bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B8: Hypoxia enhances androgen receptor activation in prostate cancer cells in response to low levels of androgens
Authors: Rudolfsson Stina , Toolanen Erik , Bergh Anders 
Published: May 2013

Abstract
Hypoxia is an important microenvironmental factor influencing tumor progression and treatment response. The understanding how hypoxia is regulating the behavior of cancer cells has to be further explored. The androgen receptor (AR) acts as a transcriptional factor controlling development or progression of prostate cancer (PC). Androgen ablation by castration is the common therapy for advanced PC but eventually most of the tumors relapse to a castration-resistant state and grow even in a low androgen environment. The remaining androgens that are still present after therapy may continue to promote AR activation. The most potent AR ligands, testosterone (T) and dihydrotestosterone (DHT), can be synthesized locally in the prostate from adrenal androgens and castration-resistant PC and bone metastases are shown to express increased levels of enzymes responsible for androgen metabolism (Akr1c3 one of several enzymes).
As castration results in a transient tissue hypoxia and solid tumors are generally hypoxic prior to treatment we investigated how hypoxia affects AR activation in androgen-sensitive prostate cancer CWR22Pc cells additional to steroidal treatment. Hypoxia upregulated the mRNA expression of the androgen-responsive NKX3.1 and prostate specific antigen (PSA), and facilitated translocation of AR to the nucleus in the presence of 0,01 nM DHT or 100 nM androstenediol. The androstenediol activation of AR simultaneously increased mRNA expression of the androgen converting enzyme Akr1c3 possibly resulting in metabolism of androstenediol to T or DHT.
This study shows that the AR can be hypersensitized to low levels of androgens in PC cells grown in a hypoxic milieu as in solid tumors and after castration. A consequence of exposure of PC cells to hypoxia is a possible increase in local biosynthesis of T and DHT from adrenal androgens or a direct ligand binding effect by adrenal androgen to activate the AR.
Citation Format: Stina Rudolfsson, Erik Toolanen, Anders Bergh. Hypoxia enhances androgen receptor activation in prostate cancer cells in response to low levels of androgens [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B8.
Abstract C15: RB status alters the response of prostate cancer to ionizing radiation
Authors: Den Robert B. , Ciment Steve , Sharma Ankur , Mellert Hestia , McMahon Steve , Dicker Adam P. , Knudsen Karen E. 
Published: May 2013

Abstract
Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. We have previously shown that RB loss results in a castrate resistant phenotype and impacts on the sensitivity of prostate cancer to different chemotherapies. However the consequences of RB status with regard to radiation response are unknown. We hypothesized that RB loss would downregulate the G1-S cell cycle checkpoint arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to ionizing radiation.
Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Gamma H2AX and 53BP1 assays were used to quantitate DNA damage; PARP cleavage and Caspase 3 were used to quantitate apoptosis; FACS analysis with BrdU was used to assess the cell cycle; beta galactosidase was used to assess senescence. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts.
Results: We observed that loss of RB increased the radioresponsiveness in both transient and clonogenic cell survival assays in both hormone sensitive and castrate resistant cell lines (p&lt;0.05). Cell death was not mediated through increased apoptosis or alterations in cell cycle. However, loss of RB effected DNA damage repair as well as cellular senescence. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p&lt;0.05).
Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. The underlying mechanism appears to be related to DNA damage repair and cellular senescence.
Citation Format: Robert B. Den, Steve Ciment, Ankur Sharma, Hestia Mellert, Steve McMahon, Adam P. Dicker, Karen E. Knudsen. RB status alters the response of prostate cancer to ionizing radiation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C15.
Abstract C27: Whole-exome sequencing identifies potential therapeutic targets for castration-resistant prostate cancer
Authors: Menon Roopika , Deng Mario , Boehm Diana , Fend Falko , Boehm Detlef , Biskup Saskia , Perner Sven 
Published: May 2013

