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  • 1.
    Adamo, Hanibal
    et al.
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Hammarsten, Peter
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Hägglöf, Christina
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Scherdin, Tove Dahl
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Egevad, Lars
    Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Bergström, Sofia Halin
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Bergh, Anders
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 5, p. 435-445Article in journal (Refereed)
    Abstract [en]

    Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

    Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

    Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

    Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

  • 2.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Prothrombotic effect of prostasomes of metastatic cell and seminal origin2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, p. 378-388Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Prostasomes are secretory granules produced by the glandular epithelial cells of the prostate. Seminal prostasomes contain high amounts of Tissue Factor (TF) but no studies of TF on malignant cell prostasomes have been made. Here we compare the expression, phosphorylation, and function of TF on prostasomes of different origin. METHODS. TF was detected on prostasomes isolated from seminal fluid and human prostate cancer cell lines (PC-3, DU145, and LNCaP) using FACS and enzyme immunoassay (EIA). Incubation of prostasomes with radioactive ATP under conditions favoring protein kinase A activity led to phosphorylation of TF as detected by immunoprecipitation and SDS-PAGE. The prothrombotic effect of prostasomes was investigated in whole blood and recalcified plasma. Blocking experiments were performed using anti-TF antibodies and corn trypsin inhibitor. RESULTS. TF was expressed on all tested prostasome preparations with lowest values found for seminal ones. Prostasomal TF was the main endogenous substrate for prostasomal protein kinase A. All tested prostasome preparations greatly enhanced the rate of clot formation in a dose-dependent fashion, that is, the clotting capability of prostasomes seemed to be related to the extent of their expression of TF. In addition, the density of the clot varied between different prostasome preparations. When incubated in whole blood, prostasomes were found to associate to WBC thereby inducing them to express and release TF. CONCLUSIONS. These data show that TF is overexpressed and also subjected to phosphorylation by malignant cell prostasomes. This suggests major roles for prostasomes in thrombotic events that occur in some advanced cases of prostate cancer.

  • 3.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mapping pro- and antiangiogenic factors on the surface of prostasomes of normal and malignant cell origin2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 8, p. 834-847Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS: VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS: VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS: Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

  • 4.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attck2005In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 62, no 2, p. 105-114Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostasomes are secretory granules produced, stored, and released, by the glandular epithelial cells of the prostate. They express the glycosylphosphatidylinositol (GPI)-anchored complement regulatory protein CD59, which has been shown to be transferred to spermatozoa and erythrocytes.

    METHODS: The CD59 content of prostasomes isolated from seminal fluid and malignant prostate cells (PC-3, DU145, and LNCaP) and the transfer of prostasomal CD59 to rabbit erythrocytes (RE) and to PIPLC-treated and unmanipulated cancer cells were investigated using FACS. All prostasomes were also incubated with RE and tested in a hemolytic assay.

    RESULTS: Prostasomes from cancer cells had higher expression of CD59 than those of normal cells. Prostasomal CD59 of different origin could be transferred to RE, malignant cell lines stripped of CD59 by PIPLC, or unmanipulated LNCaP cells. Malignant cell prostasomes had an increased ability to inhibit complement-mediated lysis compared to those from non-malignant cells.

    CONCLUSIONS: These results point to a novel mechanism by which prostasomes can protect prostatic malignant cells from complement attack.

  • 5.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 7, p. 675-686Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prostasomes are secretory granules produced, stored, and released by the glandular epithelial cells of the prostate. They express numerous enzymes whose physiological roles have so far not been fully evaluated. In this study, we investigated the expression and function of prostasomal protein kinases and ATPase.

    METHODS:

    The protein kinase activities of prostasomes isolated from seminal fluid and malignant prostate cell lines (PC-3, DU145, and LNCaP) were investigated using the model phosphorylation substrates histone and casein, as well as the plasma proteins C3 and fibrinogen, in combination with specific protein kinase inhibitors. The prostasomal ATPase activity was also evaluated. The expression of protein kinases and ATPase on prostasomes was verified by flow cytometry.

