1,721,410 research outputs found
Abstract 3909: Investigating the role of ANXA2R in metastatic prostate cancer
No full textAbstract
Skeletal metastasis is the most life-threatening complication in prostate cancer. The molecular mechanisms behind the interactions between prostate cancer and the bone marrow premetastatic niche remain unknown. Understanding and preventing such interactions could lead to new promising therapeutic strategies against lethal prostate cancer. Annexin 2 receptor (ANXA2R) was originally identified as a cell surface receptor for Annexin 2 (ANXA2) that mediates the stimulatory effects of ANXA2 during osteoclastic activation and osteoblast mineralization. Moreover, ANXA2R is able to induce apoptosis independent of its ligand, partially through activating caspases using non-conventional apoptotic pathways. Osteoblasts and marrow endothelial cells express ANXA2 which functions as a regulator of hematopoietic stem cell engraftment. Previous studies demonstrated blocking ANXA2 or its receptor prevents prostate cancer cells from establishing bone metastases in mouse models. It has been recently proven that ANXA2R does not bind to ANXA2 directly but to S100A10 present in the complex annexin A2 heterotetramer (AIIt), composed of 2 ANXA2 bound to a S100A10 dimer. Higher levels of ANXA2 and S100A10 are associated with proliferating and invasive cancers and correlate with poor prognosis. However, the loss of ANXA2 expression appears to be specific for prostate cancer. Previous work on prostate cancer has focused solely on ANXA2 as a ligand. In this study, we demonstrate that S100A10 and ANXA2 are co-localized in prostate cancer, and their expression and ANXA2R levels vary with grade in primary tumors as well as within the different metastatic sites. Given prostate cancer cells as well as bone marrow stroma can simultaneously express the ligand and receptor and levels of AIIt decrease with tumor stage in the primary site, we hypothesize prostate cancer cells require S100A10 and not only ANXA2 to spread to bone and other tissues. ANXA2R could act as a dependence receptor, mediating withdrawal-induced programed cell death in prostate cancer cells in the absence of AIIt. Furthermore, AIIt-ANXA2R interactions between prostate cancer cells and the premetastatic bone marrow niche might play an important role in the development of skeletal metastasis by inducing selective pressures on prostate cancer cells to metastasize to the bone marrow which is abundant of AIIt.
Citation Format: Gonzalo Torga, Kenneth J. Pienta. Investigating the role of ANXA2R in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3909. doi:10.1158/1538-7445.AM2017-3909</jats:p
Abstract 4005: HDAC inhibitors regulate M2 tumor-associated macrophage function through histone acetylation
No full textAbstract
Macrophage tumor infiltration in metastatic prostate cancer is a predictor of patient prognosis. Macrophages influence tumors in contrasting ways depending on their polarization: M1 macrophages have anti-tumor functions while M2 macrophages are pro-tumor. The external stimuli influencing macrophage differentiation and M2 polarization have been largely elucidated but the resulting downstream changes remain unknown. There are a number of epigenetic differences between M1 and M2 macrophages that act as important functional determinants. Recent work studying these epigenetic changes has implicated histone deacetylases (HDACs), as critical regulators in macrophage differentiation and in maintaining M1 or M2 function. Pan-HDAC inhibitors (HDIs) such as the clinically utilized suberanilohydroxamic acid (SAHA) target a wide range of HDACs and provide a means for manipulating macrophage histone acetylation. Though HDIs have been found to attenuate inflammatory functions in M1 macrophages, the field has yet to explore effects of histone acetylation in M2 macrophages. Using M2 macrophages derived from human CD14+ monocytes, we found that SAHA regulates M2 macrophage polarization and function through alteration of histone acetylation. Work is ongoing to test expression levels of canonical M2 markers such as the mannose receptor CD206 and scavenger receptor CD163 in M2 macrophages exposed to SAHA either during or after M2 polarization. Additionally, investigation into the ability of these populations to secrete M2 cytokines such as IL-10 and VEG-FA and induce EMT in prostate cancer cells is also being pursued. These results contribute to scientific knowledge of epigenetic regulation in macrophage function and elucidate strategies to decrease the pro-tumor function of tumor-infiltrating M2 macrophages. This work lays the foundation for using epigenetic regulators to modulate the tumor microenvironment and advance cancer medicine.
