bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C48: Regulation of expression of CXCL12 and its receptors CXCR4 and CXCR7 by PTEN in prostate cancer
Authors: Conley-LaComb M. Katie , Chen Yong Q. , Kim Hyeong-Reh C. , Cher Michael L. , Chinni Sreenivasa R. 
Published: May 2013

Abstract
Introduction: Expression of the chemokine CXCL12, also known as SDF-1, and its receptors, CXCR4 and CXCR7, are associated with prostate cancer (PC) metastasis. Loss of the tumor suppressor PTEN (phosphatase and tensin homolog) occurs in 30-80% of primary PCs, and up to 50% of PC bone metastases. In mouse models, prostate-specific deletion of PTEN leads to Akt activation and increased expression of CXCR4 and CXCL12. Moreover, the level of PTEN expression is inversely associated with prostate tumorigenesis. Additionally, HIF-1α, a hypoxia-induced transcription factor previously shown to induce expression of CXCR4, is regulated by Akt. Thus, we hypothesize that the PTEN loss-mediated activation of HIF-1α regulates the function of CXCR4 and CXCR7 receptor pathways in PC progression.
Methods: Prostate-specific deletion of floxed exon 5 of PTEN was achieved by Cre recombinase expressed under the control of an androgen-responsive probasin promoter. Stable cell lines developed from PTEN+/+, PTEN+/−, and PTEN−/− murine prostate epithelial cells that were isolated from the prostates of corresponding mice at 8 weeks of age, and the PTEN status in these cell lines was confirmed by genotyping and immunoblot analyses. Subsequently, these cells were treated with inhibitors of the PI3K/Akt pathway, and gene expression was determined by real time PCR.
Results: We found that loss of PTEN resulted in increased expression of CXCR4, CXCR7, and CXCL12, suggesting that loss of PTEN may play a key role in the regulation of these chemokines in prostate cancer. Additionally, expression of HIF-1α was also upregulated upon PTEN loss. Upon treatment of PTEN−/− cells with inhibitors of the PI3K/Akt pathway, the induction of CXCL12 and CXCR7 was reversed, further demonstrating the role of the PTEN regulated pathway in the expression of these genes.
Conclusions: These results suggest a molecular basis for activation of CXCL12 signaling through its receptors in prostate cancer driven by the loss of PTEN through the induction of HIF-1.
Citation Format: M. Katie Conley-LaComb, Yong Q. Chen, Hyeong-Reh C. Kim, Michael L. Cher, Sreenivasa R. Chinni. Regulation of expression of CXCL12 and its receptors CXCR4 and CXCR7 by PTEN 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 C48.
Abstract C50: Regulation of the chemokine receptors CXCR7 and CXCR4 in 3-D culture models of prostate cancer
Authors: Kiss Debra L. , Windus Louisa CE , Avery Vicky M. 
Published: May 2013

Abstract
CXCR7 was recently identified as the second member of the chemokine receptor family to bind stromal derived factor-1α (SDF-1α), a chemokine which is known to influence the establishment of cancer metastasis. Whilst expression of CXCR7 is highly restricted in non-malignant cells, it is widely expressed in many different tumor cell lines. In prostate cancer, a disease known to be highly regulated by the other SDF-1α -binding receptor CXCR4, CXCR7 has been found to regulate cell growth and invasion. In vivo prostate tumor biopsies show a pattern where CXCR7 expression increases with invasive grade, as previously reported for CXCR4. However, there is limited knowledge on the role of CXCR7 and its function in prostate cancer.
In this study, we aim to more thoroughly characterize CXCR7 function across prostate cancer cell lines, in particular its regulation of cell growth and behavior. We will also assess its expression and function in response to its ligands and inhibitors, alongside CXCR4, in order to assess how these receptors are regulated in relation to each other. For this we employ western blotting expression studies, immunocytochemical visualization, and metabolic-based proliferation assays.
Further, we will study the regulation of both CXCR7 and CXCR4 in 3D culture models of prostate cancer cell lines. Our preliminary data from 2D culture suggests that less invasive prostate cancer cell lines express higher levels of CXCR7 than more invasive cell lines, contrary to reports in vivo where CXCR7 expression was seen to increase with invasive grade. We have chosen to assess these aspects in 3D cultures of prostate cancer cell lines to determine whether culturing in 3D permits a phenotype more reflective of what has been reported for CXCR7 expression in prostate cancer in vivo.
Further elucidation of CXCR7 function with respect to CXCR4 will shed light on how these receptors contribute to regulation of the metastatic process in prostate cancer – a process known to be heavily regulated by CXCR4. As CXCR4 has been established as a therapeutic target in prostate cancer, a more detailed knowledge of the CXCR7 receptor with which it shares a partial redundancy may indicate whether combinatorial therapies may be more effective in combating prostate cancer progression.
Citation Format: Debra L. Kiss, Louisa CE Windus, Vicky M. Avery. Regulation of the chemokine receptors CXCR7 and CXCR4 in 3-D culture models of 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 C50.
Abstract C52: Semi-high-throughput whole-animal bioimaging assay identifies novel players in prostate cancer progression
Authors: Singh Ghotra Veerander Paul , H.E Shuning , Bont Hans De , Spaink H.P. , de Water Bob Van , Snaar Jagalska B. Ewa , Danen Erik H.J. 
Published: May 2013