Abstract
Aim: Castration resistant prostate cancer (CR-PCa) is the most aggresive form of prostate cancer (PCa) having a poor prognosis, and is a significant therapeutic challenge. The key to the development of novel therapeutic targets for CR-PCa is to decipher the molecular alterations underlying this lethal disease. The aim of our study was to perform whole exome sequencing and gene copy number analysis on 5 CR-PCa/normal paired formalin fixed paraffin embedded (FFPE) samples using the SOLiD4 next generation sequencing platform.
Methods: Genomic DNA was extracted from 5 CR-PCa/normal paired FFPE samples. The DNA was subjected to targeted exon capture using the Agilent Sure Select kit. The captured DNA was sequenced using the SOLiD4 next generation sequencing platform. The sequencing output was mapped, sorted, filtered and annotated using well-known human genome databases. The results were further analyzed for SNPs and copy number variations. A set of amplified/deleted genes were validated using fluorescence in-situ hybridization (FISH) assays with a PCa progression cohort. The cohort consisted of 138 cases for localized cancer, 105 patients with primary PCa and corresponding LN metastasis, and 39 samples for castration resistant tumors.
Results: Whole exome sequencing analysis identified focal regions of deletion, which included well-known tumor suppressors such as NKX3.1 and PTEN. Focal regions of amplification included well-known genes such as CMYC and AR that are known to play a role in PCa. Furthermore, we identified several amplified genes as druggable targets e.g. HDAC6, NTRK1, PLD1, SPHK1, and SIRT7. NTRK1 is a kinase that plays an active role in cell proliferation. HDAC6, PLD1, SPHK1 and SIRT7 regulate numerous complex cellular processes including signal transduction, transcription and apoptosis.
Conclusions: This is the first study to use whole exome sequencing approaches on FFPE CR-PCa material to identity novel therapeutic targets. Validation studies would further shed light into the biological understanding of the disease and its plausible treatment options.
Citation Format: Roopika Menon, Mario Deng, Diana Boehm, Falko Fend, Detlef Boehm, Saskia Biskup, Sven Perner. Whole-exome sequencing identifies potential therapeutic targets for castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C27.
Abstract C29: Prostate cancer detection and localization with diffusion-weighted imaging and 1H-MR spectroscopy
Authors: Singh Akash 
Published: May 2013

Abstract
Diffusion-weighted imaging (DWI) of the human with 1.5T MRI gives the insight of Prostate Cancer Tissue details. DWI is now used also for other Liver, Kidney, and Heart Imaging than the brain, and especially focused on detection of Cancer Tissues in prostate.1H-MR spectroscopy technique is used to detect and localize prostate cancer. One difficult sight of 1.5T prostate spectroscopy is the use of a special endorectal coil, it is a thin wire covered with a latex balloon and inserted inside the tail end of the large bowel which is rectum. We detected and identified the prostate cancer by DWI and 3D 1H-MRS with a external phase arrayed multi-coils, this is optimal tumor invasion through bowel wall and adjacent organs.
Note: This abstract was not presented at the conference because the presenter was unable to attend.
Citation Format: Akash Singh. Prostate cancer detection and localization with diffusion-weighted imaging and 1H-MR spectroscopy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C29.
Abstract C38: Whole-genome sequencing of paired androgen-dependent and -independent prostate cancer cell lines: Potential role of novel targets in PI3K and Notch signaling pathways in resistance to hormonal therapy
Authors: Dalgliesh Gillian L. , Hartley Joanne L. , O'Donnell Cary H. , Bradford James R. , McKendrick Iain , Davies Barry R. 
Published: May 2013

Abstract
The growth of the majority of prostate tumors is driven by androgens signaling through the androgen receptor. Most patients initially respond to androgen deprivation therapies such as LHRH analogues and anti-androgens like bicalutamide, but after a varying duration of treatment, patients generally develop resistance to these therapies and their tumor progresses to an androgen independent state. Molecular mechanisms that drive androgen independent disease include mutation and amplification of androgen receptor (AR), androgen-independent activation of AR, and AR-independent mechanisms. The aim of this project was to sequence the entire genome of pairs of cell lines, modeling the progression to androgen independent disease, to increase our understanding of these mechanisms and identify new therapeutic targets. Four ‘parental’ prostate cancer cell lines, all of which are sensitive to hormone deprivation, and an androgen independent derivative of each line, derived either by culturing in bicalutamide or growing in the absence of androgens, were subjected to whole genome sequencing. Genomic variants present in the androgen independent but not the parental lines, presumed to be acquired during the progression to androgen independence, were then identified. To find any commonality between the four different pairings, the derived variants were then mapped to functional biological pathways and their likely impact on protein function predicted. Interestingly, derived mutations in the PI3K and Notch signaling pathways were identified in multiple cell lines. In addition to the analysis of derived mutations, baseline characterization of genomic rearrangements and copy number changes in cell lines highlighted variability in the patterns and prevalence of these events as well as uncovering aberrations in genes known to impact prostate cancer development (PTEN, AR, TMPRSS2 rearrangement). This extensive genome sequencing effort has yielded a deeper understanding of potential pathways and molecular events that occur during the acquisition of resistance to anti-androgen therapy, using in vitro models of prostate cancer. These candidates now require validation in tissue samples from prostate cancer patients and functional assays.
Citation Format: Gillian L. Dalgliesh, Joanne L. Hartley, Cary H. O'Donnell, James R. Bradford, Iain McKendrick, Barry R. Davies. Whole-genome sequencing of paired androgen-dependent and -independent prostate cancer cell lines: Potential role of novel targets in PI3K and Notch signaling pathways in resistance to hormonal therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C38.
Abstract C40: Large-scale isolation of prostate cancer cells by combining leukapheresis and elutriation with chemoaffinity capture
Authors: Wu Lisa Y. , Abernathy Dana E. , Liu TianCheng , Van Wie Bernard J. , Davis William C. , Berkman Clifford E. 
Published: May 2013