    RESULTS:

    Prostasomes (intact or solubilized with octylglucoside or saponin) from prostate cancer cells had higher expression of protein kinases A, C, and casein kinase II compared to prostasomes isolated from seminal plasma, resulting in higher phosphorylation of both exogenous and endogenous substrates. Using intact prostasomes, it was found that prostasomes of metastatic origin had lower ATPase activity, resulting in higher residual ATP available for the phosphorylation reaction. Finally, complement component C3 and fibrinogen (two proteins whose activities are modulated by phosphorylation) were identified as physiologically relevant phosphorylation substrates.

    CONCLUSIONS:

    These results indicate that prostasomes are capable of modifying proteins possibly involved in the innate response by extracellular phosphorylation mediated by ecto-kinases. This is a novel mechanism by which prostatic malignant cells may interact with their environment.

  • 6.
    Beshara, Soheir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Letocha, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wikström, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandhagen, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Danielson, Bo G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Anemia associated with advanced prostatic adenocarcinoma: Effects of recombinant human erythropoietin1997In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 31, no 3, p. 153-160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND METHODS: Nine patients with hormone-refractory metastatic prostatic adenocarcinoma and anemia were treated with recombinant human erythropoietin (rHuEpo) at a median dose of 150 U/kg BW 3 times a week subcutaneously. Baseline hemoglobin (Hb) ranged from 70 to 116 g/L, and the study duration was 12 weeks (median patient participation period was 8 weeks). RESULTS: Four patients demonstrated a median Hb increase of 20 g/L and were considered responders. Three patients showed a median increase of 17 g/L but required blood transfusion once, and were therefore considered as partial responders. Baseline erythropoietic status showed a significant correlation between serum Epo and Hb. Inadequate Epo production, evaluated by the observed/predicted log Epo ratio, was found in two patients. Defective bone marrow activity, demonstrated by low transferrin receptor (TfR), and hypoferremia in spite of abundant iron stores were also shown. Hemorheological investigations showed elevated plasma viscosity. CONCLUSIONS: Our results indicate that suppression of erythropoiesis can be mainly explained by the depressed marrow activity. The altered hemorheology might contribute to the anemia. This anemia could possibly be corrected with rHuEpo.

  • 7.
    Carlsson, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Forsberg, Ole
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Characterization of human prostate and breast cancer cell lines for experimental T cell-based immunotherapy2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, p. 389-395Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. In order to develop experimental immunotherapy for prostate and breast cancer it is of outmost importance to have representative target cell lines that through human leukocyte antigen (HLA) class I molecules present relevant levels of peptides from tumor-associated antigens for cytotoxic T lymphocyte (CTL) recognition. METHODS. We sequenced the HLA-A and HLA-B loci of eight commonly used prostate and breast cancer cell lines and analyzed the surface expression of HLA-ABC, HLA-DR, CD40, CD80, CD86, and CD54 by flow cytometry. We also analyzed the cell lines for mRNA expression from 25 genes reported to be specifically or preferentially expressed by prostate cells. RESULTS. Among the analyzed cell lines we found that LNCaP, PC-346C and MCF-7 are HLA-A*0201 positive. However, the HLA-A2 expression level is low and only MCF-7 upregulates HLA-A2 in response to IFN-γ stimulation. MCF-7 also expresses high levels of CD54, which further improve its value as a CTL target cell line. On the other hand, LNCaP and PC-346C express 25 and 23 out of 25 prostate-related genes, respectively, while MCF-7 expresses 16 out of 25 genes. CONCLUSIONS. None of the analyzed prostate cancer cell lines are optimal CTL target cells. However, MCF-7 could in many cases be used as a complement to HLA-A*0201 positive prostate cancer cells. The LNCaP and PC-346C cell lines are rich sources of prostate-related antigens that may be valuable for cancer vaccine development.

