Special Issue "Prostate Cancer"

Guest Editor
Prof. Dr. Sven Perner
Institute of Pathology, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Website: http://www.pernerlab.de/mitarbeiter/sven_perner.htm
E-Mail: sven.perner1972@gmail.com
Phone: +49 228 287 15323
Fax: +49 228 287 9080019
Interests: understanding of the molecular biology of prostate cancer and the development of predictive biomarkers; genetics; molecular biology; TMPRSS2-ERG gene fusion; gene translocations; biomarker development

Dear Colleagues,

The prevalence of prostate cancer (PCa), in western countries, is extremely high and tends to increases with age. Statistics have shown that 1 in 6 men will be diagnosed with PCa during their lifetime. This disease is the leading cause of male cancer-related death, second only to lung cancer. Notwithstanding the sizable number of deaths, the majority of cases have indolent or slow growing tumors. In PCa, strategies for clinical decision-making and diagnosis are based on clinical examination, PSA-levels and histopathologic evaluation. However, their inaccuracy in a significant subset of patients results in an overtreatment in many men. The understanding of the cancer biology of patients suffering from Pca is key for making progress on the treatment of these patients. We would like to invite manuscripts relating to novel biomarker discovery and validation in PCa. We are also particularly interested in manuscripts deciphering the molecular and biochemical development and progression of PCa, as well as epidemiologic aspects related to PCa. This issue on the whole will focus on understanding prostate cancer at a molecular, biochemical and genetic level.

Thanks you for your collaboration.

Sven Perner
Guest Editor

Submission

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• postate cancer
• biomarker development and validation
• molecular biology
• genetics
• epidemiology
• inflammation
• cancer stem cells

Type of Paper: Article
Title: Antibody-Based Anti-Cancer Drugs Targeting Human Prostate Cancer
Authors: Gregory Lee, Bixia Ge and Mingang Zhu
Affiliation: Andrology Lab, UBC Center for Reproductive Health, The University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada;
E-Mails: andr@interchange.ubc.ca (G.L.); bge@sfu.ca (B.G.); zmingang@yahoo.com (M.Z.)
Abstract: Two monoclonal antibodies (Mabs) were selected for the preclinical development of anti-cancer drugs targeting various human cancers including that of the prostate. RP215 was shown to react with carbohydrate-associated (O-glycan-linked) epitope of the cancer cell-expressed immunoglobulin superfamily (IgSF) proteins, known as CA215 pan cancer marker. The other is GHR106 which was shown to react specifically with the extracellular domains of human GnRH receptor, highly expressed on the surface of many different cancer cells in humans. In vitro preclinical studies were performed to evaluate the efficacy of these two Mabs as the anti-cancer drugs for the cancer of prostate. These included 1) Western blot and immunohistochemical studies of the prostate cancer cells to document the surface expression of the targeting antigens, (2) induction of apoptosis and complement-dependent cytotoxicity (CDC) to prostate cancer cells upon treatment with either of these two Mabs, and (3) Effects  of these Mabs on the gene expression and gene regulation of prostate cancer cells. Similar to previous studies in other types of cancer cells, the present study strongly suggests that these two Mabs were highly effective in inducing apoptosis and CDC reaction to prostate cancer cells in vitro. Further studies also indicated that GHR106 Mab functions like long-acting (half life 15-20 days) GnRH analogs in its biological actions to cancer cells. Attempts were made to elucidate mechanisms of action of these Mabs through analysis of the gene regulations of prostate cancer cells. Chimeric forms of these two Mabs were produced with the affinity and specificity to prostate cancer cells comparable to those of murine ones. Therefore, from this study, we believe that both Mabs can be humanized and developed into suitable therapeutic agents for the treatments of the prostate cancers in humans.

