, Michael P.; Lin, Daniel W.; Ellis, William J.; Gallaher, Ian S.; Vessella, Robert L.

    2011-01-01

    Purpose Men with apparently localized prostate cancer often relapse years after radical prostatectomy (RP). We sought to determine if epithelial-like cells identified from bone marrow (BM) in patients after RP (commonly called disseminated tumor cells, DTC) were associated with biochemical recurrence (BR). Experimental Design We obtained BM aspirates from 569 men prior to RP and from 34 healthy men with PSA<2.5 ng/ml to establish a comparison group. Additionally, an analytic cohort consisting of 98 patients after RP with no evidence of disease (NED) was established to evaluate the relationship between DTC and BR. Epithelial cells in the BM were detected by magnetic bead enrichment with antibodies to CD45 and CD61 (negative selection) followed by antibodies to human epithelial antigen (positive selection) and confirmation with FITC-labeled anti-BerEP4 antibody. Results DTC were present in 72% (408/569) of patients prior to RP. There was no correlation with pathologic stage, Gleason grade, or pre-operative PSA. Three of 34 controls (8.8%) had DTC present. In patients NED post-RP, DTC were present in 56/98 (57%). DTC were detected in 12/14 (86%) NED patients post-RP who subsequently suffered BR. Presence of DTC in NED patients was an independent predictor of recurrence (HR 6.9, CI 1.03–45.9). Conclusions Approximately 70% of men undergoing RP had DTC detected in their BM prior to surgery, suggesting that these cells escape early in the disease. Though pre-operative DTC status does not correlate with pathologic risk factors, persistence of DTC after RP in NED patients was an independent predictor of recurrence. PMID:19147774

  15. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer.

    Science.gov (United States)

    Mishra, Sweta; Tai, Qin; Gu, Xiang; Schmitz, James; Poullard, Ashley; Fajardo, Roberto J; Mahalingam, Devalingam; Chen, Xiaodong; Zhu, Xueqiong; Sun, Lu-Zhe

    2015-12-29

    The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer.

  16. Intracrine prostaglandin E2 pro-tumoral actions in prostate epithelial cells originate from non-canonical pathways.

    Science.gov (United States)

    Madrigal-Martínez, Antonio; Fernández-Martínez, Ana B; Lucio Cazaña, Francisco J

    2018-04-01

    Prostaglandin E 2 (PGE 2 ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE 2 on non-transformed prostate epithelial cells are unknown, despite the fact that PGE 2 overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE 2 in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE 2 increased cell proliferation, cell migration, and production of vascular endothelial growth factor-A, and activated in vitro angiogenesis. These actions involved a non-canonic intracrine mechanism in which the actual effector was intracellular PGE 2 (iPGE 2 ) instead of extracellular PGE 2 : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE 2 , which indicated that PGE 2 activity depended on its carrier-mediated translocation from the outside to the inside of cells and that EP receptors located intracellularly (iEP) mediated the effects of PGE 2 . iPGE 2 acted through transactivation of epidermal growth factor-receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia-inducible factor-1α (HIF-1α). Interestingly, iPGE 2 also mediates the effects of PGE 2 on prostate cancer PC3 cells through the axis iPGE 2 -iEP receptors-EGFR-HIF-1α. Thus, this axis might be responsible for the growth-stimulating effects of PGE 2 on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non-canonic intracrine mechanism of PGE 2 action operates in both benign and malignant prostate epithelial cells, PGT inhibitors should be tested as a novel therapeutic modality to treat prostate proliferative disease. © 2017 Wiley Periodicals, Inc.

  17. [Epigenetics of prostate cancer].

    Science.gov (United States)

    Yi, Xiao-Ming; Zhou, Wen-Quan

    2010-07-01

    Prostate cancer is one of the most common malignant tumors in males, and its etiology and pathogenesis remain unclear. Epigenesis is involved in prostate cancer at all stages of the process, and closely related with its growth and metastasis. DNA methylation and histone modification are the most important manifestations of epigenetics in prostate cancer. The mechanisms of carcinogenesis of DNA methylation include whole-genome hypomethylation, aberrant local hypermethylation of promoters and genomic instability. DNA methylation is closely related to the process of prostate cancer, as in DNA damage repair, hormone response, tumor cell invasion/metastasis, cell cycle regulation, and so on. Histone modification causes corresponding changes in chromosome structure and the level of gene transcription, and it may affect the cycle, differentiation and apoptosis of cells, resulting in prostate cancer. Some therapies have been developed targeting the epigenetic changes in prostate cancer, including DNA methyltransferases and histone deacetylase inhibitors, and have achieved certain desirable results.

  18. alpha-Lactalbumin species variation, HAMLET formation, and tumor cell death.

    Science.gov (United States)

    Pettersson, Jenny; Mossberg, Ann-Kristin; Svanborg, Catharina

    2006-06-23

    HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of apo alpha-lactalbumin and oleic acid, formed in casein after low pH treatment of human milk. This study examined if HAMLET-like complexes are present in casein from different species and if isolated alpha-lactalbumin from those species can form such complexes with oleic acid. Casein from human, bovine, equine, and porcine milk was separated by ion exchange chromatography and active complexes were only found in human casein. This was not explained by alpha-lactalbumin sequence variation, as purified bovine, equine, porcine, and caprine alpha-lactalbumins formed complexes with oleic acid with biological activity similar to HAMLET. We conclude that structural variation of alpha-lactalbumins does not preclude the formation of HAMLET-like complexes and that natural HAMLET formation in casein was unique to human milk, which also showed the highest oleic acid content.

  19. Failure-to-thrive syndrome associated with tumor formation by Madin-Darby canine kidney cells in newborn nude mice.

    Science.gov (United States)

    Brinster, Lauren R; Omeir, Romelda L; Foseh, Gideon S; Macauley, Juliete N; Snoy, Philip J; Beren, Joel J; Teferedegne, Belete; Peden, Keith; Lewis, Andrew M

    2013-08-01

    Tumors that formed in newborn nude mice that were inoculated with 10(7) Madin-Darby canine kidney (MDCK) cells were associated with a failure-to-thrive (FTT) syndrome consisting of growth retardation, lethargy, weakness, and dehydration. Scoliosis developed in 41% of affected pups. Pups were symptomatic by week 2; severely affected pups became moribund and required euthanasia within 3 to 4 wk. Mice with FTT were classified into categories of mild, moderate, and severe disease by comparing their weight with that of age-matched normal nude mice. The MDCK-induced tumors were adenocarcinomas that invaded adjacent muscle, connective tissue, and bone; 6 of the 26 pups examined had lung metastases. The induction of FTT did not correlate with cell-line aggressiveness as estimated by histopathology or the efficiency of tumor formation (tumor-forming dose 50% endpoint range = 10(2.8) to 10(7.5)); however, tumor invasion of the paravertebral muscles likely contributed to the scoliosis noted. In contrast to the effect of MDCK cells, tumor formation observed in newborn mice inoculated with highly tumorigenic, human-tumor-derived cell lines was not associated with FTT development. We suggest that tumor formation and FTT are characteristics of these MDCK cell inocula and that FTT represents a new syndrome that may be similar to the cachexia that develops in humans with cancer or other diseases.

  20. IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2.

    Science.gov (United States)

    Merz, Constanze; von Mässenhausen, Anne; Queisser, Angela; Vogel, Wenzel; Andrén, Ove; Kirfel, Jutta; Duensing, Stefan; Perner, Sven; Nowak, Michael

    2016-04-01

    Prostate cancer is the most diagnosed cancer in men and multiple risk factors and genetic alterations have been described. The TMPRSS2-ERG fusion event and the overexpression of the transcription factor ERG are present in approximately 50% of all prostate cancer patients, however, the clinical outcome is still controversial. Prostate tumors produce various soluble factors, including the pleiotropic cytokine IL-6, regulating cellular processes such as proliferation and metastatic segregation. Here, we used prostatectomy samples in a tissue microarray format and analyzed the co-expression and the clinicopathologic data of ERG and IL-6 using immunohistochemical double staining and correlated the read-out with clinicopathologic data. Expression of ERG and IL-6 correlated strongly in prostate tissue samples. Forced expression of ERG in prostate tumor cell lines resulted in significantly increased secretion of IL-6, whereas the down-regulation of ERG decreased IL-6 secretion. By dissecting the underlying mechanism in prostate tumor cell lines we show the ERG-mediated up-regulation of the prostanoid receptors EP2 and EP3. The prostanoid receptor EP2 was overexpressed in human prostate cancer tissue. Furthermore, the proliferation rate and IL-6 secretion in DU145 cells was reduced after treatment with EP2-receptor antagonist. Collectively, our study shows that the expression of ERG in prostate cancer is linked to the expression of IL-6 mediated by the prostanoid receptor EP2. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  1. The Contributions of 8P Loss and 8Q Gain to the Malignant Phenotype in Human Prostate Tumors

    National Research Council Canada - National Science Library

    Kant, Rajiv

    2002-01-01

    .... In order to overcome this limitation, the Nl5C6 epithelial and the Nl fibroblastic cell lines were developed through immortalization of explanted human prostate tissue with the HPV and E6 and E7 proteins...

  2. Increased expression of Golgi phosphoprotein-3 is associated with tumor aggressiveness and poor prognosis of prostate cancer

    Directory of Open Access Journals (Sweden)

    Hua Xing

    2012-09-01

    Full Text Available Abstract Background To investigate the expression of Golgi phosphoprotein-3 (GOLPH3 in prostate cancer and determine its prognostic value. Methods Immunohistochemical staining for GOLPH3 was performed on tissue microarrays of 342 prostate patients. The correlation between GOLPH3 expression with its clinicopathologic factors was also analyzed in order to determine its prognostic significance. Results GOLPH3 expression of normal prostate tissues, benign prostate hyperplasia, high-grade prostatic intraepithelial neoplasia, and hormone-dependent prostate cancer (HDPC did not show any statistically significant difference. In contrast, statistically significant difference was reported in moderate/intense GOLPH3 expression in cases diagnosed with HDPC and castration resistant prostate cancer (CRPC (P P = 0.012, higher Gleason score (P = 0.017, bone metastasis (P = 0.024, higher baseline prostate-specific antigen (PSA (P = 0.038, and higher PSA nadir (P = 0.032. A significantly negative correlation was found between moderate/intense GOLPH3 expression and disease-free survival (DFS (HR = 0.28, P = 0.012 and overall survival (OS (HR = 0.42, P = 0.027. Univariated analysis indicated that moderate/intense GOLPH3 expression created a significantly prognostic impact in patients with CRPC. On the other hand, multivariate analysis indicated that GOLPH3 was a significantly independent prognostic factor of DFS (P = 0.027 in all prostate cancer patients. Conclusions In this study, it was discovered that the overexpression of GOLPH3 is associated with the transition of prostate cancer from hormone sensitive phase to hormone refractory phase. GOLPH3 might be an important prognostic factor of DFS and OS in patients with prostate cancer. In totality, GOLPH3 could be used as a novel candidate in devising a more effective therapeutic strategy to tackle CRPC. Virtual slides The virtual slide(s for this article can be found here

  3. High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer

    Science.gov (United States)

    2016-12-01

    to previously-reported unselected populations suggesting that this may be used as a prognostic marker for aggressive disease in the future. Finally...although an ETV1 fusion was detected). Importantly, paired prostate cancer specimens—particularly those representing primary and distant metastases—are...two-sided Fisher’s exact test p=0.25) (8). These findings support TP53 alterations as a marker of aggressive prostate cancer, in addition to their

  4. The PSA−/lo prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration

    Science.gov (United States)

    Qin, Jichao; Liu, Xin; Laffin, Brian; Chen, Xin; Choy, Grace; Jeter, Collene; Calhoun-Davis, Tammy; Li, Hangwen; Palapattu, Ganesh S.; Pang, Shen; Lin, Kevin; Huang, Jiaoti; Ivanov, Ivan; Li, Wei; Suraneni, Mahipal V.; Tang, Dean G.

    2012-01-01

    SUMMARY Prostate cancer (PCa) is heterogeneous and contains both differentiated and undifferentiated tumor cells, but the relative functional contribution of these two cell populations remains unclear. Here we report distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (PSA+) and low (PSA−/lo) levels of the differentiation marker PSA. PSA−/lo PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division generating PSA+ cells. Importantly, PSA−/lo PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, undergo symmetric division and are sensitive to castration. Together, our study suggests PSA−/lo cells may represent a critical source of castration-resistant PCa cells. PMID:22560078

  5. Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression.

    Science.gov (United States)

    Cortesi, Filippo; Delfanti, Gloria; Grilli, Andrea; Calcinotto, Arianna; Gorini, Francesca; Pucci, Ferdinando; Lucianò, Roberta; Grioni, Matteo; Recchia, Alessandra; Benigni, Fabio; Briganti, Alberto; Salonia, Andrea; De Palma, Michele; Bicciato, Silvio; Doglioni, Claudio; Bellone, Matteo; Casorati, Giulia; Dellabona, Paolo

    2018-03-13

    Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the pro-angiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing pro-angiogenic TIE2 + , M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumor-bearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling.

    Science.gov (United States)

    Klein, Eric A; Cooperberg, Matthew R; Magi-Galluzzi, Cristina; Simko, Jeffry P; Falzarano, Sara M; Maddala, Tara; Chan, June M; Li, Jianbo; Cowan, Janet E; Tsiatis, Athanasios C; Cherbavaz, Diana B; Pelham, Robert J; Tenggara-Hunter, Imelda; Baehner, Frederick L; Knezevic, Dejan; Febbo, Phillip G; Shak, Steven; Kattan, Michael W; Lee, Mark; Carroll, Peter R

    2014-09-01

    Prostate tumor heterogeneity and biopsy undersampling pose challenges to accurate, individualized risk assessment for men with localized disease. To identify and validate a biopsy-based gene expression signature that predicts clinical recurrence, prostate cancer (PCa) death, and adverse pathology. Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies-a discovery prostatectomy study (n=441), a biopsy study (n=167), and a prospectively designed, independent clinical validation study (n=395)-testing retrospectively collected needle biopsies from contemporary (1997-2011) patients with low to intermediate clinical risk who were candidates for active surveillance (AS). The main outcome measures defining aggressive PCa were clinical recurrence, PCa death, and adverse pathology at prostatectomy. Cox proportional hazards regression models were used to evaluate the association between gene expression and time to event end points. Results from the prostatectomy and biopsy studies were used to develop and lock a multigene-expression-based signature, called the Genomic Prostate Score (GPS); in the validation study, logistic regression was used to test the association between the GPS and pathologic stage and grade at prostatectomy. Decision-curve analysis and risk profiles were used together with clinical and pathologic characteristics to evaluate clinical utility. Of the 732 candidate genes analyzed, 288 (39%) were found to predict clinical recurrence despite heterogeneity and multifocality, and 198 (27%) were predictive of aggressive disease after adjustment for prostate-specific antigen, Gleason score, and clinical stage. Further analysis identified 17 genes representing multiple biological pathways that were combined into the GPS algorithm. In the validation study, GPS predicted high-grade (odds ratio [OR] per 20 GPS units: 2.3; 95% confidence interval [CI], 1.5-3.7; p<0.001) and high-stage (OR per 20 GPS units: 1.9; 95% CI, 1

  7. Pretreatment Serum Cystatin C Levels Predict Renal Function, but Not Tumor Characteristics, in Patients with Prostate Neoplasia

    Directory of Open Access Journals (Sweden)

    Feilong Yang

    2017-01-01

    Full Text Available To evaluate the role of Cystatin C (Cys-C in tumorigenesis and progression of prostate cancer (PCa, we retrospectively collected the clinical information from the records of 492 benign prostatic hyperplasia (BPH, 48 prostatic intraepithelial neoplasia (PIN, and 173 PCa patients, whose disease was newly diagnosed and histologically confirmed. Pretreatment serum Cys-C levels were compared across the various groups and then analyzed to identify relationships, if any, with clinical and pathological characteristics of the PCa patient group. There were no significant differences in serum Cys-C levels among the three groups (P > 0.05. In PCa patients with normal SCr levels, patient age was correlated with serum Cys-C level (P ≤ 0.001 but did not correlate with alkaline phosphatase (AKP, lactate dehydrogenase (LDH, prostate specific antigen (PSA, Gleason score, or bone metastasis status (P > 0.05. Age and SCr contributed in part to the variations in serum Cys-C levels of PCa patients (r = 0.356, P ≤ 0.001; r = 0.520, P ≤ 0.001. In conclusion, serum Cys-C levels predict renal function in patients with prostate neoplasia, but were not a biomarker for the development of prostate neoplasia, and were not correlated with the clinicopathological characteristics of PCa.