Abstract
Circulating tumor cells (CTCs) in the peripheral blood are shed from either the primary tumor or its metastases. These disseminated CTCs are directly responsible for the most cancer deaths and the major cause of prostate cancer-related mortality. Therefore, the earlier detection of CTCs and the ability to remove CTCs from circulation could result in more positive patient outcomes. However, capturing low abundant CTCs from peripheral blood remains a challenge. The cell-surface enzyme prostate-specific membrane antigen (PSMA) is an important biomarker in prostate cancer research. Its upregulation on prostate tumor cells has attracted significant attention as a target for imaging and therapeutic agents. We recently developed a technology to enrich CTCs from a large blood volume by combining apheresis and elutriation technologies with a CTC selection technology based on immobilized high-affinity irreversible PSMA inhibitor. The commercial centrifugal apheresis and elutriation processes can concentrate PCTCs from large blood volumes in a standard elutriator. In this presentation, we will describe a selective and sensitive methodology to enrich, capture, and quantify metastatic prostate cancer cells.
Citation Format: Lisa Y. Wu, Dana E. Abernathy, TianCheng Liu, Bernard J. Van Wie, William C. Davis, Clifford E. Berkman. Large-scale isolation of prostate cancer cells by combining leukapheresis and elutriation with chemoaffinity capture [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C40.
Abstract C42: Predicting prostate cancer aggressiveness and progression using a new quantitative nanoparticle assay
Authors: Huo Qun , Litherland Sally , Decker David 
Published: May 2013

Abstract
Background: Over-diagnosis and treatment of prostate cancer has been a major problem in prostate cancer care and management. Currently the most relevant prognostic factor to predict a patient's risk of death due to prostate cancer is the Gleason score of the biopsied tissue samples. However, pathological analysis is subjective, and the Gleason score is only a qualitative estimate of the cancer malignancy. Molecular biomarkers and diagnostic tests that can accurately predict prostate tumor aggressiveness are rather limited.
Method: We report here for the first time a nanoparticle test that not only can distinguish prostate cancer from normal and benign conditions, but also is capable of predicting the aggressiveness of prostate cancer quantitatively. To conduct the test, a prostate tissue lysate sample is spiked into a pure human IgG protein solution and the spiked sample is incubated with a citrate-protected gold nanoparticle solution. IgG is known to adsorb to citrate-protected gold nanoparticles to form a “protein corona” on the nanoparticle surface. From this study, we discovered that certain tumor-specific molecules can interact with IgG and change the adsorption behavior of IgG to the gold nanoparticles. This change is reflected in the nanoparticle size of the assay solution and detected by a dynamic light scattering technique. Assay data were analyzed by one-way ANOVA for multiple variant analysis, and using the Student t-test or nonparametric Mann–Whitney U-tests for pairwise analyses.
Results: IgG solutions spiked with prostate tumor tissue exhibit significantly smaller nanoparticle size than the solutions spiked with normal and benign tissues. An inverse, quantitative correlation of the average nanoparticle size of the assay solution with tumor status and histological diagnostic grading was observed from the nanoparticle test. The higher grade the tumor is, the smaller the nanoparticle size is. The test particularly revealed large differences among the intermediate Grade 2 tumors, and suggested the necessity to treat them differently.
Conclusion: The new nanoparticle test provides a quantitative measure of the prostate cancer aggressiveness. The test is easy to conduct, requires less than 5 μL of tissue lysate samples, and results are obtained in less than 10 minutes. It can be easily adapted for clinical application using the current needle-biopsy sampling system. This test will provide a more accurate tool to distinguish aggressive cancer from indolent tumor than the current diagnostic practices, if successfully validated by large cohort clinical studies.
Citation Format: Qun Huo, Sally Litherland, David Decker. Predicting prostate cancer aggressiveness and progression using a new quantitative nanoparticle assay [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C42.
Abstract C44: The identification and characterization of androgen-independent cells prior to hormonal manipulation in prostate cancer
Authors: Terada Naoki , Shiraishi Takumi , Zeng Yu , Aw-Yong Koh-Meng , Mooney Steven M. , Luo Jun , Kulkarni Prakash , Getzenberg Robert H. 
Published: May 2013