  • 8.
    Carlsson, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Tötterman, Thomas H.
    Essand, Magnus
    Generation of cytotoxic T lymphocytes specific for the prostate and breast tissue antigen TARP2004In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 61, no 2, p. 161-170Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Expansion of cytotoxic T lymphocytes (CTL) directed against peptide epitopes from antigens that are specifically expressed by normal and neoplastic prostate epithelial cells has during the last years emerged as an interesting therapeutic approach to treat advanced prostate cancer. TCRgamma alternate reading frame protein (TARP) is a protein that in males is specifically expressed by normal prostate epithelial cells and prostate cancer cells. We have evaluated TARP for human leukocyte antigen (HLA)-A*0201-restricted peptides capable of triggering TARP-specific CTL. METHODS: Dendritic cells (DC) were pulsed either with synthetic peptides derived from the natural amino acid sequence of TARP or with cognate peptides having enhanced affinity for HLA-A*0201 due to an N-terminal anchor residue substitution. The peptide-pulsed DC were used to stimulate autologous T cells ex vivo. RESULTS: We were able to generate T cells against TARP(27-35) and TARP(4-13) and their mutated counterparts TARP(V28L)(27-35) and TARP(P5L)(4-13). The use of affinity-enhanced peptides resulted in the generation of T cells recognizing target cells displaying either wild-type or mutated peptide. We further show that TARP-specific T cells can be tetramer-sorted and subsequently expanded to large numbers by general T cell stimulation, with retained specificity and activity. Sorted and expanded T cells, obtained by stimulation with TARP(P5L)(4-13), exert moderate lysis of the TARP-expressing prostate cancer cell line, LNCaP, and breast cancer cell line, MCF-7, indicating that the TARP(4-13) epitope may be endogenously processed and presented by TARP-positive, HLA-A*0201-positive cells. CONCLUSIONS: Our findings suggest that synthetic TARP peptides, such as TARP(P5L)(4-13), may play a role in prostate and breast cancer immunotherapy.

  • 9. de la Torre, M.
    et al.
    Eklöv, S.
    Häggman, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Björk, P.
    Busch, C.
    Nilsson, S.
    Elevated expression of estramustine binding protein (EMBP) in prostatic intraepithelial neoplasia (PIN) compared with malignant and benign prostatic epithelia1994In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 25, no 3, p. 125-31Article in journal (Refereed)
    Abstract [en]

    The expression of estramustine-binding protein (EMBP) was studied immunohistochemically in whole-mount prostate sections. Specimens were taken from the prostates of 15 patients who had undergone total prostatectomy due to localized (TOd-T2 NO MO) prostatic cancer (PC). Almost all the examined whole-mount sections displayed areas with prostatic intraepithelial neoplasia (PIN). PIN is regarded as the main precursor of invasive PC. High- and low-grade PIN expressed EMBP. The average positively stained areas accounted for averages of 69.2% and 48.7%, respectively. High-grade PIN contained the highest EMBP levels of all the investigated (benign and malignant) epithelia, followed by moderately differentiated PC. With regard to areas with PC, the highest levels of EMBP expression (61.3%) were observed in moderately differentiated PC; poorly differentiated PC came second. Of all the examined epithelia, EMBP levels were lowest in well-differentiated PC (25.8%). Normal prostatic epithelia and hyperplasia were characterized by low EMBP expression, although somewhat higher than well-differentiated PC. A moderate expression (45%) was observed in the seminal vesicles. According to these results, EMBP was expressed mainly in the diseased peripheral zone (PZ), where PIN and prostatic cancer have their highest prevalence.

  • 10.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Kharaziha, Pedram
    Chioureas, Dimitris
    Meersman, Niels
    Panaretakis, Theocharis
    Ronquist, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Malignant Cell-Derived Extracellular Vesicles Express Different Chromogranin Epitopes Compared to Prostasomes2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 10, p. 1063-1073Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS. We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS. A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION. Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers.

  • 11.
    Dzojic, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Loskog, Angelica
    Tötterman, Thomas H.
    Essand, Magnus
    Adenovirus-Mediated CD40 Ligand Therapy Induces Tumor Cell Apoptosis and Systemic Immunity in the TRAMP-C2 Mouse Prostate Cancer Model2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 8, p. 831-838Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The interaction between CD40 ligand (CD40L) and CD40 on antigen presenting cells is essential for the initiation of antigen-specific T-cell responses, whereas CD40L stimulation of CD40+ tumor cells can induce cellular apoptosis. We investigated the anti-tumor effects induced by CD40L gene transfer into the mouse prostate adenocarcinoma cell line TRAMP-C2, both in vitro and in vivo.