  8. Preventive effect of chemical peeling on ultraviolet induced skin tumor formation.

    Science.gov (United States)

    Abdel-Daim, Mohamed; Funasaka, Yoko; Kamo, Tsuneyoshi; Ooe, Masahiko; Matsunaka, Hiroshi; Yanagita, Emmy; Itoh, Tomoo; Nishigori, Chikako

    2010-10-01

    Chemical peeling is one of the dermatological treatments available for certain cutaneous diseases and conditions or improvement of cosmetic appearance of photoaged skin. We assessed the photochemopreventive effect of several clinically used chemical peeling agents on the ultraviolet (UV)-irradiated skin of hairless mice. Chemical peeling was done using 35% glycolic acid dissolved in distilled water, 30% salicylic acid in ethanol, 10% or 35% trichloroacetic acid (TCA) in distilled water at the right back of UV-irradiated hairless mice every 2 weeks in case of glycolic acid, salicylic acid, and 10% TCA and every 4 weeks in case of 35% TCA for totally 18 weeks after the establishment of photoaged mice by irradiation with UVA+B range light three times a week for 10 weeks at a total dose of 420 J/cm(2) at UVA and 9.6 J/cm(2) at UVB. Tumor formation was assessed every week. Skin specimens were taken from treated and non-treated area for evaluation under microscopy, evaluation of P53 expression, and mRNA expression of cyclooxygenase (COX)-2. Serum level of prostaglandin E(2) was also evaluated. All types of chemical peeling reduced tumor formation in treated mice, mostly in the treated area but also non-treated area. Peeling suppressed clonal retention of p53 positive abnormal cells and reduced mRNA expression of COX-2 in treated skin. Further, serum prostaglandin E(2) level was decreased in chemical peeling treated mice. These results indicate that chemical peeling with glycolic acid, salicylic acid, and TCA could serve tumor prevention by removing photodamaged cells. Copyright © 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  9. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

    International Nuclear Information System (INIS)

    Demir, Ummuhan; Koehler, Andrea; Schneider, Rainer; Schweiger, Susann; Klocker, Helmut

    2014-01-01

    Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin

  10. Erratum: Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment.

    Science.gov (United States)

    Kong, D; Heath, E; Chen, W; Cher, M; Powell, I; Heilbrun, L; Li, Y; Ali, S; Sethi, S; Hassan, O; Hwang, C; Gupta, N; Chitale, D; Sakr, Wa; Menon, M; Sarkar, Fh

    2013-01-01

    Androgen Receptor (AR) signaling is critically important during the development and progression of prostate cancer (PCa). The AR signaling is also important in the development of castrate resistant prostate cancer (CRPC) where AR is functional even after androgen deprivation therapy (ADT); however, little is known regarding the transcriptional and functional regulation of AR in PCa. Moreover, treatment options for primary PCa for preventing the occurrence of CRPC is limited; therefore, novel strategy for direct inactivation of AR is urgently needed. In this study, we found loss of miR-34a, which targets AR, in PCa tissue specimens, especially in patients with higher Gleason grade tumors, consistent with increased expression of AR. Forced over-expression of miR-34a in PCa cell lines led to decreased expression of AR and prostate specific antigen (PSA) as well as the expression of Notch-1, another important target of miR-34a. Most importantly, BR-DIM intervention in PCa patients prior to radical prostatectomy showed reexpression of miR-34a, which was consistent with decreased expression of AR, PSA and Notch-1 in PCa tissue specimens. Moreover, BR-DIM intervention led to nuclear exclusion both in PCa cell lines and in tumor tissues. PCa cells treated with BR-DIM and 5-aza-dC resulted in the demethylation of miR-34a promoter concomitant with inhibition of AR and PSA expression in LNCaP and C4-2B cells. These results suggest, for the first time, epigenetic silencing of miR-34a in PCa, which could be reversed by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa.[This corrects the article on p. 14 in vol. 4.].

  11. Taxane-Grafted Metal-Oxide Nanoparticles as a New Theranostic Tool against Cancer: The Promising Example of Docetaxel-Functionalized Titanate Nanotubes on Prostate Tumors.

    Science.gov (United States)

    Loiseau, Alexis; Boudon, Julien; Mirjolet, Céline; Créhange, Gilles; Millot, Nadine

    2017-08-01

    The combination of anticancer drugs and metal oxide nanoparticles is of great interest in cancer nanomedicine. Here, the development of a new nanohybrid, titanate nanotube-docetaxel (TiONts-DTX) is reported, the two parts of which are conjugated by covalent linkages. Unlike most nanoparticles currently being developed for biomedical purposes, TiONts present a needle-shaped morphology. The surface of TiONts is linked with 3-aminopropyl triethoxysilane and with a hetero-bifunctional polymer (polyethylene glycol) to create well-dispersed and biocompatible nanovectors. The prefunctionalized surface of this scaffold has valuable attachments to graft therapeutic agents (DTX in our case) as well as chelating agents (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to monitor the nanohybrids. To evaluate drug efficacy, in vitro tests have demonstrated that the association between TiONts and DTX shows cytotoxic activity against a hormone-refractory prostate cancer cell line (22Rv1) whereas TiONts without DTX do not. Finally, the first in vivo tests with intratumoral injections show that more than 70% of TiONts nanovectors are retained within the tumor for at least 7 d. Moreover, tumor growth in mice receiving TiONts-DTX is significantly slower than that in mice receiving free DTX. This nanohybrid can thus become a promising new tool in biomedicine to fight against prostate cancer. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Pimenta, Erica M. [Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States); Barnes, Betsy J., E-mail: barnesbe@njms.rutgers.edu [Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States)

    2014-04-23

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin{sup ®}) and rituximab (Rituxan{sup ®})) and the first approved cancer vaccine, Provenge{sup ®} (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

  13. Role of Tertiary Lymphoid Structures (TLS in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Directory of Open Access Journals (Sweden)

    Erica M. Pimenta

    2014-04-01

    Full Text Available Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin® and rituximab (Rituxan® and the first approved cancer vaccine, Provenge® (sipuleucel-T, investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS within the tumor microenvironment may be used to enhance immunotherapy response.

  14. A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression

    Directory of Open Access Journals (Sweden)

    María de la Luz García-Hernández

    2017-05-01

    Full Text Available ObjectiveMultiple solid cancers contain tertiary lymphoid organs (TLO. However, it is unclear whether they promote tumor rejection, facilitate tumor evasion, or simply whether they are a byproduct of chronic inflammation. We hypothesize that although chronic inflammation induces TLO formation, the tumor milieu can modulate TLO organization and functions in prostate cancer. Therefore, our study seeks to elucidate the cellular and molecular signatures in unique prostatectomy specimens from evanescent carcinoma patients to identify markers of cancer regression, which could be harnessed to modulate local immunosuppression or potentially enhance TLO function.MethodsWe used multicolor immunofluorescence to stain prostate tissues, collected at different stages of cancer progression (prostatic intraepithelial neoplasia, intermediate and advanced cancer or from patients with evanescent prostate carcinoma. Tissues were stained with antibodies specific for pro-inflammatory molecules (cyclooxygenase 2, CXCL10, IL17, tumor-infiltrating immune cells (mature DC-LAMP+ dendritic cells, CD3+ T cells, CD3+Foxp3+ regulatory T cells (Treg, T bet+ Th1 cells, granzyme B+ cytotoxic cells, and stromal cell populations (lymphatic vessels, tumor neovessels, high endothelial venules (HEV, stromal cells, which promote prostate tumor growth or are critical components of tumor-associated TLO.ResultsGenerally, inflammatory cells are located at the margins of tumors. Unexpectedly, we found TLO within prostate tumors from patients at different stages of cancer and in unique samples from patients with spontaneous cancer remission. In evanescent prostate carcinomas, accumulation of Treg was compromised, while Tbet+ T cells and CD8 T cells were abundant in tumor-associated TLO. In addition, we found a global decrease in tumor neovascularization and the coverage by cells positive for cyclooxygenase 2 (COX2. Finally, consistent with tumor regression, prostate stem cell antigen was

  15. Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms.

    Science.gov (United States)

    Li, Zhi Gang; Mathew, Paul; Yang, Jun; Starbuck, Michael W; Zurita, Amado J; Liu, Jie; Sikes, Charles; Multani, Asha S; Efstathiou, Eleni; Lopez, Adriana; Wang, Jing; Fanning, Tina V; Prieto, Victor G; Kundra, Vikas; Vazquez, Elba S; Troncoso, Patricia; Raymond, Austin K; Logothetis, Christopher J; Lin, Sue-Hwa; Maity, Sankar; Navone, Nora M

    2008-08-01

    In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.

  16. Prostate Problems

    Science.gov (United States)

    ... know the exact cause of your prostate problem. Prostatitis The cause of prostatitis depends on whether you ... prostate problem in men older than age 50. Prostatitis If you have a UTI, you may be ...

  17. O padrão 4 de Gleason e o volume tumoral no prognóstico do carcinoma da próstata Well differentiated localized prostate carcinoma: prognostic relevance of tertiary Gleason pattern 4 and tumor volume

    Directory of Open Access Journals (Sweden)

    Katia R. M. Leite

    2005-12-01

    recidivaram (p=0,046. CONCLUSÃO: O volume do adenocarcinoma de próstata é um parâmetro objetivo, de fácil avaliação e importante na previsão da recidiva bioquímica no carcinoma bem diferenciado da próstata. Por outro lado, a porcentagem do padrão menos diferenciado de Gleason também serve para prever recidiva à distância. Ambos os parâmetros devem ser incorporados em estudos futuros de terapias adjuvantes para o carcinoma da próstata.INTRODUCTION: Early introduction of adjuvant radiation or hormone therapy after radical prostatectomy has been advocated in recent literature aiming to improve survival rates in high risk prostate cancer. Traditional prognostic parameters such as serum PSA, Gleason score and clinical stage have been used to identify these cases however accuracy is far from ideal. Recently, tumor volume and presence and percentage of a tertiary less differentiated Gleason pattern have been considered better indicators of prostate cancer behavior. The purpose of this study was to evaluate the importance of presence and percentage of a Gleason pattern 4 and of tumor volume in the outcome of patients treated for well-differentiated prostate adenocarcinoma. METHODS: Seventy seven patients submitted to radical prostatectomy for well-differentiated prostate carcinoma, Gleason score 6 or less, and followed up for at least 5 years were selected. Thirty seven experienced biochemical recurrence while 40 did not. The percentage of Gleason pattern 4, the percentage of the gland involvement (considered as "tumor volume", capsular invasion and extraprostatic extension were submitted to univariate and multivariate analyses for the evaluation of possible associations with biochemical recurrence. RESULTS: Tumor volume was the most important parameter to predict biochemical recurrence by univariate and multivariate analysis. The median of tumor volume was 25.0% for patients who suffered recurrence, and 11.5% for those with no recurrence (p=0.003. The percentage of

  18. Imaging Prostatic Lipids to Distinguish Aggressive Prostate Cancer

    Science.gov (United States)

    2016-12-01

    prostatectomy samples, intraprostatic lipid as measured by MRSI and prostate tumor aggressiveness. 3) To quantify key metabolic intermediates involved in...lipid as measured by 1H MRSI, and prostate tumor aggressiveness; and 3) quantify the association between key metabolic intermediates involved in lipid

  19. Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control.

    Science.gov (United States)

    Kratochwil, Clemens; Bruchertseifer, Frank; Rathke, Hendrik; Hohenfellner, Markus; Giesel, Frederik L; Haberkorn, Uwe; Morgenstern, Alfred

    2018-05-01

    The aim of this evaluation was to identify the first indicators of efficacy for 225 Ac-labeled prostate-specific membrane antigen (PSMA)-617 therapy in a retrospectively analyzed group of patients. Methods: Forty patients with metastatic castration-resistant prostate cancer were selected for treatment with three 100 kBq/kg cycles of 225 Ac-PSMA-617 at 2-mo intervals. Prostate-specific antigen (PSA) and blood cell count were measured every 4 wk. PSMA PET/CT or PSMA SPECT/CT were used for baseline staging and imaging follow-up at month 6. Follow-up included the duration of PSA response and radiologic progression-free survival at month 6. Patient histories were reviewed for the duration of previous treatment lines, and a swimmer plot was used to intraindividually compare the duration of tumor control by PSMA therapy versus prior treatment modalities. Results: Thirty-one of 40 patients were treated per protocol. Five patients discontinued treatment because of nonresponse, and 4 because of xerostomia. Of the 38 patients surviving at least 8 wk, 24 (63%) had a PSA decline of more than 50%, and 33 (87%) had a PSA response of any degree. The median duration of tumor control under 225 Ac-PSMA-617 last-line therapy was 9.0 mo; 5 patients had an enduring response of more than 2 y. Because all patients had advanced disease, this result compares favorably with the tumor control rates associated with earlier-phase disease; the most common preceding first-, second-, third-, and fourth-line therapies were abiraterone (median duration 10.0 mo), docetaxel (6.5 mo), enzalutamide (6.5 mo), and cabazitaxel (6.0 mo), respectively. Conclusion: A positive response for surrogate parameters demonstrates remarkable antitumor activity for 225 Ac-PSMA-617. Swimmer-plot analysis indicates a promising duration of tumor control, especially considering the unfavorable prognostic profile of the selected advanced-stage patients. Xerostomia was the main reason patients discontinued therapy or refused

  20. [Fish intake and risk of prostate cancer].

    Science.gov (United States)

    Dybkowska, Ewa; Świderski, Franciszek; Waszkiewicz-Robak, Bożena

    2014-10-17

    The aim of the study was to present the current state of knowledge concerning the relationship between the consumption of fish as materials rich in long chain polyunsaturated fatty acids (LC PUFA) omega-3, and the risk of prostate cancer. Many scientific reports confirm the health benefits from the consumption of fish and protective properties of LC PUFA omega-3 in relation to prostate cancer. However, there are reports that indicate a relationship of the high consumption of PUFA with the risk of prostate cancer. The way of processing and preservation of the fish, and other factors not included in previous studies, could have some importance in the etiology of this disease. High susceptibility of PUFA to oxidation changes and the technological fish processing (smoking, high-temperature cooking methods) contribute to the formation of many compounds, such as polycyclic aromatic hydrocarbons and heterocyclic amines - which may influence the formation of cancers - including prostate cancer. It is necessary to ensure an adequate amount of LC PUFA omega-3 in the diet through the consumption of proper quality fish and fish oils. Particular attention should be paid to the high susceptibility of PUFA to the oxidative processes, and the method of processing, preservation and storage of fish. Also pollution from the environment can significantly reduce the impact of health benefits of PUFA and fish, and even be the cause of cancers, including prostate cancer. Further research in this area should be more targeted to assess the impact of nutritional factors for the development of such tumors.

  1. Comparison of 2D and 3D algorithms for adding a margin to the gross tumor volume in the conformal radiotherapy planning of prostate cancer

    International Nuclear Information System (INIS)

    Khoo, Vincent S.; Bedford, James L.; Webb, Steve; Dearnaley, David P.

    1998-01-01

    Purpose: To evaluate the adequacy of tumor volume coverage using a three-dimensional (3D) margin-growing algorithm compared to a two-dimensional (2D) margin-growing algorithm in the conformal radiotherapy planning of prostate cancer. Methods and Materials: Two gross tumor volumes (GTV) were segmented in each of 10 patients with localized prostate cancer; prostate gland only (PO) and prostate with seminal vesicles (PSV). A predetermined margin of 10 mm was applied to these two groups (PO and PSV) using both 2D and 3D margin-growing algorithms. The 2D algorithm added a transaxial margin to each GTV slice, whereas the 3D algorithm added a volumetric margin all around the GTV. The true planning target volume (PTV) was defined as the region delineated by the 3D algorithm. The adequacy of geometric coverage of the GTV by the two algorithms was examined in a series of transaxial planes throughout the target volume. Results: The 2D margin-growing algorithm underestimated the PTV by 17% (range 12-20) in the PO group and by 20% (range 13-28) for the PSV group when compared to the 3D-margin algorithm. For the PO group, the mean transaxial difference between the 2D and 3D algorithm was 3.8 mm inferiorly (range 0-20), 1.8 mm centrally (range 0-9), and 4.4 mm superiorly (range 0-22). Considering all of these regions, the mean discrepancy anteriorly was 5.1 mm (range 0-22), posteriorly 2.2 (range 0-20), right border 2.8 mm (range 0-14), and left border 3.1 mm (range 0-12). For the PSV group, the mean discrepancy in the inferior region was 3.8 mm (range 0-20), central region of the prostate was 1.8 mm ( range 0-9), the junction region of the prostate and the seminal vesicles was 5.5 mm (range 0-30), and the superior region of the seminal vesicles was 4.2 mm (range 0-55). When the different borders were considered in the PSV group, the mean discrepancies for the anterior, posterior, right, and left borders were 6.4 mm (range 0-55), 2.5 mm (range 0-20), 2.6 mm (range 0-14), and 3

  2. The specific role of radiotherapy in the management of prostate carcinoma at different stages of tumor development

    International Nuclear Information System (INIS)

    Huber, J.