Abstract
Introduction and Objectives: The Mechanisms contributing to androgen-independent progression in prostate cancer (PCa) are not fully elucidated. PCa lesions are heterogeneous and thus, it is important to understand whether among the heterogeneous collectives of cell types, androgen-independent cells exist prior to hormonal manipulation. The identification of these cells may predict patient prognosis as well as provide a better understanding of treatment resistance.
Methods: LNCaP cells (10,000 cells in 10cm dish) were grown for 40 days in normal medium. Fifty colonies were selected and 22 subclones were established. To compare their androgen-dependence, six of these clones were grown in normal and androgen-depleted medium and their cell proliferation rates were examined. Between an androgen-dependent clone (LNCaP-ADc) and an androgen-independent clone (LNCaP-AIc) gene copy number and gene expression were compared using Human SNP array 6.0 and Human Genome U133 Plus 2.0, respectively. One of the genes differentially expressed between these clones was knocked down by siRNA in LNCaP cells and the influence on cell proliferation was evaluated. The expression levels of this gene in PCa tisssue samples were examined by real-time PCR.
Results: Cell proliferation was significantly suppressed by androgen depletion in LNCaP-ADc, but not in LNCaP-AIc. Gene copy numbers were different at 1q (ADc&lt;AIc) and 15q (ADc&gt;AIc), indicating that these clones contain genetic differences. The most differentially expressed gene was SPRY1 (ADc&gt;AIc, ratio=5.699). Knocking down of SPRY1enhanced proliferation and PSA expression of LNCaP cells. SPRY1 expression in PCa tissues were negatively associated with PSA recurrence after surgical treatment (p=0.0076).
Conclusions: A random population of LNCaP cells comprises a genetically heterogeneous group of cells that have different levels of androgen dependence. Included among them are those that appear to be able to be resistant to androgen depletion. Among the changes associated with this independence, SPRY1 appears to be differentially expressed in such clones and may represent a novel biomarker for differentiating aggressive cells in PCa.
Citation Format: Naoki Terada, Takumi Shiraishi, Yu Zeng, Koh-Meng Aw-Yong, Steven M. Mooney, Jun Luo, Prakash Kulkarni, Robert H. Getzenberg. The identification and characterization of androgen-independent cells prior to hormonal manipulation in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C44.
Abstract C47: Quantitative mass spectrometry reveals that enzymes of the ketogenic pathway are upregulated during high-grade prostate cancer
Authors: Saraon Punit , Jarvi Keith , Diamandis Eleftherios P. 
Published: May 2013

Abstract
Prostate cancer is the most common malignancy and the second leading cause of cancer related deaths in men. One common treatment is androgen-deprivation therapy, which reduces symptoms in most patients. However, over time, patients develop tumors that are androgen-independent and ultimately fatal. The mechanisms that cause this transition remain largely unknown, and as a result, there are no effective treatments against androgen-independent prostate cancer. As a model platform, we used the LNCaP cell line, and its androgen independent derivative, LNCaP-SF. By using stable isotope labeling with amino acids in cell culture (SILAC) coupled to mass spectrometry, we assessed the differential global protein expression between the two cell lines. Our proteomic analysis resulted in the quantification of 3355 proteins, in total. Bioinformatic prioritization resulted in 42 up-regulated and 46 down-regulated proteins in LNCaP-SF cells, compared to LNCaP cells. Our top candidate was HMGCS2, an enzyme involved in ketogenesis, was found to be 9-fold elevated in LNCaP-SF cells, based on peptide ratios. After analyzing the remaining enzymes of this pathway (ACAT1, BDH1, HMGCL, OXCT1), we observed increased expression of these proteins in the LNCaP-SF cells. This was further verified using western blotting, indicating the importance of this pathway during the progression of prostate cancer to androgen-independence. To determine whether these enzymes are up-regulated in clinical samples, we performed qPCR analysis on human prostate cancer tissues, from which we observed significantly increased transcript levels of HMGCS2 (p&lt;0.05), OXCT1 (P&lt;0.05), ACAT1 (p&lt;0.001), and BDH1 (p&lt;0.001). In addition, the protein expression of all five ketogenic pathway enzymes was elevated in high grade prostate cancer (Gleason Grade &gt;8) based on immunohistochemistry analysis. ACAT1 displayed the most prominent protein expression patterns, as it exhibited very minimal staining in normal samples, moderate levels in low grade cancer, and high expression during high grade disease. Further assessment of ACAT1 expression demonstrated significantly greater ACAT1 expression in bone metastatic lesions (P&lt;0.001). Altogether, our results indicate that enzymes belonging to the ketogenic pathway become up-regulated during high grade prostate cancer, and could serve as potential biomarkers for diagnosis of high grade disease.
Citation Format: Punit Saraon, Keith Jarvi, Eleftherios P. Diamandis. Quantitative mass spectrometry reveals that enzymes of the ketogenic pathway are upregulated during high-grade prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C47.