    METHODS: TRAMP-C2 cells were transduced with an adenoviral vector encoding CD40L (AdCD40L). The induced expression of co-stimulatory molecules and cell viability was analyzed. AdCD40L-transduced TRAMP-C2 cells were used in prophylactic vaccination studies, while therapeutic studies were performed using peritumoral injections of AdCD40L.

    RESULTS: AdCD40L yielded reduced TRAMP-C2 cell viability and induced apoptosis in vitro. Vaccination with CD40L-expressing TRAMP-C2 cells induced anti-tumor immunity and peritumoral AdCD40L injections induced tumor growth suppression.

    CONCLUSIONS: Our observations highlight the therapeutic potential of using AdCD40L as a monotherapy or in combination with conventional chemotherapy or novel therapies (e.g., oncolytic viruses). The use of AdCD40L offers an attractive option for future clinical trials.

  • 12.
    Eriksson, Margaretha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Wedel, Hans
    Nordic School of Public Health, Gothenburg.
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Krakau, Ingvar
    Department of Internal Medicine, General Medicine Unit, Karolinska Institute, Stockholm.
    Hugosson, Jonas
    Department of Urology, The Sahlgrenska Academy at Göteborg University.
    Carlsson, Sture
    Department of Surgery, Kungälv Hospital.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    The impact of birth weight on prostate cancer incidence and mortality in a population-based study of men born in 1913 and followed up from 50 to 85 years of age2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 11, p. 1247-1254Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Insulin-like growth factor-I (IGF-I) hormone is directly associated with birth weight (BW), and high IGF-I measured in adults is associated with increased risk of prostate cancer (PCA). Whether BW and PCA are related is inconclusive to date. METHODS: BW and PCA incidence and mortality data for a population-based cohort of 1,436 singleton Swedish men born in 1913 and followed until 85 years of age were obtained. RESULTS: BW > or = 4,250 g was associated with significantly higher PCA incidence [62% (CI: 4%-151%)] and PCA mortality [82% (CI: 3%-221%)] than BW 3,001-4,249 g, even when other potential effect modifiers were taken into account. The hazards ratio for PCA incidence fell from approximately 3 at age 50 to unity at age 85. Approximately one out of every six PCA incident cases between 50 and 70 years of age could be attributed to BW > or = 4,250 g. CONCLUSIONS: In the current study PCA incidence and mortality rate appears to increase with BW.

  • 13.
    Forsberg, Ole
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    High frequency of prostate antigen-directed T cells in cancer patients compared to healthy age-matched individuals2009In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, no 1, p. 70-81Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. In order to obtain a sustained cytotoxic T lymphocyte (CTL) response against cancer cells it is preferable to have CTLs directed against multiple peptide epitopes from numerous tumor-associated antigens.

    METHODS. We used a flow cytometry-based interferon (IFN)-g secretion assay to analyze whether CD8+ T cells directed against any of 24 HLA-A*0201-binding peptides from 15 prostate-associated proteins can be found in the peripheral blood of patients with localized prostate cancer. We also investigated whether multiple prostate antigen-specific CD8+ T cells can be generated simultaneously, from a naïve T cell repertoire. In that case, dendritic cells (DCs) from peripheral blood of healthy donors were divided in six portions and separately pulsed with six peptides. The peptide-pulsed DCs were then pooled and used to stimulate autologous T cells. The T cells were re-stimulated with peptide-pulsed monocytes.

    RESULTS. We found prostate antigen-restricted CD8+ T cells in the peripheral blood in 48 out of 184 (26.1%) analyzed samples from 25 cancer patients. This is significantly higher than 17 out of 214 analyzed samples (7.9%) from 10 healthy age-matched male individuals (p = 0.0249). In the cases when antigen-specific T cells could not be detected, we were able to generate IFN-g-producing CD8+ T cells specific for up to three prostate antigens simultaneously from a naïve T cell repertoire.

    CONCLUSIONS. CD8+ T cells directed against prostate antigen peptides can be found in, or generated from, peripheral blood. This indicates that such T cells could be expanded ex vivo for adoptive transfer to prostate cancer patients.