    1987-01-01

    The study described here was based on the case reports of 135 patients of the Radiological Department at Kiel's University Hospital, who were treated for carcinomas of the prostate at any time during the period between 1965 and 1980. It was the aim of these evaluations to define the particular role of radiotherapy in the management of carcinomas of the prostate and to compare it to that of other methods of treatment (hormones, surgery). Percutaneous local irradiation of the carcinoma or irradiation of metastases were the criteria of inclusion into this retrospective study. The stage of the tumour was a decisive factor in the final analysis of the results. (orig.) [de

  3. Aryl hydrocarbon receptors in urogenital sinus mesenchyme mediate the inhibition of prostatic epithelial bud formation by 2,3,7,8-tetrachlorodibenzo-p-dioxin

    International Nuclear Information System (INIS)

    Ko, Kinarm; Moore, Robert W.; Peterson, Richard E.

    2004-01-01

    In utero exposure of male C57BL/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents prostatic epithelial buds from forming in the ventral region of the urogenital sinus (UGS) and reduces the number of buds that form in the dorsolateral region. This inhibition of budding is aryl hydrocarbon receptor (AHR) dependent and appears to be the primary cause of lobe-specific prostate abnormalities in TCDD-exposed mice. TCDD can inhibit prostatic epithelial bud formation by acting directly on the UGS in vitro, but whether it does so via AHR in UGS mesenchyme, epithelium, or both was unknown. To address this issue, UGS mesenchyme and epithelium from gestation day (GD) 15 wild-type C57BL/6J male mice were isolated, recombined, and cultured in vitro for 5 days with 10 -8 M 5α-dihydrotestosterone (DHT) and either 10 -9 M TCDD or vehicle. Prostatic epithelial buds were viewed by light microscopy after removal of mesenchyme. Effects depended greatly on which portions of the mesenchyme were used: TCDD had little if any effect when whole UGS epithelium (UGE) was recombined with ventral plus dorsolateral mesenchyme, tended to reduce bud numbers in recombinants made with UGE and dorsolateral mesenchyme, and severely reduced bud numbers in recombinants made with UGE and ventral mesenchyme (VM). [VM + UGE] recombinants prepared from wild-type and AHR knockout (Ahr -/- ) mice were then cultured with DHT to determine the site of action of TCDD. AHR null mutation alone had no effect on budding. TCDD severely inhibited prostatic epithelial bud formation in recombinants that contained mesenchymal AHR, whereas bud formation was not inhibited by TCDD in recombinants lacking mesenchymal AHR, regardless of epithelial AHR status. These results demonstrate that UGS mesenchyme and not UGS epithelium is the site of action of TCDD. Therefore, the initial events responsible for abnormal UGS (and ultimately prostate) development occur within the UGS mesenchyme, and changes in gene expression

  4. Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src.

    Directory of Open Access Journals (Sweden)

    Maoyong Fu

    Full Text Available Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2, a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling.

  5. Aneuploidy theory explains tumor formation, the absence of immune surveillance, and the failure of chemotherapy.

    Science.gov (United States)

    Rasnick, David

    2002-07-01

    The autocatalyzed progression of aneuploidy accounts for all cancer-specific phenotypes, the Hayflick limit of cultured cells, carcinogen-induced tumors in mice, the age distribution of human cancer, and multidrug-resistance. Here aneuploidy theory addresses tumor formation. The logistic equation, phi(n)(+1) = rphi(n) (1 - phi(n)), models the autocatalyzed progression of aneuploidy in vivo and in vitro. The variable phi(n)(+1) is the average aneuploid fraction of a population of cells at the n+1 cell division and is determined by the value at the nth cell division. The value r is the growth control parameter. The logistic equation was used to compute the probability distribution for values of phi after numerous divisions of aneuploid cells. The autocatalyzed progression of aneuploidy follows the laws of deterministic chaos, which means that certain values of phi are more probable than others. The probability map of the logistic equation shows that: 1) an aneuploid fraction of at least 0.30 is necessary to sustain a population of cancer cells; and 2) the most likely aneuploid fraction after many population doublings is 0.70, which is equivalent to a DNA(index)=1.7, the point of maximum disorder of the genome that still sustains life. Aneuploidy theory also explains the lack of immune surveillance and the failure of chemotherapy.

  6. 68Ga-PSMA-11 PET/CT-derived metabolic parameters for determination of whole-body tumor burden and treatment response in prostate cancer.

    Science.gov (United States)

    Schmidkonz, Christian; Cordes, Michael; Schmidt, Daniela; Bäuerle, Tobias; Goetz, Theresa Ida; Beck, Michael; Prante, Olaf; Cavallaro, Alexander; Uder, Michael; Wullich, Bernd; Goebell, Peter; Kuwert, Torsten; Ritt, Philipp

    2018-05-03

    We aimed at evaluating the role of 68 Ga-PSMA-11 PET/CT-derived metabolic parameters for assessment of whole-body tumor burden and its capability to determine therapeutic response in patients with prostate cancer. A total of 142 patients with biochemical recurrence of prostate cancer underwent PET/CT with [ 68 Ga]Ga-PSMA-HBED-CC ( 68 Ga-PSMA-11). Quantitative assessment of all 641 68 Ga-PSMA-11-positive lesions in the field of view was performed to calculate PSMA-derived parameters, including whole-body PSMA tumor volume (PSMA-TV) and whole-body total lesion PSMA (TL-PSMA), as well as the established SUVmax and SUVmean values. All PET-derived parameters were tested for correlation with serum PSA levels and for association with Gleason scores. In 23 patients who underwent 68 Ga-PSMA-11 PET/CT before and after therapy with either external beam radiation, androgen deprivation, or docetaxel chemotherapy, SUVmax and TL-PSMA were compared to radiographic response assessment of CT images based on RECIST 1.1 criteria and to biochemical response determined by changes of serum PSA levels. PSMA-TV and TL-PSMA demonstrated a significant correlation with serum PSA levels (P PET and biochemical response was 87% (95% confidence interval, 0.66-0.97; Cohen's κ = 0.78; P PET and CT were most likely due to limitations of CT and RECIST in rating small lymph nodes as metastases, as well as bone involvement, which was sometimes not detectable in CT. 68 Ga-PSMA-11 PET/CT-derived metabolic tumor parameters showed promising results for evaluation of treatment response. Especially, TL-PSMA demonstrated higher agreement rates with biochemical response compared to SUVmax. Larger, ideally prospective trials are needed to help to reveal the full potential of metabolic parameters derived from PET imaging with 68 Ga-PSMA-11.

  7. PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

    Science.gov (United States)

    Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

    2018-01-01

    Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

  8. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study

    NARCIS (Netherlands)

    Schröder, Fritz H.; Kurth, Karl Heinz; Fosså, Sophie D.; Hoekstra, Wytze; Karthaus, Peter P. M.; Debois, Muriel; Collette, Laurence

    2004-01-01

    The timing of endocrine treatment for prostate cancer remains controversial. The issue is addressed in protocol 30846 of the European Organisation for Research and Treatment of Cancer for patients with lymph node positive cancer without local treatment of the primary tumor. A total of 302 patients

  9. State of cellular and humoral immune system in women of reproductive age with tumor-like ovary formations

    Directory of Open Access Journals (Sweden)

    O. S. Shapoval

    2014-12-01

    Full Text Available Aim. Violations occurring in the immune system in women with ovary tumor-like formations are one of the most important factors in the pathogenesis and development of the disease. In order to study features of immune disorders in 105 women of reproductive age with tumor-like ovary formations determination of cellular and humoral immunity indices was carried out. Methods and results. Variants of immunological reactivity in women with tumor-like ovary formations with different possibilities of reproductive function implementing were established. Conclusion. This indicates that the identification of one of the variants of immunological reactivity disorder in the precurative stage is one of the components of the effective prescribed therapy necessary to select the appropriate tactics of medical correction of homeostasis.

  10. In vitro and in vivo studies in Balb-c and nude mice of a new {sup 177}Lu-Bombesin analog developed for prostate tumor diagnosis and treatment

    Energy Technology Data Exchange (ETDEWEB)

    Pujatti, Priscilla B.; Santos, Josefina S.; Couto, Renata M.; Araujo, Elaine B. de; Mengatti, Jair [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Diretoria de Radiofarmacia], e-mail: priscillapujatti@yahoo.com.br; Suzuki, Miriam F. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Biotecnologia

    2009-07-01

    In this work we describe the radiolabeling with {sup 177}Lu and some properties of the novel bombesin analog BBNp6 - DOTA-X-BBN(6-14), where X is a spacer of six aminoacids. Bombesin (BBN) is an analog of human gastrin releasing peptide (GRP) isolated from the skin of the frog Bombina bombina in 1970. Development of radiolabeled BBN derivatives as agents for diagnostic imaging and systemic radiotherapy has increased considerable because of the observation that GRP receptors (GRPr) are over-expressed in a variety of human tumor cells, such as prostate tumor cells. {sup 177}Lu-labeled peptides are attractive due to the excellent radiophysical properties and commercial availability of the radiometal. BBNp6 was labeled with high yield after reacting with 92.5 MBq of {sup 177}LuCl3 at 90 deg C for 30 minutes and this mixture kept stable for more than 96 hours at 4 deg C and 1 hour in human plasma. In vivo studies showed a multicompartimental distribution model with fast blood clearance, mainly performed by renal pathway. In addition, {sup 177}Lu-BBNp6 showed high affinity for PC-3 tumor xenografts, but not for pancreas and intestine (GRP positive tissues), suggesting its specificity and usefulness for prostate tumor treatment. Moreover, scintigraphic images showed that this derivative can also be a tool in this tumor diagnosis. So, BBNp6 is a promising radiopharmaceutical for prostate tumor imaging and treatment. (author)

  11. Antibody Responses to Prostate-Associated Antigens in Patients with Prostatitis and Prostate Cancer

    Science.gov (United States)

    Maricque, Brett B.; Eickhoff, Jens C.; McNeel, Douglas G.

    2010-01-01

    Background An important focus of tumor immunotherapy has been the identification of appropriate antigenic targets. Serum-based screening approaches have led to the discovery of hundreds of tumor-associated antigens recognized by IgG. Our efforts to identify immunologically recognized proteins in prostate cancer have yielded a multitude of antigens, however prioritizing these antigens as targets for evaluation in immunotherapies has been challenging. In this report, we set out to determine whether the evaluation of multiple antigenic targets would allow the identification of a subset of antigens that are common immunologic targets in patients with prostate cancer. Methods Using a phage immunoblot approach, we evaluated IgG responses in patients with prostate cancer (n=126), patients with chronic prostatitis (n=45), and men without prostate disease (n=53). Results We found that patients with prostate cancer or prostatitis have IgG specific for multiple common antigens. A subset of 23 proteins was identified to which IgG were detected in 38% of patients with prostate cancer and 33% patients with prostatitis versus 6% of controls (pprostate and prostate cancer, and suggest that IgG responses to a panel of commonly recognized prostate antigens could be potentially used in the identification of patients at risk for prostate cancer or as a tool to identify immune responses elicited to prostate tissue. PMID:20632317

  12. Interleukin-30: A novel microenvironmental hallmark of prostate cancer progression.

    Science.gov (United States)

    Di Carlo, Emma

    2014-01-01

    Metastatic prostate cancer is a leading cause of cancer-related death in men worldwide. We have recently discovered that IL-30 shapes the microenvironment of prostate cancer and tumor-draining lymph nodes to favor tumor progression. IL-30 supports tumor growth in vitro, and IL-30 expression in prostate cancer patients is associated with high tumor grade and metastatic stage of disease. Thus, IL-30 may constitute a valuable target for modern therapeutic approaches to hamper prostate cancer progression.

  13. Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

    NARCIS (Netherlands)

    Crespo, M.; van Dalum, Guus; Ferraldeschi, R.; Zafeiriou, Z.; Sideris, S.; Lorente, D.; Bianchini, D.; Rodrigues, D.N.; Rijsnaes, R.; Miranda, S.; Figueiredo, I.; Flohr, P.; Nowakowska, K.; de Bono, J.S.; Terstappen, Leonardus Wendelinus Mathias Marie; Attard, G.

    2015-01-01

    Background: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated

  14. The prognostic value of SUMO1/Sentrin specific peptidase 1 (SENP1) in prostate cancer is limited to ERG-fusion positive tumors lacking PTEN deletion

    International Nuclear Information System (INIS)

    Burdelski, Christoph; Menan, Devi; Tsourlakis, Maria Christina; Kluth, Martina; Hube-Magg, Claudia; Melling, Nathaniel; Minner, Sarah; Koop, Christina; Graefen, Markus; Heinzer, Hans; Wittmer, Corinna; Sauter, Guido; Simon, Ronald; Schlomm, Thorsten; Steurer, Stefan; Krech, Till

    2015-01-01

    Posttranscriptional protein modification by SUMOylation plays an important role in tumor development and progression. In the current study we analyzed prevalence and prognostic impact of the de-SUMOylation enzyme SENP1 in prostate cancer. SENP1 expression was analyzed by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancer specimens. Results were compared to tumor phenotype, ERG status, genomic deletions of 3p, 5q, 6q and PTEN, and biochemical recurrence. SENP1 immunostaining was detectable in 34.5 % of 9,516 interpretable cancers and considered strong in 7.3 %, moderate in 14.9 % and weak in 12.3 % of cases. Strong SENP1 expression was linked to advanced pT stage (p < 0.0001), high Gleason grade (p < 0.0001), positive lymph node status (p = 0.0019), high pre-operative PSA levels (p = 0.0037), and PSA recurrence (p < 0.0001). SENP1 expression was strongly associated with positive ERG fusion status as determined by both in situ hybridization (FISH) and immunohistochemistry as well as with PTEN deletions. Detectable SENP1 immunostaining was found in 41 % of ERG positive and in 47 % of PTEN deleted cancers but in only 30 % of ERG negative and 30 % of PTEN non-deleted cancers (p < 0.0001 each). Deletions of 3p, 5q, and 6q were unrelated to SENP1 expression. Subset analyses revealed that the prognostic impact of SENP1 expression was solely driven by the subgroup of ERG positive, PTEN undeleted cancers. In this subgroup, the prognostic role of SENP1 expression was independent of the preoperative PSA level, tumor stage, Gleason grade, and the status of the resection margin. SENP1 expression has strong prognostic impact in a molecularly defined subset of cancers. This is per se not surprising as the biologic impact of each individual molecular event is likely to be dependent on its cellular environment. However, such findings challenge the concept of finding clinically relevant molecular signatures that are equally applicable to all

  15. X-Ray longitudinal and computed tomography in the diagnosis of peripheral tumor-like formations of the lungs

    International Nuclear Information System (INIS)

    Sokolov, V.A.; Kartashov, V.M.; Piven', A.I.; Krasnoborova, S.Yu.; Blinova, L.V.; Savel'ev, A.V.

    1997-01-01

    Fifty eight patients with peripheral tumor-like formations of the lung (33 with cancer and 25 with benign formations) were examined by longitudinal tomography and CT. The potentialities f the two techniques in detecting the major semiotic signs of cancer and malignant formations were compared. The main or major signs, such as the shape of shadow and the pattern of outlines, which make it possible to differentiate bening and malignant formations, are virtually equally imaged by the two techniques. CT is superior to X-ray longitudinal tomography in revealing minor calcifications and microdestructions, hyperplastic intrathoracic lymph nodes. The significance of some symptoms for differential diagnosis calls for further clarification

  16. Comparison of 2D and 3D algorithms for adding a margin to the gross tumor volume in the conformal radiotherapy planning of prostate cancer

    International Nuclear Information System (INIS)

    Khoo, V.S.; Bedford, J.L.; Webb, S.; Dearnaley, D.P.