Abstract
Although genetic mouse models for cancer and human tumor cell xenotransplantation models in rodents remain essential, such systems are costly, slow, and not amenable to high-throughput assays for cancer drug target discovery. There is a clear need to develop fast, semi-automated in vivo systems for medium to high-throughput screening applications in preclinical target discovery and lead compound identification. In this study, we developed an automated, semi-high throughput, noninvasive and quantitative platform for imaging one critical aspect of cancer progression, namely tumor cell dissemination, in a zebrafish xenotransplantation model. This is the first semi-automated whole organism based bio-imaging assay of tumor progression in a vertebrate. We have used this platform to screen for prostate cancer relevant drug and gene targets, and have identified novel regulators of prostate cancer dissemination. Using 3D in vitro invasion assays, we show a critical role for these molecules in prostate cancer migration strategies. Further validation of these targets is underway in mouse models and human cancer specimens.
Citation Format: Veerander Paul Singh Ghotra, Shuning H.E., Hans De Bont, H.P. Spaink, Bob Van de Water, B. Ewa Snaar Jagalska, Erik H.J. Danen. Semi-high-throughput whole-animal bioimaging assay identifies novel players in prostate cancer progression [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 C52.
Abstract C57: The expression of 2′-5′ oligoadenylate synthetase in prostate cancer and its effect on prostate cancer cell cycle
Authors: Mandal Sanjay Kumar , Chaudhary Jaideep 
Published: May 2013

Abstract
2-5 oligoadenylate synthetase (OAS) is an IFN inducible enzyme that is part of innate immune response. During viral infections 2′-5′ OAS is activated by viral dsRNA or cellular RNA with significant double strand structure to synthesize 2-5 oligoadenylates (2-5A) from ATP; which in turn activates RNaseL, the latent ribonuclease. RNAseL degrades infectious RNA which imparts antiviral protection to the cell. OAS-RNaseL system also degrades cellular RNA and inhibits protein synthesis. The role of RNAseL as a tumor suppressor has been studied in prostate cancer cell lines and has been linked to hereditary prostate cancer (HPC). However HPC accounts for less than 9% of the overall prostate cancer incidence but the role of RNAseL in sporadic prostate cancer has not been established. Since OAS1 is the rate limiting enzyme in RNaseL activation, we therefore hypothesized that OAS could potentially act as tumor suppressor in the context of sporadic prostate cancer.
Methods: Immunohistochemistry was performed on human prostate cancer and normal prostate tissue to determine the expression of OAS1. RT-PCR and western blot was performed to detect the expression of OAS1 in LNCaP, DU145 and PC3 cell lines. Two alternative approaches were then used to investigate the effect of OAS1 on cell survival and its potential mechanism of action: OAS1 was over-expressed in LNCaP whereas it was silenced in DU145 cells. Cell cycle and apoptosis was quantitated by FACS analysis and the expression of key regulatory genes was determined by qRT-PCR and western blot analysis.
Results: Immunohistochemistry demonstrated that OAS1 expression is high in the normal prostate but decreased progressively with stage in prostate cancer. OAS1 was not expressed in LNCaP cells but its expression was high in DU145 and PC3 prostate cancer lines. Overexpression of OAS1 in LNCaP cells induced apoptosis and G1 arrest that was associated with increased p53, BAX and p21 expression. Alternatively, silencing of OAS in DU145 cells led to an increase in S phase and G2 cell population with a concomitant decrease in apoptosis.
Conclusion: Our prostate cancer cell line and prostate cancer tissue data strongly suggest that OAS1 is a candidate tumor suppressor that could be used as a potential biomarker for prostate cancer. Moreover, our previous study had shown a link between OAS1 polymorphism and prostate cancer incidence. Collectively data suggest the role of immune/inflammatory pathway in prostate cancer progression.
Citation Format: Sanjay Kumar Mandal, Jaideep Chaudhary. The expression of 2′-5′ oligoadenylate synthetase in prostate cancer and its effect on prostate cancer cell cycle [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 C57.
Abstract C68: Phenotypic and functional heterogeneity of prostate cancer stem cells
Authors: Liu Xin , Chen Xin , Laffin Brian , Yin Binglan , Calhoun-Davis Tammy , Wang-Johanning Feng , Tang Dean G. 
Published: May 2013