  • 14. Markt, Sarah C
    et al.
    Shui, Irene M
    Unger, Robert H
    Urun, Yuksel
    Berg, Christine D
    Black, Amanda
    Brennan, Paul
    Bueno-de-Mesquita, H Bas
    Gapstur, Susan M
    Giovannucci, Edward
    Haiman, Christopher
    Henderson, Brian
    Hoover, Robert N
    Hunter, David J
    Key, Timothy J
    Khaw, Kay-Tee
    Canzian, Federico
    Larranga, Nerea
    Le Marchand, Loic
    Ma, Jing
    Naccarati, Alessio
    Siddiq, Afshan
    Stampfer, Meir J
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Stevens, Victoria L
    Stram, Daniel O
    Tjønneland, Anne
    Travis, Ruth C
    Trichopoulos, Dimitrios
    Ziegler, Regina G
    Lindstrom, Sara
    Kraft, Peter
    Mucci, Lorelei A
    Choueiri, Toni K
    Wilson, Kathryn M
    ABO blood group alleles and prostate cancer risk: Results from the breast and prostate cancer cohort consortium (BPC3)2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 15, p. 1677-81Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer.

    METHODS: We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score ≥8 or locally advanced/metastatic disease (stage T3/T4/N1/M1).

    RESULTS: We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95%CI = 0.87-1.08; Type B: OR = 0.92, 95%CI =n0.77-1.09; Type AB: OR = 1.25, 95%CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk.

    CONCLUSIONS: ABO blood type was not associated with risk of aggressive prostate cancer.

  • 15.
    Olsson, Mats
    et al.
    Karolinska University Hospital, Stockholm.
    Gustafsson, Ove
    Skogastierna, Cristine
    Tolf, Anna
    Karolinska University Hospital, Stockholm.
    Rietz, Barbara Du
    Morfin, Robert
    Rane, Anders
    Ekström, Lena
    Regulation and expression of human CYP7B1 in prostate: overexpression of CYP7B1 during progression of prostatic adenocarcinoma.2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 13, p. 1439-46Article in journal (Refereed)
    Abstract [en]

    This is the first report showing that CYP7B1 is overexpressed in high-grade PIN and in prostate cancer and that local methylation of CYP7B1 promoter region may have significant effect on gene transcription.

  • 16.
    Ronquist, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    García Rodríguez, LA
    Ruigómez, A
    Johansson, Saga
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Frithz, G
    Svärdsudd, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Association between captopril, other antihypertensive drugs and risk of prostate cancer2004In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 58, no 1, p. 50-56Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    There has been some debate on the existence of an association between hypertension, antihypertensive medications and cancer risk.

    METHODS

    We performed a nested case-control study to assess the association between the risk of prostate cancer and the use of the angiotensin converting enzyme (ACE)-inhibitor captopril, and other antihypertensive drugs. We used data from the General Practice Research Database in UK.

    RESULTS

    We found an incidence rate of prostate cancer of 1.61 per 1,000 person-years among male patients aged 50–79 years old. Patients with a history of benign prostatic hyperplasia and/or prostatism carried a two-fold greater risk of prostate cancer than those without such antecedents. None of the other studied co-morbidities were associated with prostate cancer. We found that users of captopril had a relative risk of 0.7 (95% CI: 0.4–1.2) to develope prostate cancer. None of the other studied individual ACE-inhibitors shared a similar effect with the one observed for captopril.

    CONCLUSIONS

    No clear association was apparent between the use of antihypertensive drugs and prostate cancer. However, specific focus on users of captopril showed a lower risk of subsequent prostate cancer. Further research is needed to explore this association.

  • 17.
    Ronquist, Göran K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Prostasomes are heterogeneous regarding size and appearance but affiliated to one DNA-containing exosome family2012In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 72, no 16, p. 1736-1745Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prostate acinar epithelial cells release microvesicles (prostasomes) that possess pleiotropic biological effects relevant for successful fertilization. Prostasomes are formed in a similar way as exosomes but are heterogeneous as regards size and appearance. Like exosomes they are thought to be mediators of intercellular communication.

    METHODS:

    We prepared seminal prostasomes in accordance with the prevailing protocol for exosome preparation including passage through a 0.2 µm filter and centrifugation in a sucrose gradient.