    1997-01-01

    Purpose: To evaluate the adequacy of tumor volume coverage using a three dimensional (3D) margin growing algorithm compared to a two dimensional (2D) margin growing algorithm in the conformal radiotherapy planning of prostate cancer. Methods and Materials: Two gross tumor volumes (GTV) were segmented in each of ten patients with localized prostate cancer: prostate gland only (PO) and prostate with seminal vesicles (PSV). A margin of 10 mm was applied to these two groups (PO and PSV) using both the 2D and 3D margin growing algorithms. The true planning target volume (PTV) was defined as the region delineated by the 3D algorithm. Adequacy of geometric coverage of the GTV with the two algorithms was examined throughout the target volume. Discrepancies between the two margin methods were measured in the transaxial plane. Results: The 2D algorithm underestimated the PTV by 17% (range 12-20) in the PO group and by 20% (range 13-28) for the PSV group when compared to the 3D algorithm. For both the PO and PSV groups, the inferior coverage of the PTV was consistently underestimated by the 2D margin algorithm when compared to the 3D margins with a mean radial distance of 4.8 mm (range 0-10). In the central region of the prostate gland, the anterior, posterior, and lateral PTV borders were underestimated with the 2D margin in both the PO and PSV groups by a mean of 3.6 mm (range 0-9), 2.1 mm (range 0-8), and 1.8 (range 0-9) respectively. The PTV coverage of the PO group superiorly was radially underestimated by 4.5mm (range 0-14) when comparing the 2D margins to the 3D margins. For the PSV group, the junction region between the prostate and the seminal vesicles was underestimated by the 2D margin by a mean transaxial distance of 18.1 mm in the anterior PTV border (range 4-30), 7.2 mm posteriorly (range 0-20), and 3.7 mm laterally (range 0-14). The superior region of the seminal vesicles in the PSV group was also consistently underestimated with a radial discrepancy of 3.3 mm

  17. Long Non-Coding RNA MEG3 Inhibits Cell Proliferation and Induces Apoptosis in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Gang Luo

    2015-11-01

    Full Text Available Background/Aims: Long non-coding RNAs (lncRNAs play important roles in diverse biological processes, such as cell growth, apoptosis and migration. Although downregulation of lncRNA maternally expressed gene 3 (MEG3 has been identified in several cancers, little is known about its role in prostate cancer progression. The aim of this study was to detect MEG3 expression in clinical prostate cancer tissues, investigate its biological functions in the development of prostate cancer and the underlying mechanism. Methods: MEG3 expression levels were detected by qRT-PCR in both tumor tissues and adjacent non-tumor tissues from 21 prostate cancer patients. The effects of MEG3 on PC3 and DU145 cells were assessed by MTT assay, colony formation assay, western blot and flow cytometry. Transfected PC3 cells were transplanted into nude mice, and the tumor growth curves were determined. Results: MEG3 decreased significantly in prostate cancer tissues relative to adjacent normal tissues. MEG3 inhibited intrinsic cell survival pathway in vitro and in vivo by reducing the protein expression of Bcl-2, enhancing Bax and activating caspase 3. We further demonstrated that MEG3 inhibited the expression of cell cycle regulatory protein Cyclin D1 and induced cell cycle arrest in G0/G1 phase. Conclusions: Our study presents an important role of MEG3 in the molecular etiology of prostate cancer and implicates the potential application of MEG3 in prostate cancer therapy.

  18. Development of lutetium-labeled bombesin derivates: relationship between structure and diagnostic-therapeutic activity for prostate tumor; Desenvolvimento de derivados da bombesina radiomarcados com lutecio-177: relacao estrutura e potencial diagnostico-terapeutico para tumor de prostata

    Energy Technology Data Exchange (ETDEWEB)

    Pujatti, Priscilla Brunelli

    2009-07-01

    Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor peptide - have been shown to be massively over expressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel series of bombesin derivatives with lutetium-177 and to evaluate the relationship between their structure and diagnostic-therapeutic activity for prostate tumor. The generic structure of studied peptides is DOTA-Phe-(Gly){sub n}-BBN(6-14), where DOTA is the chelator, n is the number of glycine amino acids of Phe-(Gly){sub n} spacer and BBN(6-14) is the bombesin sequence from the amino acid 6 to the amino acid 14. Preliminary studies were done to establish the ideal labeling conditions for obtaining the highest yield of labeled bombesin derivatives, determined by instant thin layer chromatography (ITLC-SG) and high performance liquid chromatography (HPLC). The stability of the preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C and the partition coefficient was determined in n:octanol:water. In vivo studies were performed in both healthy Balb-c and Nude mice bearing PC-3 xenografts, in order to characterize the biological properties of labeled peptides. In vitro studies involved the evaluation of cold bombesin derivatives effect in PC-3 cells proliferation. Bombesin derivatives were successfully labeled with high yield at optimized conditions and exhibited high stability at 4 degree C. The analysis of

  19. [Large benign prostatic hiperplasia].

    Science.gov (United States)

    Soria-Fernández, Guillermo René; Jungfermann-Guzman, José René; Lomelín-Ramos, José Pedro; Jaspersen-Gastelum, Jorge; Rosas-Nava, Jesús Emmanuel

    2012-01-01

    the term prostatic hyperplasia is most frequently used to describe the benign prostatic growth, this being a widely prevalent disorder associated with age that affects most men as they age. The association between prostate growth and urinary obstruction in older adults is well documented. large benign prostatic hyperplasia is rare and few cases have been published and should be taken into account during the study of tumors of the pelvic cavity. we report the case of an 81-year-old who had significant symptoms relating to storage and bladder emptying, with no significant elevation of prostate specific antigen. this is a rare condition but it is still important to diagnose and treat as it may be related to severe obstructive uropathy and chronic renal failure. In our institution, cases of large prostatic hyperplasia that are solved by suprapubic adenomectomy are less than 3%.

  20. Elevated Prostate Health Index (phi) and Biopsy Reclassification During Active Surveillance of Prostate Cancer.

    Science.gov (United States)

    Andreas, Darian; Tosoian, Jeffrey J; Landis, Patricia; Wolf, Sacha; Glavaris, Stephanie; Lotan, Tamara L; Schaeffer, Edward M; Sokoll, Lori J; Ross, Ashley E

    2016-07-01

    The Prostate Health Index (phi) has been FDA approved for decision-making regarding prostate biopsy. Phi has additionally been shown to positively correlate with tumor volume, extraprostatic disease and higher Gleason grade tumors. Here we describe a case in which an elevated phi encouraged biopsy of a gentleman undergoing active surveillance leading to reclassification of his disease as high risk prostate cancer.

  1. Prostate resonance imaging: morphology and metabolism

    International Nuclear Information System (INIS)

    Ocantos, Jorge A.; Pietrani, Marcelo A.; Paganini, Lisandro

    2007-01-01

    The cancer of prostate is the most frequent neoplasms and the third cause of death in men, although the average of survival of patients it improved, the cancer of prostate is an important problem in health. The majority of these tumors are of slow growth and the early detection allows high probabilities of definitive treatment. The neoplasms of prostate detected at present are smaller than the detected ones 20 years ago behind, nevertheless exist big differences in the aggressiveness of these tumors. The images are very important in the management of prostate cancer, and the magnetic resonance imaging of the prostate is a new tool in the evaluation of prostate cancer [es

  2. The Downregulation of the Expression of CD147 by Tumor Suppressor REIC/Dkk-3, and Its Implication in Human Prostate Cancer Cell Growth Inhibition.

    Science.gov (United States)

    Mori, Akihiro; Watanabe, Masami; Sadahira, Takuya; Kobayashi, Yasuyuki; Ariyoshi, Yuichi; Ueki, Hideo; Wada, Koichiro; Ochiai, Kazuhiko; Li, Shun-Ai; Nasu, Yasutomo

    2017-04-01

    The cluster of differentiation 147 (CD147), also known as EMMPRIN, is a key molecule that promotes cancer progression. We previously developed an adenoviral vector encoding a tumor suppressor REIC/Dkk-3 gene (Ad-REIC) for cancer gene therapy. The therapeutic effects are based on suppressing the growth of cancer cells, but, the underlying molecular mechanism has not been fully clarified. To elucidate this mechanism, we investigated the effects of Ad-REIC on the expression of CD147 in LNCaP prostate cancer cells. Western blotting revealed that the expression of CD147 was significantly suppressed by Ad-REIC. Ad-REIC also suppressed the cell growth of LNCaP cells. Since other researchers have demonstrated that phosphorylated mitogen-activated protein kinases (MAPKs) and c-Myc protein positively regulate the expression of CD147, we investigated the correlation between the CD147 level and the activation of MAPK and c-Myc expression. Unexpectedly, no positive correlation was observed between CD147 and its possible regulators, suggesting that another signaling pathway was involved in the downregulation of CD147. This is the first study to show the downregulation of CD147 by Ad-REIC in prostate cancer cells. At least some of the therapeutic effects of Ad-REIC may be due to the downregulation of the cancer-progression factor, CD147.

  3. Preliminary experience on the use of the Adnatest® system for detection of circulating tumor cells in prostate cancer patients.

    Science.gov (United States)

    Todenhöfer, Tilman; Hennenlotter, Jörg; Feyerabend, Susan; Aufderklamm, Stefan; Mischinger, Johannes; Kühs, Ursula; Gerber, Valentina; Fetisch, Jasmin; Schilling, David; Hauch, Siegfried; Stenzl, Arnulf; Schwentner, Christian

    2012-08-01

    The Adnatest® system combines immunomagnetic enrichment of epithelial cells with polymerase chain reaction for prostate cancer (PC)-specific transcripts for the detection circulating tumor cells (CTCs). We evaluated the Adnatest® in patients with castration-resistant PC receiving docetaxel chemotherapy. CTCs were assessed in 16 patients with castration-resistant PC before cycles one and three of chemotherapy. Furthermore, markers of stem cells and epithelial-mesenchymal transition were assessed. Treatment response was assessed by imaging and prostate-specific antigen measurements. Before chemotherapy, 11 patients were Adnatest®-positive whereas five patients were Adnatest®-positive before cycle three. A positive Adnatest® correlated with radiological progression (p=0.02). Rates of disease progression in epidermal growth factor receptor (EGFR)-positive and -negative patients were 100% and 7.7% (p=0.03). In this preliminary study, the Adnatest® detected CTCs in a considerable proportion of patients with castration-resistant PC. First data on certain markers (EGFR and aldehyd dehydrogenase 1) encourage future studies investigating transcripts predicting treatment response.

  4. MRI diagnosis for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tamada, Tsutomu; Nagai, Kiyohisa; Imai, Shigeki; Kajihara, Yasumasa; Jo, Yoshimasa; Tanaka, Hiroyoshi; Fukunaga, Masao (Kawasaki Medical School, Kurashiki, Okayama (Japan)); Matsuki, Takakazu

    1998-01-01

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  5. MRI diagnosis for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tamada, Tsutomu; Nagai, Kiyohisa; Imai, Shigeki; Kajihara, Yasumasa; Jo, Yoshimasa; Tanaka, Hiroyoshi; Fukunaga, Masao [Kawasaki Medical School, Kurashiki, Okayama (Japan); Matsuki, Takakazu

    1998-12-31

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  6. The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors

    DEFF Research Database (Denmark)

    Seminatore, Christine; Polentes, Jerome; Ellman, Ditte

    2010-01-01

    Risk of tumorigenesis is a major obstacle to human embryonic and induced pluripotent stem cell therapy. Likely linked to the stage of differentiation of the cells at the time of implantation, formation of teratoma/tumors can also be influenced by factors released by the host tissue. We have...... analyzed the relative effects of the stage of differentiation and the postischemic environment on the formation of adverse structures by transplanted human embryonic stem cell-derived neural progenitors....

  7. Role of endorectal MR imaging and MR spectroscopic imaging in defining treatable intraprostatic tumor foci in prostate cancer: Quantitative analysis of imaging contour compared to whole-mount histopathology

    International Nuclear Information System (INIS)

    Anwar, Mekhail; Westphalen, Antonio C.; Jung, Adam J.; Noworolski, Susan M.; Simko, Jeffry P.; Kurhanewicz, John; Roach, Mack; Carroll, Peter R.; Coakley, Fergus V.

    2014-01-01

    Purpose: To investigate the role of endorectal MR imaging and MR spectroscopic imaging in defining the contour of treatable intraprostatic tumor foci in prostate cancer, since targeted therapy requires accurate target volume definition. Materials and methods: We retrospectively identified 20 patients with prostate cancer who underwent endorectal MR imaging and MR spectroscopic imaging prior to radical prostatectomy and subsequent creation of detailed histopathological tumor maps from whole-mount step sections. Two experienced radiologists independently reviewed all MR images and electronically contoured all suspected treatable (⩾0.5 cm 3 ) tumor foci. Deformable co-registration in MATLAB was used to calculate the margin of error between imaging and histopathological contours at both capsular and non-capsular surfaces and the treatment margin required to ensure at least 95% tumor coverage. Results: Histopathology showed 17 treatable tumor foci in 16 patients, of which 8 were correctly identified by both readers and an additional 2 were correctly identified by reader 2. For all correctly identified lesions, both readers accurately identified that tumor contacted the prostatic capsule, with no error in contour identification. On the non-capsular border, the median distance between the imaging and histopathological contour was 1.4 mm (range, 0–12). Expanding the contour by 5 mm at the non-capsular margin included 95% of tumor volume not initially covered within the MR contour. Conclusions: Endorectal MR imaging and MR spectroscopic imaging can be used to accurately contour treatable intraprostatic tumor foci; adequate tumor coverage is achieved by expanding the treatment contour at the non-capsular margin by 5 mm

  8. Fundamental considerations in the design of fluorine-18 labeled progestins and androgens as imaging agents for receptor-positive tumors of the breast and prostate

    International Nuclear Information System (INIS)

    Brandes, S.J.; Katzenellenbogen, J.A.

    1988-01-01

    A review is given of the structural and functional features which are important in the design and development of imaging agents for the progesterone receptor (PR) and the androgen receptor (AR) directed towards imaging receptor-positive tumors in the breast and prostate respectively. In particular the effects of various substituents on the biological activities and homologous receptor binding of progesterone, testosterone, nortestosterone and dihydrotestosterone are discussed. The effect of fluorine substitution on the affinities of progestins and androgens for their respective receptors is described. Other ligand systems that have high affinity for AR and PR and which may provide good bases for the design of fluorine-substituted imaging agents are also discussed. Finally, previous studies with radiolabelled progestins and androgens are described. (U.K.)

  9. Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Kregel, Steven; Kiriluk, Kyle J.; Rosen, Alex M.; Cai, Yi; Reyes, Edwin E.; Otto, Kristen B.; Tom, Westin; Paner, Gladell P.; Szmulewitz, Russell Z.; Vander Griend, Donald J.

    2013-01-01

    Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways. PMID:23326489

  10. Lowering T Cell Activation Thresholds and Deregulating Homeostasis to Facilitate Immunotherapeutic Responses to Treat Prostate Cancer

    National Research Council Canada - National Science Library

    Kwon, Eugene D

    2006-01-01

    ... to develop immune-based therapies for prostate cancer Hence, relatively straightforward manipulations that induce specific T cell responses against prostate tumors or epithelial tissues, especially...

  11. Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

    Science.gov (United States)

    2015-12-01

    prostate cancer162. Other immunomagnetic-based systems, such as the AdnaTest (AdnaGen, Langenhagen, Germany ), MagSweeper Table 1. CTC enrichment based on...of p53 is common in metastatic PC, and loss of p53 function may promote EMT through TWIST1 deregulation , or through a separate pathway involving...microRNA deregulation [55]. Inhibitor of differentiation/DNA binding (Id-1) is another bHLH transcription factor that has a dominant negative effect on

  12. Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpiperidin-4-yl)-2-iodo benzamide, 2-[125I]BP: a potential σ receptor marker for human prostate tumors

    International Nuclear Information System (INIS)

    John, Christy S.; Gulden, Mary E.; Li, Jinghua; Bowen, Wayne D.; McAfee, John G.; Thakur, Mathew L.

    1998-01-01

    The preclinical evaluation of a σ receptor-specific radiopharmaceutical that binds to human prostate tumor cells with a high affinity is described. We have synthesized and radioiodinated 2-[ 125 I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-[ 125 I]BP) that possesses high affinity for both σ-1 and σ-2 receptor subtypes that are expressed on a variety of tumor cells. 2-IBP was synthesized, purified and characterized by routine spectroscopic and analytical methods. Radioiodination was accomplished using an oxidative iododestannylation reaction in the presence of chloramine T in high yields (76%-93%) with a very high-specific activity (1700-1900 Ci/mmol). The in vitro competition binding studies of 2-[ 125 I]BP with various σ receptor ligands in LnCAP human prostate tumor cells showed a dose-dependent saturable binding. The inhibition constants (K i , nM) for binding of 2-[ 125 I]BP to human prostate tumor cells for 4-IBP, haloperidol and 2-IBP were 4.09, 6.34 and 1.6 nM, respectively. The clearance of 2-[ 125 I]BP, in Sprague-Dawley rats, was rapid from the blood pool, other normal tissues and the total body. Tissue distribution studies in nude mice bearing human prostate tumor (DU-145) also showed a fast clearance from normal organs. The tumor had the highest percentage of injected dose per gram (%ID/g) of all tissues at 4 h as well as 24 h (2.0 ± 0.05 and 0.147 ± 0.038 ID/g, respectively) postinjection. The in vivo receptor binding specificity was demonstrated using haloperidol (a known high-affinity σ receptor ligand). A significant decrease (>50%, p = 0.001) was observed in tumor concentration when haloperidol was used as a blocking agent. The high affinity of 2-[ 125 I]BP for σ receptor-binding sites, its fast in vivo clearance from normal organs and its high uptake and retention in tumor implies that 2-[ 123 I]BP or 2-[ 131 I]BP may be a promising tracer for noninvasive imaging of human prostate tumors

  13. Imaging of the prostate

    International Nuclear Information System (INIS)

    Turgut, A.