Type of Paper: Article
Title: Metastasising, Luciferase-Transduced MAT-Lu Rat Prostate Cancer Models: Follow Up of Bolus Therapy with Doxorubicin as Model Drug
Authors: P. Jantscheff, N. Esser, A. Geipel, P. Woias, F. Goldschmidtböing and U. Massing
Affiliation: Tumor Biology Center, Clinical Research, Department of Lipids & Liposomes, Breisacher Str. 117, D-79106 Freiburg, Germany;
E-Mail: jantscheff@tumorbio.uni-freiburg.de (P.J.)
Abstract: Most fatal outcomes of prostate carcinoma (PCa) result from hormone-refractory variants of the tumour, especially from metastatic spread rather than from primary tumour burden. The goal of the study was to establish and apply rat MAT-Lu prostate cancer tumour models for improved non-invasive live follow up of tumour growth and metastasis by in vivo bioluminescence. We established luciferase transduced MAT-Lu rat PCa cells and studied tumour growth and metastatic processes in an ectopic and orthotopic setting. An intravenous bolus treatment with doxorubicin was used to demonstrate the basic applicability of in vivo imaging to follow up therapeutic intervention in these models. In vitro analysis of tissue homogenates confirmed preferential lung metastasis (6/8) of subcutaneous tumours. Our sensitive method, however, detects for the first time metastasis also in lymph node (of 4/8 animals), spleen (2/8), kidney (1/8), liver (2/8), and bone tissue (femur: 1/4 and lumbar spine: 2/4). Orthotopic implantation resulted in a different metastatic pattern with preferential invasion into lymph nodes (3/3), spleen (3/3), and stomach (3/3). Bone invasion was similar to subcutaneous implantation but found -as also metastatic lesions in other examined tissues- in all animals (3/3). Intravenous bolus treatment of MAT-Lu PCa with doxorubicin reduced subcutaneous tumour growth and the number of metastatic lesions, as determined by in vivo imaging and in vitro analysis. The two models are highly sensitive and useful to follow up therapeutic anti-tumour and anti-metastatic interventions. Additionally, a possible applicability of the models to study basic principles of metronomic therapies via jugular vein catheter using newly established active microport pumping systems is presented as supplementary data.

Type of Paper: Article
Title: The Expression of ATIP in Human Prostate Cancer Biopsies
Author: Simon Louis
Affiliation: Department of Medicine, Austin Health, Clinical Pharmacology and Therapeutics Unit, Studley Rd, Level 5 Lance Townsend Building, Heidelberg 3084, Victoria, Australia; E-Mail: simonnsl@unimelb.edu.au
Abstract: Background: Angiotensin II (Ang II), the main effector of the renin angiotensin system, acts upon two distinct transmembrane receptors, the Ang II type 1 (AT1-) and the type 2 (AT2-) receptor, to induce a wide range of effects in man.  The AT2-receptor through an interaction with its putative signaling partner ATIP (AT2-receptor interacting protein) inhibits the mitogenic effects of EGF in prostate cancer cell lines representing both early and late stage disease.  This pilot study examines for the first time the expression of ATIP in malignant human prostatic biopsies. Methods: Immunohistochemistry was used to examine ATIP expression in fixed LNCaP and PC3 prostate cancer cells and sections of human biopsies containing benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and well, moderately and poorly differentiated prostate cancer. Results: ATIP mRNA expression was relatively low in RWPE1 normal prostatic cells compared to androgen-dependent LNCaP prostate cancer cells.  ATIP immunostaining was not detected in either the basal or columnar epithelial cell layers surrounding BPH glands, however, it was observed in the neoplastic epithelial cells of HGPIN, and in the cytoplasms of the malignant cells in all grades of prostate cancer.  In addition, ATIP immunostaining was identified in the cytoplasms of LNCaP and PC3 prostate cancer cell lines. Conclusions: The consistent appearance of ATIP staining in the precancerous epithelial cells and its absence in normal epithelial cells strongly suggests that re-expression of ATIP occurs at an early phase in the malignant process and that ATIP re-expression may be and early indicator of malignant development. The continued expression of ATIP in all grades of prostate cancer suggests that the AT2-receptor/ATIP signalling pathway is present and that it may continue to be a potential therapeutic target even following the development of androgen-independence.