Abstract
Recent evidence in many tumor systems suggests that there may exist several or even many tumorigenic subpopulations in each tumor. Utilizing 4 xenograft human prostate cancer (PCa) models, including two AR+/PSA+ (LAPC9 and LAPC4) and two AR-/PSA- (Du145 and PC3) xenografts, and by performing exhaustive limiting-dilution tumor regeneration assays in NOD/SCID mice using purified PCa cells based on functional properties (i.e., side population and Aldefluor assays) or preferential expression of surface markers (ABCG2, CD44, or integrin α2β1), we provide evidence for both the phenotypic and functional heterogeneity of PCa stem cells (i.e., PCa cell subpopulations with enhanced tumor-regeneration activity). Our results show that no single marker or assay seems to be able to capture all tumorigenic subsets in all 4 xenografts. We further show that different tumor-initiating subpopulations appear to co-exist in a common tumorigenic pool. We also demonstrate that some tumorigenic PCa cells overexpress stem cell-associated gene expression profiles. Finally, we provide evidence that primary prostate tumors possess subsets of tumor cells that bear similar phenotypic features to those in xenografts. Our results raise the possibility that different PCa patient tumors may harbor CSCs with distinct phenotypic and functional properties.
Note: This abstract was not presented at the conference because the presenter was unable to attend.
Citation Format: Xin Liu, Xin Chen, Brian Laffin, Binglan Yin, Tammy Calhoun-Davis, Feng Wang-Johanning, Dean G. Tang. Phenotypic and functional heterogeneity of prostate cancer stem cells [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 C68.
Abstract C7: Targeting the androgen receptor with novel combination therapeutic strategies in metastatic/castrate-resistant prostate cancer
Authors: Ellis Leigh , Ramakrishnan Swathi , Ku Shengyu , Pili Roberto 
Published: May 2013

Abstract
While recent advances have resulted in the FDA approval of novel therapies for metastatic/castrate resistant prostate cancer, responses are not often durable and novel therapeutic interventions are still required. Recent work within our laboratory has resulted in the development of a novel orthotopic syngeneic transplant mouse model of prostate cancer. Further, treatment with a HDAC and mTORC1 inhibitor in combination resulted in greater anti-tumor and increased overall survival in tumor bearing animals. HDAC/mTORC1 combination therapy also resulted in decreased androgen receptor (AR) transcriptional activity without loss of AR protein expression. Current investigations are underway to delineate molecular mechanisms underlying sustained AR expression. Through this understanding, novel therapeutic interventions which will augment combined HDAC/mTORC1 inhibitor therapy are under investigation.
Citation Format: Leigh Ellis, Swathi Ramakrishnan, Shengyu Ku, Roberto Pili. Targeting the androgen receptor with novel combination therapeutic strategies in metastatic/castrate-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 C7.
Abstract IA10: Overcoming castration-resistant prostate cancer
Authors: Sawyers Charles L. 
Published: May 2013

Abstract
Resistance to antiandrogen therapy is associated with increased expression of androgen receptor (AR) mRNA, AR gene amplification or AR mutation. Increased AR levels are necessary and sufficient to promote hormone-refractory growth in models and, paradoxically, alter the cellular response to classic AR antagonists such that they function as weak agonists. Therefore, second generation antiandrogens must overcome these resistance mechanisms. We searched for novel AR antagonists that might retain function in the context of increased AR expression through a cell-based screen. Using the high affinity AR agonist RU59063 as a starting point, we synthesized and screened over 200 compounds to construct a structure/activity profile that defines features of the scaffold essential for receptor binding and for maximal antagonism. We focused our further efforts on a novel compound MDV3100, which retains potent antiandrogen activity in cells expressing increased levels of AR, blocks AR function in mice and impairs the growth of LNCaP and LAPC-4 xenografts engineered to express high levels of AR, whereas bicalutamide had minimal activity. MDV3100 inhibits AR with 10-fold greater affinity than bicalutamide and functions through a novel mechanism of action that impairs nuclear translocation and DNA binding. MDV3100 produced sustained PSA responses (greater than 50% reduction) in about ∼55 percent of men with castrate-resistant prostate cancer in a 140 patient phase I-II clinical trial. In a phase III registration study of 1119 men with castration resistance, chemotherapy refractory prostate cancer, MDV3100 prolonged survival compared to best supportive care (18.4 months versus 13.6 months; hazard ratio 0.631).
The heterogeneity of clinical response to anti-androgen therapy suggests additional molecular determinants of drug resistance. By conducting an integrated genomic analysis of 214 prostate cancers, we have defined a common set of molecular lesions and pathways that may define distinct subsets of prostate cancer as well as responder/non-responder populations to antiandrogen therapy. In preclinical models we found that tumors with PTEN loss are relatively insensitive to androgen ablation therapy due to reciprocal negative feedback between the AR and PI3K signaling pathways. PTEN-mediated resistance can be overcome with combined AR + PI3K pathway inhibition. Studies of these and other molecular abnormalities reveal unique features of prostate cancer progression with implications for downstream drug development.
Citation Format: Charles L. Sawyers. Overcoming 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 IA10.
Abstract IA12: Conducting hypothesis testing trials for the treatment of advanced prostate cancer
Authors: de Bono Johann S. 
Published: May 2013