    2012-01-01

    Full text: The main role of imaging in prostatic diseases is for prostate cancer. Transrectal ultrasound (TRUS) and magnetic resonance imaging (MRI) are the most commonly used imaging tools used for the diagnosis of the diseases of the prostate gland. The main indications for TRUS is the evaluation for prostate cancer and guidance for prostate biopsy. On TRUS, the transition zone with a hypoechoic appearance can be differentiated from the peripheral zone, which appears relatively echogenic and homogenous in echotexture. Prostate cancer mainly involves the peripheral zone, though one fifth of the disease can be detected in the transition zone, which is the major site for hyperplastic changes in older men. Color Doppler ultrasound may be helpful for the differentiation of low-risk, hypovascular tumors from high-risk, hypervascular tumors, as the latter group is associated with higher Gleason tumor grades consistent with higher risk for extraprostatic spread. Nevertheless, targeted prostate biopsy solely based on high-frequency color or power Doppler imaging is not recommended, as the technique has inherent risk of missing a significant number of cancers. Although power Doppler ultrasound can enable the operator to perform more accurate sampling of the prostate by determining sites of focal hypervascularity, it has not been found to be superior to color Doppler ultrasound. It has been reported to be useful only for targeted biopsies with limited number of biopsy cores. Microbubble contrast agents may enable better visualization of prostatic microvasculature and cancerous prostate tissue. By means of contrast-enhanced ultrasound (CEUS), the number of cores may be decreased by performing targeted biopsies. Importantly, the detection of the signals reflected by the microbubbles can be enhanced by the phase inversion (pulse-inversion) technology. Prostate cancer appears as a dark zone on elastography representing limited elasticity or compressibility. By means of the

  14. Radiosynthesis, biodistribution and imaging of [11C]YM155, a novel survivin suppressant, in a human prostate tumor-xenograft mouse model

    International Nuclear Information System (INIS)

    Murakami, Yoshihiro; Matsuya, Takahiro; Kita, Aya; Yamanaka, Kentaro; Noda, Akihiro; Mitsuoka, Keisuke; Nakahara, Takahito; Miyoshi, Sosuke; Nishimura, Shintaro

    2013-01-01

    Introduction: Sepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [ 11 C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts. Methods: Methods utilizing [ 11 C]acetyl chloride and [ 11 C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [ 11 C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [ 11 C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS). Results: Sufficient quantities of radiopharmaceutical grade [ 11 C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16–22%, within a synthesis time of 47 min. The radiochemical purity was higher than 99%, and the specific activity was 29–60 GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean ± SE) were observed in tumor (0.0613 ± 0.0056), kidneys (0.0513 ± 0.0092), liver (0.0368 ± 0.0043) and cecum (0.0623 ± 0.0070). The highest tumor uptake was observed at an early time point (from 10 min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [ 11 C]YM155, at 40 min after injection, were 26.5 (± 2.9) and 25.6 (± 3.6), respectively. Conclusion: A rapid method for producing a radiopharmaceutical grade [ 11 C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [ 11 C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent

  15. Real-time estimation of prostate tumor rotation and translation with a kV imaging system based on an iterative closest point algorithm

    International Nuclear Information System (INIS)

    Tehrani, Joubin Nasehi; O’Brien, Ricky T; Keall, Paul; Poulsen, Per Rugaard

    2013-01-01

    Previous studies have shown that during cancer radiotherapy a small translation or rotation of the tumor can lead to errors in dose delivery. Current best practice in radiotherapy accounts for tumor translations, but is unable to address rotation due to a lack of a reliable real-time estimate. We have developed a method based on the iterative closest point (ICP) algorithm that can compute rotation from kilovoltage x-ray images acquired during radiation treatment delivery. A total of 11 748 kilovoltage (kV) images acquired from ten patients (one fraction for each patient) were used to evaluate our tumor rotation algorithm. For each kV image, the three dimensional coordinates of three fiducial markers inside the prostate were calculated. The three dimensional coordinates were used as input to the ICP algorithm to calculate the real-time tumor rotation and translation around three axes. The results show that the root mean square error was improved for real-time calculation of tumor displacement from a mean of 0.97 mm with the stand alone translation to a mean of 0.16 mm by adding real-time rotation and translation displacement with the ICP algorithm. The standard deviation (SD) of rotation for the ten patients was 2.3°, 0.89° and 0.72° for rotation around the right–left (RL), anterior–posterior (AP) and superior–inferior (SI) directions respectively. The correlation between all six degrees of freedom showed that the highest correlation belonged to the AP and SI translation with a correlation of 0.67. The second highest correlation in our study was between the rotation around RL and rotation around AP, with a correlation of −0.33. Our real-time algorithm for calculation of rotation also confirms previous studies that have shown the maximum SD belongs to AP translation and rotation around RL. ICP is a reliable and fast algorithm for estimating real-time tumor rotation which could create a pathway to investigational clinical treatment studies requiring

  16. Prostate Ultrasound

    Medline Plus

    Full Text Available ... ultrasound or with a rectal examination, an ultrasound-guided biopsy can be performed. This procedure involves advancing ... of the Prostate) Prostate Cancer Ultrasound- and MRI-Guided Prostate Biopsy Images related to Ultrasound - Prostate Sponsored ...

  17. Prostate Ultrasound

    Medline Plus

    Full Text Available ... is enlarged, also known as benign prostatic hyperplasia (BPH) , with measurements acquired as needed for any treatment ... caption Related Articles and Media Benign Prostatic Hyperplasia (BPH) (Enlargement of the Prostate) Prostate Cancer Ultrasound- and ...

  18. Paraganglioma of Prostatic Origin

    Directory of Open Access Journals (Sweden)

    B. Padilla-Fernández

    2012-01-01

    Full Text Available Introduction Paragangliomas are usually benign tumors arising from chromaffin cells located outside the adrenal gland. Prostatic paraganglioma is an unusual entity in adult patients, with only 10 cases reported in the medical literature. Case Report A 34-year-old male with a history of chronic prostatitis consulted for perineal pain. On digital rectal examination the prostate was enlarged and firm, without nodules. The PSA level was 0.8 ng/mL and the catecholamines in the urine were elevated. On ultrasound a retrovesical 9 cm mass of undetermined origin measuring was present. A PET-CT scan showed a pelvic lesion measuring 9 cm with moderate increase in glucidic metabolism localized in the area of the prostate. A biopsy of the prostate revealed a neuroendocrine tumor, possibly a prostatic paraganglioma. A body scintigraphy with MIBG I-123 ruled out the presence of metastases or multifocal tumor. A radical prostatectomy with excision of the pelvic mass was performed under adrenergic blockade. One year after surgery the patient is asymptomatic and disease free. Discussion/Conclusions Prostatic paraganglioma is a rare, usually benign tumor, which should be considered in the differential diagnosis of prostate tumors in young males. Its diagnosis is based on the determination of catecholamine in blood and 24-hour urine and in imaging studies principally scintigraphy with MIBG I-123. Diagnostic confirmation is by histopathological study. The treatment consists of radical resection under adrenergic blockade and volume expansion. Given the limited number of cases reported, it is difficult to establish prognostic factors. Malignancy is defined by clinical criteria, and requires life long follow-up.

  19. Radiation therapy of newly diagnosed, advanced prostatic cancer and hormonally relapsed prostatic cancer

    International Nuclear Information System (INIS)

    Suzuki, Minoru; Fujiwara, Kazuhisa; Hayakawa, Katsumi; Hida, Shuichi

    1994-01-01

    Ten patients with newly diagnosed, advanced prostatic cancer were treated with radiotherapy and hormone therapy to improve tumor control and survival. Eight patients with hormonally relapsed prostatic cancer were treated with radiotherapy to improve their quality of life. Local control of the tumor was achieved in 9 of 10 patients with newly diagnosed, advanced prostatic cancer. Five of eight patients with hormonally relapsed prostatic cancer obtained improved quality of life. Combined radiotherapy and hormone therapy were effective in the treatment of newly diagnosed, advanced prostatic cancer, and radiotherapy was useful for improving the quality of life of patients with hormonally relapsed prostatic cancer. (author)

  20. The role and strategy of IMRT in radiotherapy of pelvic tumors: Dose escalation and critical organ sparing in prostate cancer

    International Nuclear Information System (INIS)

    Liu, Y.-M.; Shiau, C.-Y.; Lee, M.-L.; Huang, P.-I.; Hsieh, C.-M.; Chen, P.-H.; Lin, Y.-H.; Wang, L.-W.; Yen, S.-H.

    2007-01-01

    Purpose: To investigate the intensity-modulated radiotherapy (IMRT) strategy in dose escalation of prostate and pelvic lymph nodes. Methods and Materials: Plan dosimetric data of 10 prostate cancer patients were compared with two-dimensional (2D) or IMRT techniques for pelvis (two-dimensional whole pelvic radiation therapy [2D-WPRT] or IM-WPRT) to receive 50 Gy or 54 Gy and additional prostate boost by three-dimensional conformal radiation therapy or IMRT (3D-PBRT or IM-PBRT) techniques up to 72 Gy or 78 Gy. Dose-volume histograms (DVHs), normal tissue complication probabilities (NTCP) of critical organ, and conformity of target volume in various combinations were calculated. Results: In DVH analysis, the plans with IM-WPRT (54 Gy) and additional boost up to 78 Gy had lower rectal and bladder volume percentage at 50 Gy and 60 Gy, compared with those with 2D-WPRT (50 Gy) and additional boost up to 72 Gy or 78 Gy. Those with IM-WPRT (54 Gy) also had better small bowel sparing at 30 Gy and 50 Gy, compared with those with 2D-WPRT (50 Gy). In NTCP, those with IM-WPRT and total dose of 78 Gy achieved lower complication rates in rectum and small bowel, compared with those of 2D-WPRT with total dose of 72 Gy. In conformity, those with IM-WPRT had better conformity compared with those with 2D-WPRT with significance (p < 0.005). No significant difference in DVHs, NTCP, or conformity was found between IM-PBRT and 3D-PBRT after IM-WPRT. Conclusions: Initial pelvic IMRT is the most important strategy in dose escalation and critical organ sparing. IM-WPRT is recommended for patients requiring WPRT. There is not much benefit for critical organ sparing by IMRT after 2D-WPRT

  1. Tumor-associated endothelial cells display GSTP1 and RARβ2 promoter methylation in human prostate cancer

    Directory of Open Access Journals (Sweden)

    Pohida Thomas J

    2006-03-01

    Full Text Available Abstract Background A functional blood supply is essential for tumor growth and proliferation. However, the mechanism of blood vessel recruitment to the tumor is still poorly understood. Ideally, a thorough molecular assessment of blood vessel cells would be critical in our comprehension of this process. Yet, to date, there is little known about the molecular makeup of the endothelial cells of tumor-associated blood vessels, due in part to the difficulty of isolating a pure population of endothelial cells from the heterogeneous tissue environment. Methods Here we describe the use of a recently developed technique, Expression Microdissection, to isolate endothelial cells from the tumor microenvironment. The methylation status of the dissected samples was evaluated for GSTP1 and RARβ2 promoters via the QMS-PCR method. Results Comparing GSTP1 and RARβ2 promoter methylation data, we show that 100% and 88% methylation is detected, respectively, in the tumor areas, both in epithelium and endothelium. Little to no methylation is observed in non-tumor tissue areas. Conclusion We applied an accurate microdissection technique to isolate endothelial cells from tissues, enabling DNA analysis such as promoter methylation status. The observations suggest that epigenetic alterations may play a role in determining the phenotype of tumor-associated vasculature.

  2. Characterization of adenoviral transduction profile in prostate cancer cells and normal prostate tissue.

    Science.gov (United States)

    Ai, Jianzhong; Tai, Phillip W L; Lu, Yi; Li, Jia; Ma, Hong; Su, Qin; Wei, Qiang; Li, Hong; Gao, Guangping

    2017-09-01

    Prostate diseases are common in males worldwide with high morbidity. Gene therapy is an attractive therapeutic strategy for prostate diseases, however, it is currently underdeveloped. As well known, adeno virus (Ad) is the most widely used gene therapy vector. The aims of this study are to explore transduction efficiency of Ad in prostate cancer cells and normal prostate tissue, thus further providing guidance for future prostate pathophysiological studies and therapeutic development of prostate diseases. We produced Ad expressing enhanced green fluorescence protein (EGFP), and characterized the transduction efficiency of Ad in both human and mouse prostate cancer cell lines in vitro, as well as prostate tumor xenograft, and wild-type mouse prostate tissue in vivo. Ad transduction efficiency was determined by EGFP fluorescence using microscopy and flow cytometry. Cell type-specific transduction was examined by immunofluorescence staining of cell markers. Our data showed that Ad efficiently transduced human and mouse prostate cancer cells in vitro in a dose dependent manner. Following intratumoral and intraprostate injection, Ad could efficiently transduce prostate tumor xenograft and the major prostatic cell types in vivo, respectively. Our findings suggest that Ad can efficiently transduce prostate tumor cells in vitro as well as xenograft and normal prostate tissue in vivo, and further indicate that Ad could be a potentially powerful toolbox for future gene therapy of prostate diseases. © 2017 Wiley Periodicals, Inc.

  3. Multiple urinary bladder masses from metastatic prostate adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Richard Choo

    2010-12-01

    Full Text Available We present an unusual case of metastatic prostate adenocarcinoma that manifested with multiple exophytic intravesical masses, mimicking a multifocal primary bladder tumor. Biopsy with immunohistochemical analysis confirmed metastatic prostate adenocarcinoma. The patient was treated palliatively with external beam radiotherapy to prevent possible symptoms from local tumor progression. This case illustrates that when a patient with known prostate cancer presents with multifocal bladder tumors, the possibility of metastatic prostate cancer should be considered.

  4. Differential Expression of Matrix Metalloproteinase-2 Expression in Disseminated Tumor Cells and Micrometastasis in Bone Marrow of Patients with Nonmetastatic and Metastatic Prostate Cancer: Theoretical Considerations and Clinical Implications—An Immunocytochemical Study

    Directory of Open Access Journals (Sweden)

    Nigel P. Murray

    2012-01-01

    Full Text Available Matrix metalloproteinase-2 (MMP-2 is important in the dissemination and invasion of tumor cells and activates angiogenesis. We present an immunocytochemical study of MMP-2 expression in circulating prostate cells (CPCs, disseminated tumor cells (DTCs, and micrometastasis (mM in bone marrow of men with prostate cancer. Methods and Patients. Tumor cells were identified with anti-PSA immunocytochemistry. Positive samples underwent processing with anti-MMP-2, its expression was compared with Gleason score, concordance of expression, and metastatic and nonmetastatic disease. Results. 215 men participated, CPCs were detected in 62.7%, DTCs in 62.2%, and mM in 71.4% in nonmetastatic cancer; in metastatic cancer all had CPCs, DTCs, and mM detected. All CPCs and DTCs expressed MMP-2; in mM MMP-2 expression was positively associated with increasing Gleason score. MMP-2 expression in CPCs and DTCs showed concordance. In low grade tumors, mM and surrounding stromal cells were MMP-2 negative, with variable expression in high grade tumors; in metastatic disease, both mM and stromal cells were MMP-2 positive. Conclusions. CPCs and DTCs are different from mM, with inhibition of MMP-2 expression in mM of low grade tumors. With disease progression, MMP-2 expression increases in both mM and surrounding stromal cells, with implications for the use of bisphosphonates or MMP-2 inhibitors.

  5. Epigenetics in prostate cancer.

    Science.gov (United States)

    Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

    2011-01-01

    Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  6. Epigenetics in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Costantine Albany

    2011-01-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  7. Prostatic specific antigen for prostate cancer detection

    Directory of Open Access Journals (Sweden)

    Lucas Nogueira

    2009-10-01

    Full Text Available Prostate-specific antigen (PSA has been used for prostate cancer detection since 1994. PSA testing has revolutionized our ability to diagnose, treat, and follow-up patients. In the last two decades, PSA screening has led to a substantial increase in the incidence of prostate cancer (PC. This increased detection caused the incidence of advanced-stage disease to decrease at a dramatic rate, and most newly diagnosed PC today are localized tumors with a high probability of cure. PSA screening is associated with a 75% reduction in the proportion of men who now present with metastatic disease and a 32.5% reduction in the age-adjusted prostate cancer mortality rate through 2003. Although PSA is not a perfect marker, PSA testing has limited specificity for prostate cancer detection, and its appropriate clinical application remains a topic of debate. Due to its widespread use and increased over-detection, the result has been the occurrence of over-treatment of indolent cancers. Accordingly, several variations as regards PSA measurement have emerged as useful adjuncts for prostate cancer screening. These procedures take into consideration additional factors, such as the proportion of different PSA isoforms (free PSA, complexed PSA, pro-PSA and B PSA, the prostate volume (PSA density, and the rate of change in PSA levels over time (PSA velocity or PSA doubling time. The history and evidence underlying each of these parameters are reviewed in the following article.