Type of Paper: Article
Title: The Expression of ATIP in Human Prostate Cancer Biopsies
Author: Simon Louis
Affiliation: Department of Medicine, Austin Health, Clinical Pharmacology and Therapeutics Unit, Studley Rd, Level 5 Lance Townsend Building, Heidelberg 3084, Victoria, Australia; E-Mail: simonnsl@unimelb.edu.au
Abstract: Background: Angiotensin II (Ang II), the main effector of the renin angiotensin system, acts upon two distinct transmembrane receptors, the Ang II type 1 (AT1-) and the type 2 (AT2-) receptor, to induce a wide range of effects in man.  The AT2-receptor through an interaction with its putative signaling partner ATIP (AT2-receptor interacting protein) inhibits the mitogenic effects of EGF in prostate cancer cell lines representing both early and late stage disease.  This pilot study examines for the first time the expression of ATIP in malignant human prostatic biopsies. Methods:  Immunohistochemistry was used to examine ATIP expression in fixed LNCaP and PC3 prostate cancer cells and sections of human biopsies containing benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and well, moderately and poorly differentiated prostate cancer. Results: ATIP mRNA expression was relatively low in RWPE1 normal prostatic cells compared to androgen-dependent LNCaP prostate cancer cells.  ATIP immunostaining was not detected in either the basal or columnar epithelial cell layers surrounding BPH glands, however, it was observed in the neoplastic epithelial cells of HGPIN, and in the cytoplasms of the malignant cells in all grades of prostate cancer.  In addition, ATIP immunostaining was identified in the cytoplasms of LNCaP and PC3 prostate cancer cell lines. Conclusions: The consistent appearance of ATIP staining in the precancerous epithelial cells and its absence in normal epithelial cells strongly suggests that re-expression of ATIP occurs at an early phase in the malignant process and that ATIP re-expression may be and early indicator of malignant development. The continued expression of ATIP in all grades of prostate cancer suggests that the AT2-receptor/ATIP signalling pathway is present and that it may continue to be a potential therapeutic target even following the development of androgen-independence.

Type of Paper: Article
Title: Functions of Cell Surface GRP78 in Survival and Proliferation of Cancer Cells
Authors: Mario Gonzalez-Gronow, Lihong Mo, Emma E. Fridel, Salvatore V. Pizzo and Uma K. Misra
Affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA; E-Mail: gonza002@mc.duke.edu (M.G.-G.)
Abstract: Associations of GRP78 on the cell surface with a large diversity of partners give this molecule the capacity to serve as a receptor of many different agonists. The molecule appears to be compartmentalized to respond differently to agonists that bind to either its N- or C-terminal domains. For example, prostate cancer cells, activated α₂M-macroglobulin (α₂M*) or anti-GRP78 autoantibodies, mimicking α₂M*, bind to GRP78 N-terminal domain and initiate signaling pathways which stimulate endoplasmic reticulum (ER) stress responses, leading to limited apoptosis and promotion of cell cancer growth, whereas antibodies against GRP78 C-terminus suppress cell proliferation and promote apoptosis. In this study, we investigated the effect of these GRP78 agonists on Akt/PkB serine/threonine kinase. Prostate cancer cells incubated with α₂M* increase the recruitment and activation of Akt at the plasma membrane via stimulation of phosphatidyl (3,4,5-)-triphosphate synthesis, yet the antibodies against GRP78 CV-terminus inhibit this process. Furthermore, α₂M* also causes upregulation of mTORC1 activation, transcriptional and translational upregulation of fatty acid synthase, ATP-citrate lyase, SREBP-1 and acetyl carboxylase. Cells incubated with the antibody against GRP78 C-terminus or transfected with dsRNA also show and enhanced suppression of lipogenic activities. Our results show that ligation of GRP78 at the cell surface directly affects Akt/PkB serine/threonine kinase, one of the most versatile proteins kinases at the core of human physiology and disease.

Type of Paper: Review
Title: Bioactive Food Compounds as Epigenetic Modulators in Prostate Cancer Prevention
Author: Clarissa Gerhauser, Joseph Huang, Christoph Plass
Affiliation: German Cancer Research Center, Epigenomics and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; E-mail: c.gerhauser@dkfz.de
Abstract: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men in industrialized countries, and the second leading cause of male cancer-related death. Epigenetic mechanisms, including changes in DNA methylation, chromatin modifications and noncoding RNAs, contribute to PCa development. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events, they have been identified as promising new targets for cancer therapy and prevention. Micronutrients and naturally derived food substances currently under investigation for PCa prevention include green tea; soy and phytoestrogens; lycopene and tomato products; Allium and cruciferous vegetables, selenium, vitamins A, C, D, E, and various combinations thereof. The planned review will summarize their impact on DNA methylation of candidate genes (GSTP1, RARb2, p16, RASSF1A, hTERT), histone modifying enzymes (histone deacetylases, histone acetyl transferases, histone methyltransferases) and consequences on cell cycle, apoptosis and hormone signalling, miRNAs and their target genes, as well as results of in vivo studies in the transgenic TRAMP model, and prostate cancer xenograft studies.