Abstract
There are multiple challenges to the successful development of novel therapeutics for advanced prostate cancer. These include: 1) The identification of novel targets for drug discovery for treating this disease; 2) Intraand inter-patient molecular heterogeneity; 3) The pattern of disease metastases resulting in largely bone disease that is not readily measurable radiologically by standard imaging methods; 4) Difficulty accessing metastatic disease that can be interrogated to elucidate mechanisms of resistance; 5) The widespread use of PSA changes to drive therapeutic decisions; 6) The lack of a proven intermediate endpoint of overall survival to accelerate drug development. Nevertheless, major progress has been made with five novel agents being shown to improve overall survival in this patient population including abiraterone acetate, alpharadin, cabazitaxel, MDV3100 and Sipuleucel T.
Citation Format: Johann S. de Bono. Conducting hypothesis testing trials for the treatment of advanced 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 IA12.
Abstract IA17: Stem cells and prostate cancer
Authors: Witte Owen N. 
Published: May 2013

Abstract
Prostate cancer initiation and progression is associated with a myriad of genetic and epigenetic changes that drives the transformation process in specific cells of origin. Our group has developed a dissociated cell tissue regeneration system in which rodent or human epithelial tissue can be combined with supportive mesenchyme from the urogenital sinus to produce a tissue structure with glandular development. Introduction of specific oncogenic influences can drive normal tissue structure to a malignant histology with invasion and epithelial to mesenchymal transition. An efficient cell of origin from the basal layer of the gland has been defined for mouse and human tissue for this process and can produce malignant glands with luminal characteristics as well as other cellular phenotypes. Recent work has defined a set of changes in the adjacent stroma that can strongly influence the epithelium in its conversion to a cancerous state.
Citation Format: Owen N. Witte. Stem cells and 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 IA17.
Abstract IA18: Altered AR gene architecture and splicing in castration-resistant prostate cancer
Authors: Dehm Scott M. 
Published: May 2013

Abstract
Reactivation of the androgen receptor (AR) during androgen depletion therapy (ADT) underlies castration-resistant prostate cancer (CRPCa). Altered splicing of the AR gene and synthesis of constitutively-active COOH-terminally truncated AR variants lacking the AR ligand binding domain has emerged as an important mechanism of ADT-resistance in CRPCa. To understand mechanisms that may promote synthesis of these species, we have been studying the PCa progression models in which altered AR splicing patterns were originally discovered. Remarkably, these models all harbor distinct intragenic rearrangements in the AR gene, which are linked to their individual splicing signatures. For example, the CRPCa 22Rv1 cell line harbors a 35kb intragenic tandem duplication of AR exon 3 and flanking sequences, which results in expression of an exon 3-duplicated full-length AR and multiple truncated AR variant species. The CRPCa LuCaP 86.2 xenograft harbors an 8,579 bp deletion of AR exons 5, 6, and 7, which promotes synthesis of the truncated AR v567es variant. Targeted paired-end re-sequencing of the AR gene in CWR-R1 cells led to the discovery of a 48 kb deletion in AR intron 1, which is linked to a splice switch favoring synthesis of the AR-V7/AR3 variant. Copy number imbalances occur across the length of the AR gene in clinical CRPCa, often concurrent with amplification, indicating complex patterns of intragenic AR gain and loss in human disease. These findings portend ongoing discovery of diverse truncated AR variants in CRPCa and define a new class of AR gene alterations that may drive ADT-resistance at this stage of the disease.
Citation Format: Scott M. Dehm. Altered AR gene architecture and splicing in 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 IA18.