  8. Prostatic specific antigen for prostate cancer detection.

    Science.gov (United States)

    Nogueira, Lucas; Corradi, Renato; Eastham, James A

    2009-01-01

    Prostate-specific antigen (PSA) has been used for prostate cancer detection since 1994. PSA testing has revolutionized our ability to diagnose, treat, and follow-up patients. In the last two decades, PSA screening has led to a substantial increase in the incidence of prostate cancer (PC). This increased detection caused the incidence of advanced-stage disease to decrease at a dramatic rate, and most newly diagnosed PC today are localized tumors with a high probability of cure. PSA screening is associated with a 75% reduction in the proportion of men who now present with metastatic disease and a 32.5% reduction in the age-adjusted prostate cancer mortality rate through 2003. Although PSA is not a perfect marker, PSA testing has limited specificity for prostate cancer detection, and its appropriate clinical application remains a topic of debate. Due to its widespread use and increased over-detection, the result has been the occurrence of over-treatment of indolent cancers. Accordingly, several variations as regards PSA measurement have emerged as useful adjuncts for prostate cancer screening. These procedures take into consideration additional factors, such as the proportion of different PSA isoforms (free PSA, complexed PSA, pro-PSA and B PSA), the prostate volume (PSA density), and the rate of change in PSA levels over time (PSA velocity or PSA doubling time). The history and evidence underlying each of these parameters are reviewed in the following article.

  9. Practical aspects of MRI of the prostate

    Directory of Open Access Journals (Sweden)

    Dragoș Cuzino

    2014-12-01

    Full Text Available The article presents the main aspects of sectional anatomy, lymph nodes and adjacent structures as well as MRI examination standard protocol for prostate cancer diagnosis. Using MRI multiparametric examination we succeed in classifying efficiently the malignant prostatic tumors using PI- RADS system. Also, using MRI multiparametric examination we can evaluate the effectiveness of prostate cancer treatment

  10. Mitochondrial mutations drive prostate cancer aggression

    DEFF Research Database (Denmark)

    Hopkins, Julia F.; Sabelnykova, Veronica Y.; Weischenfeldt, Joachim

    2017-01-01

    Nuclear mutations are well known to drive tumor incidence, aggression and response to therapy. By contrast, the frequency and roles of mutations in the maternally inherited mitochondrial genome are poorly understood. Here we sequence the mitochondrial genomes of 384 localized prostate cancer...... in prostate cancer, and suggest interplay between nuclear and mitochondrial mutational profiles in prostate cancer....

  11. Interaction of Munc18c and syntaxin4 facilitates invadopodium formation and extracellular matrix invasion of tumor cells.

    Science.gov (United States)

    Brasher, Megan I; Martynowicz, David M; Grafinger, Olivia R; Hucik, Andrea; Shanks-Skinner, Emma; Uniacke, James; Coppolino, Marc G

    2017-09-29

    Tumor cell invasion involves targeted localization of proteins required for interactions with the extracellular matrix and for proteolysis. The localization of many proteins during these cell-extracellular matrix interactions relies on membrane trafficking mediated in part by SNAREs. The SNARE protein syntaxin4 (Stx4) is involved in the formation of invasive structures called invadopodia; however, it is unclear how Stx4 function is regulated during tumor cell invasion. Munc18c is known to regulate Stx4 activity, and here we show that Munc18c is required for Stx4-mediated invadopodium formation and cell invasion. Biochemical and microscopic analyses revealed a physical association between Munc18c and Stx4, which was enhanced during invadopodium formation, and that a reduction in Munc18c expression decreases invadopodium formation. We also found that an N-terminal Stx4-derived peptide associates with Munc18c and inhibits endogenous interactions of Stx4 with synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2). Furthermore, expression of the Stx4 N-terminal peptide decreased invadopodium formation and cell invasion in vitro Of note, cells expressing the Stx4 N-terminal peptide exhibited impaired trafficking of membrane type 1 matrix metalloproteinase (MT1-MMP) and EGF receptor (EGFR) to the cell surface during invadopodium formation. Our findings implicate Munc18c as a regulator of Stx4-mediated trafficking of MT1-MMP and EGFR, advancing our understanding of the role of SNARE function in the localization of proteins that drive tumor cell invasion. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Biological evaluation of 177Lu-labeled DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 for gastrin-releasing peptide receptor-positive prostate tumor targeting

    International Nuclear Information System (INIS)

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Choi, Sang Mu; Lee, So young; Nam, Sung Soo; Park, Ul Jae; Park, Soo Hyun

    2015-01-01

    Bombesin binds with selectivity and high affinity to a Gastrin-releasing peptide receptor (GRPR), which is highly overexpressed in prostate cancer cells. The present study describes the in vitro and in vivo biological characteristics of DOTA-Ala(SO 3 H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH 2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with 177 Lu as previously published. A saturation assay on PC-3 human prostate cancer cells revealed that the Kd value of the radiolabeled peptide was 1.88 nM with a maximum binding capacity (Bmax) of 289.3 fmol/10 6 cells. The radio-peptide slowly internalized, and 24.4 ± 0.5% of the total binding was internalized in 4 hr. Biodistribution studies were conducted in healthy and PC-3 xenografted balb/c mice, which showed high uptake and retention of tumor-associated radioactivity in PC-3 xenografted mice. The tumor-to-blood ratio was 126.02 ± 9.36 at 1.5 hr p.i., and was increased to 216.33 ± 61.58 at 24 hr p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and rapidly cleared from the blood pool. The GRPR is also over-expressed in Korean prostate cancer patients. These results suggest that this 177 Lu-labeled peptide has promising characteristics for application in nuclear medicine, namely for the diagnosis and treatment of GRPR over-expressing prostate tumors

  13. Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo

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    Roberta Lotti

    2016-01-01

    Full Text Available Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC originate from alterations in keratinocyte stem cells (KSC gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD and non-RAD (NRAD cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, β1-integrin, while it increases the level of differentiation markers (K10, involucrin. Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in RasG12V-IκBα-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1α, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development.

  14. Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells.

    Science.gov (United States)

    Książkiewicz, Magdalena; Markiewicz, Aleksandra; Zaczek, Anna J

    2012-01-01

    The occurrence of either regional or distant metastases is an indicator of poor prognosis for cancer patients. The mechanism of their formation has not yet been fully uncovered, which limits the possibility of developing new therapeutic strategies. Nevertheless, the discovery of circulating tumor cells (CTCs), which are responsible for tumor dissemination, and cancer stem cells (CSCs), required for tumor growth maintenance, shed light on the metastatic cascade. It seems that CTCs and CSCs are not necessarily separate populations of cancer cells, as CTCs generated in the process of epithelial-mesenchymal transition (EMT) can bear features characteristic of CSCs. This article describes the mechanisms of CTC and CSC formation and characterizes their molecular hallmarks. Moreover, we present different types of EMT occurring in physiological and pathological conditions, and we demonstrate its crucial role in providing CTCs with a CSC phenotype. The article delineates molecular changes acquired by cancer cells undergoing EMT that facilitate metastasis formation. Deeper understanding of those processes is of fundamental importance for the development of new strategies of early cancer detection and effective cancer treatment approaches that will be translated into clinical practice. Copyright © 2012 S. Karger AG, Basel.

  15. Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation

    Directory of Open Access Journals (Sweden)

    R. A. Gafanov

    2018-01-01

    Full Text Available Prostate cancer (PC is one of the most common causes of death from malignant neoplasms in men in many countries around the world. Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. Despite the constant dependence on androgen receptor signals in castration resistance, the use of new anti-androgenic drugs invariably leads to the stability  of the ongoing treatment. The interaction of androgen receptor and alternative (phosphoinositide-3-kinases, PI3K pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

  16. Metformin inhibits epithelial–mesenchymal transition in prostate cancer cells: Involvement of the tumor suppressor miR30a and its target gene SOX4

    International Nuclear Information System (INIS)

    Zhang, Jing; Shen, Chengwu; Wang, Lin; Ma, Quanping; Xia, Pingtian; Qi, Mei; Yang, Muyi; Han, Bo

    2014-01-01

    Highlights: • Metformin inhibits TGF-β-induced EMT in prostate cancer (PCa) cells. • Metformin upregulates tumor suppressor miR30a and downregulates SOX4 in PCa cells. • SOX4 is a target gene of miR30a. - Abstract: Tumor metastasis is the leading cause of mortality and morbidity of prostate cancer (PCa) patients. Epithelial–mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. Recent evidence suggested that diabetic patients treated with metformin have lower PCa risk and better prognosis. This study was aimed to investigate the effects of metformin on EMT in PCa cells and the possible microRNA (miRNA)-based mechanisms. MiRNAs have been shown to regulate various processes of cancer metastasis. We herein showed that metformin significantly inhibits proliferation of Vcap and PC-3 cells, induces G0/G1 cell cycle arrest and inhibits invasiveness and motility capacity of Vcap cells. Metformin could inhibit TGF-β-induced EMT in Vcap cells, as manifested by inhibition of the increase of N-cadherin (p = 0.013), Vimentin (p = 0.002) and the decrease of E-cadherin (p = 0.0023) and β-catenin (p = 0.034) at mRNA and protein levels. Notably, we demonstrated significant upregulation of miR30a levels by metformin (P < 0.05) and further experiments indicated that miR30a significantly inhibits proliferation and EMT process of Vcap cells. Interestingly, we identified that SOX4, a previously reported oncogenic transcriptional factor and modulator of EMT, is a direct target gene of miR30a. Finally, we screened the expression of miR30a and SOX4 in 84 PCa cases with radical prostatectomy. Of note, SOX4 overexpression is significantly associated with decreased levels of miR30a in PCa cases. In all, our study suggested that inhibition of EMT by metformin in PCa cells may involve upregulation of miR30a and downregulation of SOX4

  17. Focal therapy in prostate cancer

    NARCIS (Netherlands)

    van den Bos, W.

    2016-01-01

    Interesting developments took place in the treatment of prostate cancer including focal therapy for less aggressive organ-confined prostate cancer. Fortunately, curative treatment is often still an option for patients suffering from the lower staged tumors. In carefully selected patients, the

  18. Importance of hyaluronan biosynthesis and degradation in cell differentiation and tumor formation

    Directory of Open Access Journals (Sweden)

    Heldin P.

    2003-01-01

    Full Text Available Hyaluronan is an important connective tissue glycosaminoglycan. Elevated hyaluronan biosynthesis is a common feature during tissue remodeling under both physiological and pathological conditions. Through its interactions with hyaladherins, hyaluronan affects several cellular functions such as cell migration and differentiation. The activities of hyaluronan-synthesizing and -degrading enzymes have been shown to be regulated in response to growth factors. During tumor progression hyaluronan stimulates tumor cell growth and invasiveness. Thus, elucidation of the molecular mechanisms which regulate the activities of hyaluronan-synthesizing and -degrading enzymes during tumor progression is highly desired.

  19. Multiple Primary Cancers: Simultaneously Occurring Prostate ...

    African Journals Online (AJOL)

    2016-05-20

    May 20, 2016 ... occurring prostate cancer and other primary tumors-our experience and literature ..... thyroid cancers, pancreatic tumors, renal cancers, and melanoma. ... Hsing AW, Yeboah E, Biritwum R, Tettey Y, De Marzo AM,. Adjei A, et ...

  20. Large gastrointestinal stromal tumor and advanced adenocarcinoma in the rectum coexistent with an incidental prostate carcinoma: A case report

    Directory of Open Access Journals (Sweden)

    Toshiaki Suzuki

    2014-01-01

    CONCLUSION: Radical surgery with perioperative adjuvant chemotherapy using tyrosine kinase inhibitors is the choice for treatment of large GISTs with a malignant potential. Our report suggests that aggressive surgical approach would be feasible, when a secondary tumor is present near the GIST.

  1. The Prostate

    Science.gov (United States)

    ... Publications Reports What You Need To Know About™ Prostate Cancer This booklet is about prostate cancer. Learning about medical care for your cancer ... ePub This booklet covers: The anatomy of the prostate and basics about prostate cancer Treatments for prostate ...

  2. Contemporary Management of Prostate Cancer

    Science.gov (United States)

    Cotter, Katherine; Konety, Badrinath; Ordonez, Maria A.

    2016-01-01

    Prostate cancer represents a spectrum ranging from low-grade, localized tumors to devastating metastatic disease. We discuss the general options for treatment and recent developments in the field. PMID:26949522

  3. Imaging and prostate cancer

    International Nuclear Information System (INIS)

    Schwartz, Lawrence H.

    1996-01-01

    The use of imaging in evaluating patients with prostate cancer is highly dependent upon the purpose of the evaluation. Ultrasound, Computed Tomography, Magnetic Resonance Imaging, TC-99m Bone Scanning, and Positron Emission Tomography may all be utilized for imaging in prostate cancer. The utility of each of these modalities depends upon the intended purpose: for instance, screening, staging, or evaluating for progression of disease in patients with prostate cancer. Transrectal ultrasound is performed by placing a 5MHz to 7.5 MHz transducer in the rectum and imaging the prostate in the coronal and sagittal planes. Prostate cancer generally appears as an area of diminished echogenocity in the peripheral zone of the prostate gland. However, up to 24% of prostate cancers are isoechoic and cannot be well distinguished from the remainder of the peripheral zone. In addition, the incidence of malignancy in a lesion judged to be suspicious on ultrasound is between 20% and 25%. Therefore, while ultrasound is the least expensive of the three cross sectional imaging modalities, its relatively low specificity precludes it from being used as a screening examination. Investigators have also looked at the ability of ultrasound to evaluate the presence and extent of extracapsular spread of prostate cancer. The RDOG (Radiology Diagnostic Oncology Group) multi-institutional cooperative trial reported a disappointing overall accuracy of ultrasound of 58% for staging prostate cancer. The accuracy was somewhat higher 63%, for patients with advanced disease. The other cross-sectional imaging modalities available for imaging the prostate include Computed Tomography and Magnetic Resonance Imaging. Computed Tomography is useful as an 'anatomic' imaging technique to detect lymph node enlargement. It is not sensitive in detecting microscopic nodal involvement with tumor, or tumor in non-enlarged pelvic lymph nodes. The primary prostate neoplasm is generally the same attenuation as the normal

  4. Effects of Focal vs Total Cryotherapy and Minimum Tumor Temperature on Patient-reported Quality of Life Compared With Active Surveillance in Patients With Prostate Cancer.

    Science.gov (United States)

    Werneburg, Glenn T; Kongnyuy, Michael; Halpern, Daniel M; Salcedo, Jose M; Chen, Connie; LeSueur, Amanda; Kosinski, Kaitlin E; Schiff, Jeffrey T; Corcoran, Anthony T; Katz, Aaron E

    2018-03-01

    To investigate the effects of focal (hemiablation) or total cryotherapy and minimum tumor temperature on patient-reported quality of life (QoL) in patients with prostate cancer. An Institutional Review Board-approved database was reviewed for patients who underwent cryotherapy or active surveillance (AS). QoL questionnaire responses were collected and scores were analyzed for differences between focal and total cryotherapy and between very cold (total of 197 patients responded to a total of 547 questionnaires. Focal and total cryotherapy patients had initially lower sexual function scores relative to AS (year 1 mean difference focal: -31.7, P total: -48.1, P total cryotherapy sexual function scores were not statistically significantly different from the AS cohort by postprocedural year 4. Very cold and moderate-cold temperatures led to initially lower sexual function scores relative to AS (year 1 very cold: -38.1, P total cryotherapy and between very cold and moderate-cold temperature groups. Focal cryotherapy and moderate-cold (≥-76°C) temperature were associated with favorable sexual function relative to total cryotherapy and very cold temperature, respectively. No significant differences in urinary function or bowel habits were observed between groups. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Enabling or Cultivating? The Role of Prostate Cancer Patients' Received Partner Support and Self-Efficacy in the Maintenance of Pelvic Floor Exercise Following Tumor Surgery.

    Science.gov (United States)

    Hohl, Diana Hilda; Knoll, Nina; Wiedemann, Amelie; Keller, Jan; Scholz, Urte; Schrader, Mark; Burkert, Silke

    2016-04-01

    To manage incontinence following tumor surgery, prostate cancer patients are advised to perform pelvic floor exercise (PFE). Patients' self-efficacy and support from partners were shown to facilitate PFE. Whereas support may enhance self-efficacy (enabling function), self-efficacy may also cultivate support (cultivation function). Cross-lagged inter-relationships among self-efficacy, support, and PFE were investigated. Post-surgery patient-reported received support, self-efficacy, PFE, and partner-reported provided support were assessed from 175 couples at four times. Autoregressive models tested interrelations among variables, using either patients' or partners' reports of support. Models using patients' data revealed positive associations between self-efficacy and changes in received support, which predicted increased PFE. Using partners' accounts of support provided, these associations were partially cross-validated. Furthermore, partner-provided support was related with increases in patients' self-efficacy. Patients' self-efficacy may cultivate partners' support provision for patients' PFE, whereas evidence of an enabling function of support as a predictor of self-efficacy was inconsistent.