Type of Paper: Article
Title: Redox Characteristics of Selected Prostate Cancer Cell Lines
Authors: Luksana Chaiswing ¹ and Terry D. Oberley 1, 2
Affiliations: ¹ Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
² Pathology and Laboratory Medicine Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA; E-Mail: lchaiswing@wisc.edu (L.C.)
Abstract: Several cancer chemotherapeutic drugs and radiation mediate their effects, at least in part, by oxidative stress. To better understand this process, we analyzed certain biochemical properties affecting reduction-oxidation (redox) balance in selected prostate epithelial and prostate cancer cell lines. WPE1-NB26 is a prostate cancer cell line derived from benign immortalized RWPE1 human prostate epithelial cells. LNCaP-C42 is a prostate cancer cell line, derived from LNCaP cells, that is more invasive than the parental cell line. WPE1-NB26 cells demonstrated significantly higher levels of total antioxidant activity and intra- and extracellular glutathione (GSH)/glutathione disulfide (GSSG) ratios, but lower levels of intracellular reactive oxygen/nitrogen species ROS/RNS) when compared with RWPE1 cells. LNCaP-C42 exhibited higher levels of intracellular ROS/RNS and lower levels of antioxidant protein expression in comparison to less aggressive LNCaP cells. Specific cell types showed distinct cytotoxic responses to redox-modulating compounds. WPE1-NB26 cells were more sensitive to phenethyl isothiocyanate than RWPE1 cells, while LNCaP cells were more sensitive to tumor necrosis factor or tumor necrosis factor-related apoptosis-inducing ligand than benign PrEC prostate epithelial cells. These results are consistent with the hypothesis that cancer cell redox state may modulate responses to redox-modulating therapeutic regimens.

Type of Paper: Article
Title: Bioanalytical Study of Prostate Cancer Tumour Markers on the RNA and Protein Level
Author: Rene Kizek
Affiliation: Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno Czech Republic; E-Mail: kizek@sci.muni.cz
Abstract: Current diagnostic techniques are not efficient to distinguish latent and low-risk forms of prostate cancer from high-risk forms. Our study is focused on determination of tumour markers of aggressive - high-grade - forms of prostate cancer. We determined markers in serum of 133 patients (82 cases and 51 controls) and in cells of cell lines (Gleason score 9-derived 22Rv1 and normal tissue derived PNT1A) on RNA and protein level. Alpha-methylacyl-CoA racemase (AMACR), caveolin-1 (Cav-1), metallothionein (MT), p53, NF-kB, c-FOS, c-JUN, Ki-67, ZIP1 and ZnT-1 were determined and compared to PSA levels. Significantly (p < 0.05) decreased (> 4 fold) expression of Cav-1, NF-kB, c-FOS, and c-JUN and significantly elevated expression (> 2 fold) of MT, AMACR, PSA, Ki-67, MMP-9, and ZIP1 and ZnT-1 (> 25 fold) was determined on RNA level in studied cell lines. On the other hand, significant reduction (> 20 fold) of MT on protein level in cell lines was determined. We determined also significantly enhanced (4.5 fold) MT level in patients serum. No significant changes were determined in AMACR and Cav-1 levels. These findings indicate possible alternative role MT to PSA prostate cancer marker. Interestingly, we determined significantly higher Cav-1 level in serums of patients (2.5 fold compared to T 1–3) in stage four  and significant positive correlation of Cav-1 (Gleason score - GS, r = 0.29 at p = 0.028). These findings suggest Cav-1 as a potential marker of high-malignant prostate tumours. In addition, MT is GS and AMACR independent with borderline significance (p = 0.56) decreasing in dependence on the GS.
Keywords: tumour disease; prostate cancer, tumour marker; immunodetection; electrochemistry; PCR; molecular biology techniques.