    RESULTS:

    We compared the "filterable prostasomes" with those trapped on the filter ("nonfilterable prostasomes") and, qualitatively, no conspicuous differences were apparent regarding ultrastructure and SDS-PAGE banding pattern. Moreover, both types of prostasomes contained DNA fragments and Western blot revealed presence of prostate specific membrane antigen (PSMA), CD38, and annexin A1.

    CONCLUSIONS:

    Reasonably, prostasomes could be included in the exosome family and be regarded as one entity containing chromosomal DNA.

  • 18.
    Ronquist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human Prostasomes Contain Chromosomal DNA2009In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, no 7, p. 737-743Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. The aim of this study was to perform a comprehensive evaluation of the occurrence of DNA in human prostasomes. METHODS. Prostasomes were purified from seminal fluid (seminal prostasomes) and from PC-3-cells (PC-3 cell prostasomes). DNA extracted from both sources of prostasomes was visualized on agarose gels. Further, theDNAwas cloned and sequenced (13 clones from seminal prostasomal DNAand 16 clones from PC-3 cell prostasomal DNA) and identified by alignment in the BLAST-nucleotide search database. In order to decide if the DNA was internally or externally located in/on prostasomes, prostasomes were treated with nuclease (DNase) and A260 was measured before and after treatment. Additionally, flow cytometric studies were performed with membrane permeable and membrane impermeable DNA stains. RESULTS. We identified human chromosomal DNA in purified prostasomes from both sources and treatment with DNase demonstrated that the prostasome-shielded DNA was protected from enzyme attack. Membrane-permeable DNA stain raised the fluorescence contrary to membrane-impermeable stain. Clearly discernible nucleic acid of prostasomes was separated on 1% agarose gel yieldingDNAfragments of about 13 kbp and below with a marked band at about 1 kbp. Cloning and sequencing of 13 fragments from seminal prostasomes and 16 from PC-3 cell prostasomes revealed a chromosomal origin of the DNA. In purified seminal prostasomes, 4 out of 13 DNA clones featured gene sequences (31%). The corresponding figure for PC3-derived prostasomes was 4 out of 16 clones featuring gene sequences (25%). CONCLUSION. Human prostasomes contain chromosomal DNA. Both nuclease treatment and differential DNA stainings indicated an inside location of the prostasomal DNA. Our findings suggest a DNA-delivery function of prostasomes to sperm cells.

  • 19. Szulkin, Robert
    et al.
    Whitington, Thomas
    Eklund, Martin
    Aly, Markus
    Eeles, Rosalind A
    Easton, Douglas
    Kote-Jarai, Z Sofia
    Amin Al Olama, Ali
    Benlloch, Sara
    Muir, Kenneth
    Giles, Graham G
    Southey, Melissa C
    Fitzgerald, Liesel M
    Henderson, Brian E
    Schumacher, Fredrick
    Haiman, Christopher A
    Schleutker, Johanna
    Wahlfors, Tiina
    Tammela, Teuvo L J
    Nordestgaard, Børge G
    Key, Tim J
    Travis, Ruth C
    Neal, David E
    Donovan, Jenny L
    Hamdy, Freddie C
    Pharoah, Paul
    Pashayan, Nora
    Khaw, Kay-Tee
    Stanford, Janet L
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Schaid, Daniel J
    Maier, Christiane
    Vogel, Walther
    Luedeke, Manuel
    Herkommer, Kathleen
    Kibel, Adam S
    Cybulski, Cezary
    Lubiński, Jan
    Kluźniak, Wojciech
    Cannon-Albright, Lisa
    Brenner, Hermann
    Butterbach, Katja
    Stegmaier, Christa
    Park, Jong Y
    Sellers, Thomas
    Lin, Hui-Yi
    Lim, Hui-Yi
    Slavov, Chavdar
    Kaneva, Radka
    Mitev, Vanio
    Batra, Jyotsna
    Clements, Judith A
    Spurdle, Amanda
    Teixeira, Manuel R
    Paulo, Paula
    Maia, Sofia
    Pandha, Hardev
    Michael, Agnieszka
    Kierzek, Andrzej
    Gronberg, Henrik
    Wiklund, Fredrik
    Prediction of individual genetic risk to prostate cancer using a polygenic score.2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 13, p. 1467-74Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.

    METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.

    RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.

    CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.

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