  6. Longitudinal comparison of quality of life after real-time tumor-tracking intensity-modulated radiation therapy and radical prostatectomy in patients with localized prostate cancer

    International Nuclear Information System (INIS)

    Shinohara, Nobuo; Maruyama, Satoru; Abe, Takashige; Nonomura, Katsuya; Shimizu, Shinichi; Nishioka, Kentaro; Shirato, Hiroki; C-Hatanaka, Kanako; Oba, Koji

    2013-01-01

    The purpose of this study was to compare the quality of life (QOL) in patients with localized prostate cancer (PC) after intensity-modulated radiation therapy assisted with a fluoroscopic real-time intensity-modulated radiation therapy (RT-IMRT) tumor-tracking system versus the QOL after radical prostatectomy (RP). Between 2003 and 2006, 71 patients were enrolled in this longitudinal prospective study. Each patient was allowed to decide which treatment modality they would receive. Of the 71 patients, 23 patients underwent RT-IMRT, while 48 opted for RP. No patient received neo-adjuvant or adjuvant hormone therapy. The global QOL and disease-specific-QOL were evaluated before treatment and again at 1, 3 and 5 years after treatment. There was no significant difference in the background characteristics between the two groups. The 5-year biochemical progression-free survival was 90% in the RT-IMRT and 79% in the RP group. In the RT-IMRT group, there was no significant deterioration of the global QOL or disease-specific QOL through 5 years post-treatment. In the RP group, the urinary function, sexual function, and sexual bother indicators significantly deteriorated after treatment. Urinary and sexual function was significantly better in the RT-IMRT group at 1, 3 and 5 years post-treatment compared to the RP group. RT-IMRT may be a preferable treatment for localized PC because of similar efficacy to RP but better post-treatment QOL. (author)

  7. Multiple primary cancers: Simultaneously occurring prostate cancer ...

    African Journals Online (AJOL)

    We also reviewed the existing literatures for possible biologic links between prostatic carcinoma and other primary tumors. ... The primary tumors co-existing with prostate cancer were colonic adenocarcinoma, rectal adenocarcinoma, urinary bladder transitional cell carcinoma, primary liver cell carcinoma, and thyroid ...

  8. Prostate Diseases

    Science.gov (United States)

    ... Home › Aging & Health A to Z › Prostate Diseases Font size A A A Print Share Glossary Basic ... body. Approximately 3 million American men have some type of prostate disease. The most common prostate diseases ...

  9. Prostate brachytherapy

    Science.gov (United States)

    Implant therapy - prostate cancer; Radioactive seed placement; Internal radiation therapy - prostate; High dose radiation (HDR) ... place the seeds that deliver radiation into your prostate. The seeds are placed with needles or special ...

  10. Prostate Ultrasound

    Medline Plus

    Full Text Available ... Physician Resources Professions Site Index A-Z Ultrasound - Prostate Ultrasound of the prostate uses sound waves to ... Ultrasound Imaging? What is Ultrasound Imaging of the Prostate? Ultrasound is safe and painless, and produces pictures ...

  11. Prostate Ultrasound

    Medline Plus

    Full Text Available ... Z Ultrasound - Prostate Ultrasound of the prostate uses sound waves to produce pictures of a man’s prostate ... pictures of the inside of the body using sound waves. Ultrasound imaging, also called ultrasound scanning or ...

  12. A rare prostatic diagnosis of an old man: a pure prostatic leiomyoma

    NARCIS (Netherlands)

    Ulden-Bleumink, W.M. van; Dom, P.G.; Ramakers, B.P.C.; Adrichem, N.P. van

    2013-01-01

    A pure leiomyoma of the prostate is a rare benign tumor. An 82-year-old man was referred to our urology department with gross hematuria and complete urinary retention. Examination revealed a benign prostatic hyperplasia. Transrectal ultrasound showed a prostate of 125 mL. Serum PSA was 1.9 microg/L.

  13. Fish intake and risk of prostate cancer

    Directory of Open Access Journals (Sweden)

    Ewa Dybkowska

    2014-10-01

    Full Text Available The aim of the study was to present the current state of knowledge concerning the relationship between the consumption of fish as materials rich in long chain polyunsaturated fatty acids (LC PUFA omega-3, and the risk of prostate cancer. Many scientific reports confirm the health benefits from the consumption of fish and protective properties of LC PUFA omega-3 in relation to prostate cancer. However, there are reports that indicate a relationship of the high consumption of PUFA with the risk of prostate cancer. The way of processing and preservation of the fish, and other factors not included in previous studies, could have some importance in the etiology of this disease. High susceptibility of PUFA to oxidation changes and the technological fish processing (smoking, high-temperature cooking methods contribute to the formation of many compounds, such as polycyclic aromatic hydrocarbons and heterocyclic amines – which may influence the formation of cancers – including prostate cancer. It is necessary to ensure an adequate amount of LC PUFA omega-3 in the diet through the consumption of proper quality fish and fish oils. Particular attention should be paid to the high susceptibility of PUFA to the oxidative processes, and the method of processing, preservation and storage of fish. Also pollution from the environment can significantly reduce the impact of health benefits of PUFA and fish, and even be the cause of cancers, including prostate cancer. Further research in this area should be more targeted to assess the impact of nutritional factors for the development of such tumors.

  14. AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients.

    Science.gov (United States)

    Okegawa, Takatsugu; Ninomiya, Naoki; Masuda, Kazuki; Nakamura, Yu; Tambo, Mitsuhiro; Nutahara, Kikuo

    2018-06-01

    We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. © 2018 Wiley Periodicals, Inc.

  15. A Rare Prostatic Diagnosis of an Old Man: A Pure Prostatic Leiomyoma

    Directory of Open Access Journals (Sweden)

    W. M. van Ulden-Bleumink

    2013-01-01

    Full Text Available A pure leiomyoma of the prostate is a rare benign tumor. An 82-year-old man was referred to our urology department with gross hematuria and complete urinary retention. Examination revealed a benign prostatic hyperplasia. Transrectal ultrasound showed a prostate of 125 mL. Serum PSA was 1.9 µg/L. A simple retropubic prostatectomy was performed. Histopathological examination showed a pure leiomyoma of the prostate, without the presence of glandular prostate tissue. The diagnosis, characteristics, and treatment of this tumor are described.

  16. Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism

    Czech Academy of Sciences Publication Activity Database

    Rychtarčíková, Zuzana; Lettlová, Sandra; Tomkova, Veronika; Korenková, Vlasta; Langerová, Lucie; Simonova, Ekaterina; Zjablovskaja, Polina; Alberich-Jorda, Meritxell; Neužil, Jiří; Truksa, Jaroslav

    2017-01-01

    Roč. 8, č. 4 (2017), s. 6376-6398 ISSN 1949-2553 R&D Projects: GA ČR GA13-28830S; GA ČR GA15-03796S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 ; RVO:68378050 Keywords : tumor-initiating cells * breast cancer * iron metabolism Subject RIV: FD - Oncology ; Hematology; EB - Genetics ; Molecular Biology (UMG-J) OBOR OECD: Cell biology; Cell biology (UMG-J) Impact factor: 5.168, year: 2016

  17. Comparison of telomerase activity in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic hyperplasia

    Directory of Open Access Journals (Sweden)

    Soleiman Mahjoub

    2006-11-01

    Full Text Available BACKGROUND: Telomerase is a reverse transcriptase enzyme that synthesizes telomeric DNA on chromosome ends. The enzyme is important for the immortalization of cancer cells because it maintains the telomeres. METHODS: Telomerase activity (TA was measured by fluorescence-based telomeric repeat amplification protocol (FTRAP assay in prostate carcinoma and benign prostatic hyperplasia (BPH. RESULTS: TA was present in 91.4% of 70 prostate cancers, 68.8% of 16 prostatic intraepithelial neoplasia (PIN, 43.3% of 30 BPH*, 21.4% of 14 atrophy and 20% of 15 normal samples adjacent to tumor. There was not any significant correlation between TA, histopathological tumor stage or gleason score. In contrast to high TA in the BPH* tissue from the cancer-bearing gland, only 6.3% of 32 BPH specimens from patients only diagnosed with BPH were telomerase activity-positive. CONCLUSIONS: These results indicate that TA is present in most prostate cancers. The high rate of TA in tissue adjacent to tumor may be attributed either to early molecular alteration of cancer that was histologically unapparent, or to the presence of occult cancer cells. Our findings suggest that the re-expression of telomerase activity could be one step in the transformation of BPH to PIN. KEY WORDS: Telomerase activity, prostate cancer, prostatic intraepithelial neoplasia, benign prostatic hyperplasia.

  18. Selective modulation of endoplasmic reticulum stress markers in prostate cancer cells by a standardized mangosteen fruit extract.

    Directory of Open Access Journals (Sweden)

    Gongbo Li

    Full Text Available The increased proliferation of cancer cells is directly dependent on the increased activity of the endoplasmic reticulum (ER machinery which is responsible for protein folding, assembly, and transport. In fact, it is so critical that perturbations in the endoplasmic reticulum can lead to apoptosis. This carefully regulated organelle represents a unique target of cancer cells while sparing healthy cells. In this study, a standardized mangosteen fruit extract (MFE was evaluated for modulating ER stress proteins in prostate cancer. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells (PrECs procured from two patients undergoing radical prostatectomy were treated with MFE. Flow cytometry, MTT, BrdU and Western blot were used to evaluate cell apoptosis, viability, proliferation and ER stress. Next, we evaluated MFE for microsomal stability and anti-cancer activity in nude mice. MFE induced apoptosis, decreased viability and proliferation in prostate cancer cells. MFE increased the expression of ER stress proteins. Interestingly, MFE selectively promotes ER stress in prostate cancer cells while sparing PrECs. MFE suppressed tumor growth in a xenograft tumor model without obvious toxicity. Mangosteen fruit extract selectively promotes endoplasmic reticulum stress in cancer cells while sparing non-tumorigenic prostate epithelial cells. Furthermore, in an in vivo setting mangosteen fruit extract significantly reduces xenograft tumor formation.

  19. Selective modulation of endoplasmic reticulum stress markers in prostate cancer cells by a standardized mangosteen fruit extract.

    Science.gov (United States)

    Li, Gongbo; Petiwala, Sakina M; Pierce, Dana R; Nonn, Larisa; Johnson, Jeremy J

    2013-01-01

    The increased proliferation of cancer cells is directly dependent on the increased activity of the endoplasmic reticulum (ER) machinery which is responsible for protein folding, assembly, and transport. In fact, it is so critical that perturbations in the endoplasmic reticulum can lead to apoptosis. This carefully regulated organelle represents a unique target of cancer cells while sparing healthy cells. In this study, a standardized mangosteen fruit extract (MFE) was evaluated for modulating ER stress proteins in prostate cancer. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells (PrECs) procured from two patients undergoing radical prostatectomy were treated with MFE. Flow cytometry, MTT, BrdU and Western blot were used to evaluate cell apoptosis, viability, proliferation and ER stress. Next, we evaluated MFE for microsomal stability and anti-cancer activity in nude mice. MFE induced apoptosis, decreased viability and proliferation in prostate cancer cells. MFE increased the expression of ER stress proteins. Interestingly, MFE selectively promotes ER stress in prostate cancer cells while sparing PrECs. MFE suppressed tumor growth in a xenograft tumor model without obvious toxicity. Mangosteen fruit extract selectively promotes endoplasmic reticulum stress in cancer cells while sparing non-tumorigenic prostate epithelial cells. Furthermore, in an in vivo setting mangosteen fruit extract significantly reduces xenograft tumor formation.

  20. Epigenetic Regulation in Prostate Cancer Progression.

    Science.gov (United States)

    Ruggero, Katia; Farran-Matas, Sonia; Martinez-Tebar, Adrian; Aytes, Alvaro

    2018-01-01

    An important number of newly identified molecular alterations in prostate cancer affect gene encoding master regulators of chromatin biology epigenetic regulation. This review will provide an updated view of the key epigenetic mechanisms underlying prostate cancer progression, therapy resistance, and potential actionable mechanisms and biomarkers. Key players in chromatin biology and epigenetic master regulators has been recently described to be crucially altered in metastatic CRPC and tumors that progress to AR independency. As such, epigenetic dysregulation represents a driving mechanism in the reprograming of prostate cancer cells as they lose AR-imposed identity. Chromatin integrity and accessibility for transcriptional regulation are key features altered in cancer progression, and particularly relevant in nuclear hormone receptor-driven tumors like prostate cancer. Understanding how chromatin remodeling dictates prostate development and how its deregulation contributes to prostate cancer onset and progression may improve risk stratification and treatment selection for prostate cancer patients.

  1. Optimization, biological evaluation and microPET imaging of copper-64-labeled bombesin agonists, [64Cu-NO2A-(X)-BBN(7-14)NH2], in a prostate tumor xenografted mouse model

    International Nuclear Information System (INIS)

    Lane, Stephanie R.; Nanda, Prasanta; Rold, Tammy L.; Sieckman, Gary L.; Figueroa, Said D.; Hoffman, Timothy J.; Jurisson, Silvia S.; Smith, Charles J.

    2010-01-01

    Gastrin-releasing peptide receptors (GRPr) are a member of the bombesin (BBN) receptor family. GRPr are expressed in high numbers on specific human cancers, including human prostate cancer. Therefore, copper-64 ( 64 Cu) radiolabeled BBN(7-14)NH 2 conjugates could have potential for diagnosis of human prostate cancer via positron-emission tomography (PET). The aim of this study was to produce [ 64 Cu-NO2A-(X)-BBN(7-14)NH 2 ] conjugates for prostate cancer imaging, where X=pharmacokinetic modifier (beta-alanine, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 9-aminonanoic acid or para-aminobenzoic acid) and NO2A=1,4,7-triazacyclononane-1,4-diacetic acid [a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)]. Methods: [(X)-BBN(7-14)NH 2 ] Conjugates were synthesized by solid-phase peptide synthesis (SPPS), after which NOTA was added via manual conjugation. The new peptide conjugates were radiolabeled with 64 Cu radionuclide. The receptor-binding affinity was determined in human prostate PC-3 cells, and tumor-targeting efficacy was determined in PC-3 tumor-bearing severely combined immunodeficient (SCID) mice. Whole-body maximum intensity microPET/CT images of PC-3 tumor-bearing SCID mice were obtained 18 h postinjection (pi). Results: Competitive binding assays in PC-3 cells indicated high receptor-binding affinity for the [NO2A-(X)-BBN(7-14)NH 2 ] and [ nat Cu-NO2A-(X)-BBN(7-14)NH 2 ] conjugates. In vivo biodistribution studies of the [ 64 Cu-NO2A-(X)-BBN(7-14)NH 2 ] conjugates at 1, 4 and 24 h pi showed very high uptake of the tracer in GRPr-positive tissue with little accumulation and retention in nontarget tissues. High-quality, high-contrast microPET images were obtained, with xenografted tumors being clearly visible at 18 h pi. Conclusions: NO2A chelator sufficiently stabilizes copper(II) radiometal under in vivo conditions, producing conjugates with very high uptake and retention in targeted GRPr. Preclinical evaluation of these

  2. Assessment of the role of circulating breast cancer cells in tumor formation and metastatic potential using in vivo flow cytometry

    Science.gov (United States)

    Hwu, Derrick; Boutrus, Steven; Greiner, Cherry; Dimeo, Theresa; Kuperwasser, Charlotte; Georgakoudi, Irene

    2011-04-01

    The identification of breast cancer patients who will ultimately progress to metastatic disease is of significant clinical importance. The quantification and assessment of circulating tumor cells (CTCs) has been proposed as one strategy to monitor treatment effectiveness and disease prognosis. However, CTCs have been an elusive population of cells to study because of their small number and difficulties associated with isolation protocols. In vivo flow cytometry (IVFC) can overcome these limitations and provide insights in the role these cells play during primary and metastatic tumor growth. In this study, we used two-color IVFC to examine, for up to ten weeks following orthotopic implantation, changes in the number of circulating human breast cells expressing GFP and a population of circulating hematopoietic cells with strong autofluorescence. We found that the number of detected CTCs in combination with the number of red autofluorescent cells (650 to 690 nm) during the first seven days following implantation was predictive in development of tumor formation and metastasis eight weeks later. These results suggest that the combined detection of these two cell populations could offer a novel approach in the monitoring and prognosis of breast cancer progression, which in turn could aid significantly in their effective treatment.

  3. Acute intracranial hematoma formation following excision of a cervical subdural tumor: a report of two cases and literature review.

    Science.gov (United States)

    Ma, Xuexiao; Zhang, Yan; Wang, Ting; Li, Guizhi; Zhang, Guoqing; Khan, Hassan; Xiang, Hongfei; Chen, Bohua

    2014-01-01

    An intracranial hematoma is a rare, yet significant, complication following spinal surgery. The authors describe two cases with acute intracranial hematoma formation after excision of a cervical subdural schwannoma. One was a 14-year-old girl who developed bilateral intracranial extradural hematomas immediately following excision of the C4 subdural schwannoma. The other was a 59-year-old woman who had an acute cerebellar hematoma after removal of the C2-C5 subdural schwannoma. During the surgeries of both cases, spinal dura was partially removed together with the tumor and the dural sac could not be repaired, resulting in large amounts of intraoperative CSF loss and persistent postoperative CSF leakage. Both patients failed to regain consciousness from anesthesia after surgery, and a cranial CT scan identified large intracranial hematomas. Urgent hematoma evacuation was ultimately performed to save the patients. Based on the authors' experience and literature review, a conclusion was drawn that considerable CSF leakage and a sharp decrease of CSF pressure are common features during the excision of a spinal subdural tumor, which may lead to acute intracranial hematomas. Continual postoperative monitoring in patients with this condition should be of a very high priority. A CT or MRI should be immediately investigated to exclude intracranial hematomas for any patient with delayed emergence from anesthesia following spinal surgery. Hematoma evacuation is indispensable once an intracranial hematoma is identified in the patient who fails to regain consciousness from anesthesia post surgery. Furthermore, the possible pathophysiological mechanisms responsible for the formation of an intracranial hematoma after spinal procedures, particularly after manipulations of a cervical subdural tumor, are discussed.

  4. Somatic mutagenesis with a Sleeping Beauty transposon system leads to solid tumor formation in zebrafish.

    Directory of Open Access Journals (Sweden)

    Maura McGrail

    2011-04-01

    Full Text Available Large-scale sequencing of human cancer genomes and mouse transposon-induced tumors has identified a vast number of genes mutated in different cancers. One of the outstanding challenges in this field is to determine which genes, when mutated, contribute to cellular transformation and tumor progression. To identify new and conserved genes that drive tumorigenesis we have developed a novel cancer model in a distantly related vertebrate species, the zebrafish, Danio rerio. The Sleeping Beauty (SB T2/Onc transposon system was adapted for somatic mutagenesis in zebrafish. The carp ß-actin promoter was cloned into T2/Onc to create T2/OncZ. Two transgenic zebrafish lines that contain large concatemers of T2/OncZ were isolated by injection of linear DNA into the zebrafish embryo. The T2/OncZ transposons were mobilized throughout the zebrafish genome from the transgene array by injecting SB11 transposase RNA at the 1-cell stage. Alternatively, the T2/OncZ zebrafish were crossed to a transgenic line that constitutively expresses SB11 transposase. T2/OncZ transposon integration sites were cloned by ligation-mediated PCR and sequenced on a Genome Analyzer II. Between 700-6800 unique integration events in individual fish were mapped to the zebrafish genome. The data show that introduction of transposase by transgene expression or RNA injection results in an even distribution of transposon re-integration events across the zebrafish genome. SB11 mRNA injection resulted in neoplasms in 10% of adult fish at ∼10 months of age. T2/OncZ-induced zebrafish tumors contain many mutated genes in common with human and mouse cancer genes. These analyses validate our mutagenesis approach and provide additional support for the involvement of these genes in human cancers. The zebrafish T2/OncZ cancer model will be useful for identifying novel and conserved genetic drivers of human cancers.

  5. Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

    Science.gov (United States)

    Luo, Wei; Yu, Wei-Dong; Ma, Yingyu; Chernov, Mikhail; Trump, Donald L.; Johnson, Candace S.

    2013-01-01

    Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

  6. Prostate cancer

    International Nuclear Information System (INIS)

    Murphy, G.P.; Kuss, R.; Khoury, S.; Chatelain, C.; Denis, L.

    1987-01-01

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results

  7. Prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, G.P.; Kuss, R., Khoury, S.; Chatelain, C.; Denis, L.

    1987-01-01

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results.

  8. Differential effect of alpha-difluoromethylornithine on the in vivo uptake of 14C-labeled polyamines and methylglyoxal bis(guanylhydrazone) by a rat prostate-derived tumor

    International Nuclear Information System (INIS)

    Heston, W.D.; Kadmon, D.; Covey, D.F.; Fair, W.R.

    1984-01-01

    The uptake of exogenously administered radiolabeled polyamines by a rat prostate-derived tumor line, the Dunning R3327 MAT-Lu, and various normal tissues was studied. Pretreatment of tumor cells in vitro with alpha-difluoromethylornithine (DFMO), a polyamine synthesis inhibitor, resulted in a markedly enhanced uptake of both [ 14 C]putrescine and [14 C]spermidine. The in vitro uptake of [ 14 C]putrescine by these cells was effectively inhibited by unlabeled spermine, spermidine, 1,8-diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane, 1,4-diaminopentane, and 1,4-diaminobutane, but less effectively by 1,4-diamino-2,3-butene and 1,4-diamino-2,3-butyne. The diamines, 1,3-diaminopropane and 1,2-diaminoethane, were ineffective in inhibiting [ 14 C]putrescine uptake in vitro into the R3327 MAT-Lu cell line. When tumor-bearing animals were pretreated with DFMO or with DFMO and 5-alpha-dihydrotestosterone propionate, the tumor and prostate uptake of [ 14 C]putrescine and [ 14 C]-cadaverine was enhanced but not substantially increased in other tissues. In contrast to the in vitro results, spermidine and spermine were not enhanced substantially by DFMO pretreatment into any tissue, and their uptake into the tumor actually decreased. Ethylenediamine, which does not utilize the polyamine transport system, did not have its uptake increased into any tissue following DFMO pretreatment. The chemotherapeutic agent, methylglyoxal bis(guanylhydrazone), which utilizes the polyamine transport system for uptake into cells, exhibited uptake behavior different from that of the polyamines

  9. Differential effect of alpha-difluoromethylornithine on the in vivo uptake of 14C-labeled polyamines and methylglyoxal bis(guanylhydrazone) by a rat prostate-derived tumor

    Energy Technology Data Exchange (ETDEWEB)

    Heston, W.D.; Kadmon, D.; Covey, D.F.; Fair, W.R.

    1984-03-01

    The uptake of exogenously administered radiolabeled polyamines by a rat prostate-derived tumor line, the Dunning R3327 MAT-Lu, and various normal tissues was studied. Pretreatment of tumor cells in vitro with alpha-difluoromethylornithine (DFMO), a polyamine synthesis inhibitor, resulted in a markedly enhanced uptake of both (/sup 14/C)putrescine and (14 C)spermidine. The in vitro uptake of (/sup 14/C)putrescine by these cells was effectively inhibited by unlabeled spermine, spermidine, 1,8-diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane, 1,4-diaminopentane, and 1,4-diaminobutane, but less effectively by 1,4-diamino-2,3-butene and 1,4-diamino-2,3-butyne. The diamines, 1,3-diaminopropane and 1,2-diaminoethane, were ineffective in inhibiting (/sup 14/C)putrescine uptake in vitro into the R3327 MAT-Lu cell line. When tumor-bearing animals were pretreated with DFMO or with DFMO and 5-alpha-dihydrotestosterone propionate, the tumor and prostate uptake of (/sup 14/C)putrescine and (/sup 14/C)-cadaverine was enhanced but not substantially increased in other tissues. In contrast to the in vitro results, spermidine and spermine were not enhanced substantially by DFMO pretreatment into any tissue, and their uptake into the tumor actually decreased. Ethylenediamine, which does not utilize the polyamine transport system, did not have its uptake increased into any tissue following DFMO pretreatment. The chemotherapeutic agent, methylglyoxal bis(guanylhydrazone), which utilizes the polyamine transport system for uptake into cells, exhibited uptake behavior different from that of the polyamines.

  10. About the Prostate

    Science.gov (United States)

    ... PCF: Many vs Cancer Contact Us About the Prostate Prostate Cancer Basics Risk Factors Prostate Cancer Prevention ... that connects to the anus. Ultrasound of the prostate Prostate Zones The prostate is divided into several ...

  11. Loss of Serglycin Promotes Primary Tumor Growth and Vessel Functionality in the RIP1-Tag2 Mouse Model for Spontaneous Insulinoma Formation.

    Directory of Open Access Journals (Sweden)

    Andrew Hamilton

    Full Text Available The serglycin proteoglycan is mainly expressed by hematopoietic cells where the major function is to retain the content of storage granules and vesicles. In recent years, expression of serglycin has also been found in different forms of human malignancies and a high serglycin expression level has been correlated with a more migratory and invasive phenotype in the case of breast cancer and nasopharyngeal carcinoma. Serglycin has also been implicated in the development of the tumor vasculature in multiple myeloma and hepatocellular carcinoma where reduced expression of serglycin was correlated with a less extensive vasculature. To further investigate the contribution of serglycin to tumor development, we have used the immunocompetent RIP1-Tag2 mouse model of spontaneous insulinoma formation crossed into serglycin deficient mice. For the first time we show that serglycin-deficiency affects orthotopic primary tumor growth and tumor vascular functionality of late stage carcinomas. RIP1-Tag2 mice that lack serglycin develop larger tumors with a higher proliferative activity but unaltered apoptosis compared to normal RIP1-Tag2 mice. The absence of serglycin also enhances the tumor vessel functionality, which is better perfused than in tumors from serglycin wild type mice. The presence of the pro-angiogenic modulators vascular endothelial growth factor and hepatocyte growth factor were decreased in the serglycin deficient mice which suggests a less pro-angiogenic environment in the tumors of these animals. Taken together, we conclude that serglycin affects multiple aspects of spontaneous tumor formation, which strengthens the theory that serglycin acts as an important mediator in the formation and progression of tumors.

  12. An Embryonic Growth Pathway is Reactivated in Human Prostate Cancer

    National Research Council Canada - National Science Library

    Bushman, Wade

    2005-01-01

    .... This research postulates that prostate cancer cells commandeer this normal epithelial-mesenchymal signaling pathway to recruit stromal cells to support abnormal tumor growth and tests the hypothesis...

  13. An Embryonic Growth Pathway is Reactivated in Human Prostate Cancer

    National Research Council Canada - National Science Library

    Bushman, Wade

    2003-01-01

    .... This research postulates that prostate cancer cells commandeer this normal epithelial-mesenchymal signaling pathway to recruit stromal cells to support abnormal tumor growth and tests the hypothesis...

  14. Enhancing the Anti-tumor Activity of ErbB Blockers with Histone Deaccetylase(HDAC)Inhibition in Prostate Cancer Cell Lines

    National Research Council Canada - National Science Library

    Chinnaiyan, Prakash; Harari, Paul M

    2007-01-01

    .... Continuing work with additional prostate cancer cell lines and examining other biologic end-points, including cell cycle kinetics, angiogenesis, and invasion. Promising results will then be evaluated in vivo.

  15. Failure-free survival following brachytherapy alone or external beam irradiation alone for T1-2 prostate tumors in 2222 patients: results from a single practice

    International Nuclear Information System (INIS)

    Brachman, David G.; Thomas, Theresa; Hilbe, Joseph; Beyer, David C.

    2000-01-01

    Purpose: To evaluate failure-free survival (FFS) for brachytherapy (BT) alone compared to external beam radiotherapy (EBRT) alone for Stage T1-2 Nx-No Mo patients over the same time period by a single community-based practice in the prostate-specific antigen (PSA) era. Materials and Methods: The database of Arizona Oncology Services (a multiphysician radiation oncology practice in the Phoenix metropolitan area) was reviewed for patients meeting the following criteria: (1) T1 or T2 Nx-No Mo prostate cancer; (2) no prior or concurrent therapy including hormones; (3) treatment period 12/88-12/95; and (4) treatment with either EBRT alone or BT alone ( 125 I or 103 Pd). This yielded 1527 EBRT and 695 BT patients; no patients meeting the above criteria were excluded from analysis. Median follow-up for EBRT patients was 41.3 months and, for BT patients, 51.3 months. Patients were not randomized to either therapy but rather received EBRT or BT based upon patient, treating, and/or referring physician preference. PSA failure was defined according to the ASTRO consensus guidelines. The median patient age was 74 years for both groups. Results: Failure-free survival at 5 years for EBRT and BT are 69% and 71%, respectively (p = 0.91). For T stage, no significant difference in FFS at 5 years is observed between EBRT and BT for either T1 (78% vs. 83%, p = 0.47) or T2 (67% vs. 67%, p = 0.89) tumors. Analysis by Gleason score shows superior outcomes for Gleason 8-10 lesions treated with EBRT vs. BT (5-year FFS 52% vs. 28%, p = 0.04); outcomes for lower grade lesions (Gleason 4-6) when analyzed by Gleason score alone do not significantly differ according to treatment received. Patients with initial PSA values of 10-20 ng/dL have an improved FFS with EBRT vs. BT at 5 years (70% vs. 53%, p = 0.001); outcomes for patients with initial PSA ranges of 0-4 ng/dL, of > 4-10 ng/dL, and > 20 ng/dL did not differ significantly by treatment received. FFS was also determined for presenting

  16. Engineered FGF-2 expression induces glandular epithelial hyperplasia in the murine prostatic dorsal lobe.

    NARCIS (Netherlands)

    Takahashi, N.; Takeuchi, T.; Nishimatsu, H.; Kamijo, T.; Tomita, K.; Schalken, J.A.; Teshima, S.; Kitamura, T.

    2004-01-01

    OBJECTIVE: It is known that androgens and stromal-epithelial interactions are required for the formation and growth of the prostate. FGF-2 is overexpressed in prostatic stromal cells in benign prostatic hypertrophy (BPH)/prostate cancer. This supports the paracrine/autocrine growth of prostatic

  17. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Thobe, Megan N. [Section of Urology, Department of Surgery, The University of Chicago, Chicago, IL 60637 (United States); Clark, Robert J. [Department of Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637 (United States); Bainer, Russell O. [Department of Human Genetics, The University of Chicago, Chicago, IL 60637 (United States); Prasad, Sandip M.; Rinker-Schaeffer, Carrie W., E-mail: crinkers@uchicago.edu [Section of Urology, Department of Surgery, The University of Chicago, Chicago, IL 60637 (United States)

    2011-01-27

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies.

  18. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    International Nuclear Information System (INIS)

    Thobe, Megan N.; Clark, Robert J.; Bainer, Russell O.; Prasad, Sandip M.; Rinker-Schaeffer, Carrie W.

    2011-01-01

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies

  19. Comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatography for screening anti-tumor components from Radix Sophorae flavescentis.

    Science.gov (United States)

    Wang, Qiang; Xu, Junnan; Li, Xiang; Zhang, Dawei; Han, Yong; Zhang, Xu

    2017-07-01

    Radix Sophorae flavescentis is generally used for the treatment of different stages of prostate cancer in China. It has ideal effects when combined with surgical treatment and chemotherapy. However, its active components are still ambiguous. We devised a comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatography system for screening anti-prostate cancer components in Radix Sophorae flavescentis. Gefitinib and dexamethasone were chosen as positive and negative drugs respectively for validation and optimization the selectivity and suitability of the comprehensive two-dimensional chromatographic system. Five compounds, sophocarpine, matrine, oxymatrine, oxysophocarpine, and xanthohumol were found to have significant retention behaviors on the PC-3 cell membrane chromatography and were unambiguously identified by time-of-flight mass spectrometry. Cell proliferation and apoptosis assays confirmed that all five compounds had anti-prostate cancer effects. Matrine and xanthohumol had good inhibitory effects, with half maximal inhibitory concentration values of 0.893 and 0.137 mg/mL, respectively. Our comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatographic system promotes the efficient recognition and rapid analysis of drug candidates, and it will be practical for the discovery of prostate cancer drugs from complex traditional Chinese medicines. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Replacement of E-cadherin by N-cadherin in the mammary gland leads to fibrocystic changes and tumor formation.

    Science.gov (United States)

    Kotb, Ahmed M; Hierholzer, Andreas; Kemler, Rolf

    2011-10-26

    E-cadherin (E-cad; cadherin 1) and N-cadherin (N-cad; cadherin 2) are the most prominent members of the cadherin family of cell adhesion molecules. Although they share many structural and functional features, they are expressed in an almost mutually exclusive manner in vivo. To explore functional differences between the two cadherins in vivo, we recently generated a knock-in line in which N-cad is expressed from the E-cad locus. In combination with a conditional gene inactivation approach, we expressed N-cad in the absence of E-cad (referred to as Ncadk.i.) in alveolar epithelial cells of the mammary gland starting in late pregnancy. We found that the sole presence of N-cad induces constitutively active fibroblast growth factor (Fgf) signaling and a precocious involution resulting in massive apoptosis of alveolar cells. To block apoptosis, we conditionally deleted one allele of p53 in Ncadk.i. mice and observed a temporal rescue of alveolar morphology and function. However, an accumulation of fibrotic tissue and cysts with increasing age and lactation cycles was observed. This phenotype closely resembled fibrocystic mastopathy (FM), a common disorder in humans, which is thought to precede breast cancer. Concordantly, 55% of Ncadk.i. mice harboring a heterozygous p53 deletion developed malignant and invasive tumors. Our results demonstrate a possible role for N-cad in the formation of fibrosis and cysts in the mammary gland. Moreover, we show that these lesions precede the development of malignant tumors. Thus, we provide a new mouse model to investigate the molecular mechanisms of fibrocystic mastopathy and the transition from benign to malignant tumors.

  1. Circular RNA alterations are involved in resistance to avian leukosis virus subgroup-J-induced tumor formation in chickens.

    Science.gov (United States)

    Zhang, Xinheng; Yan, Yiming; Lei, Xiaoya; Li, Aijun; Zhang, Huanmin; Dai, Zhenkai; Li, Xinjian; Chen, Weiguo; Lin, Wencheng; C