Citation Format: Amber E. de Groot, Jelani C. Zarif, Kenneth J. Pienta. HDAC inhibitors regulate M2 tumor-associated macrophage function through histone acetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4005. doi:10.1158/1538-7445.AM2017-4005</jats:p
Abstract 903: CXCR4 and CXCR7 play distinct and overlapping roles in prostate cancer dissemination to bone
No full textAbstract
Approximately 28,000 men die of prostate cancer (PCa) each year in the US, and 90-100% of them will be due to bone metastasis. It has been demonstrated that PCa cells detach from the primary tumor and “home” to bone. Osteoblasts (bone-forming cells) secrete the chemoattractant stromal-derived factor 1 (SDF-1, also known as CXCL12), and PCa cells express the receptors for SDF-1, C-X-C chemokine receptors 4 and 7 (CXCR4 and CXCR7). PCa cells use these receptors to enter the chemoprotective bone microenvironment, specifically, the hematopoietic stem cell (HSC) niche in the endosteum. While small molecule inhibition of CXCR4 can mobilize PCa cells from the bone marrow microenvironment, it is unknown whether CXCR7 plays a compensatory role when CXCR4 is antagonized. SDF-1 is known to bind with greater affinity to CXCR7 compared to CXCR4 indicating a possible role of CXCR7 in tumor migration to the endosteal niche. Therefore, it is crucial to determine the individual and combined roles of CXCR4 and CXCR7 in the formation and treatment of PCa bone metastases. To answer these questions, first we assessed CXCR4 and CXCR7 expression across a panel of prostate cancer cell lines. We then transiently overexpressed and knocked down CXCR4 and CXCR7 in PCa cells and found CXCR4 and CXCR7 expression in vitro to directly correlate to cell viability and migration in PC3 PCa cells. To further test dissemination and metastasis in bone, we are making stable overexpression and knockout cells and will perform in vivo metastasis experiments. We have developed a novel immunofluorescence protocol for detecting and quantifying tumor cells in murine blood and bone marrow and will use this technique to determine the ability of PCa cells to disseminate to bone in the presence or absence of CXCR4 and/or CXCR7. This will be quickly translatable because we are currently running a first-in-prostate cancer clinical trial to determine whether small molecule inhibition of CXCR4 to mobilize PCa tumor cells from the bone marrow, combined with docetaxel, will benefit metastatic PCa patients. If we determine that CXCR7 plays a compensatory role in dissemination and/or metastasis, we will need to add CXCR7 inhibition to our treatment strategy to obtain the most efficient benefit for patients.
Citation Format: Sounak Roy, Kenneth C. Valkenburg, Kenneth J. Pienta. CXCR4 and CXCR7 play distinct and overlapping roles in prostate cancer dissemination to bone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 903. doi:10.1158/1538-7445.AM2017-903</jats:p
Abstract 853: C1orf116, a gene with unknown function, is a novel driver of epithelial phenotype in epithelial-to-mesenchymal transition in human cancer
No full textAbstract
Metastatic prostate cancer is an incurable lethal disease and is the cause of death for 28,000 men in the US annually. In order for a cancer cell to metastasize from the primary tumor, it must move. In a critical early event of metastasis, a rare population of cells in the primary tumor undergoes a phenotype switch from a proliferating epithelial cell to gaining the migratory capacity of a mesenchymal cell, a process, termed epithelial-to-mesenchymal transition (EMT). To identify previously overlooked regulators of EMT, we undertook a multi-study gene expression array analysis (15 published gene expression studies; 95 total samples; 6 cancer types) and identified C1orf116 as a candidate driver of the epithelial phenotype in EMT across multiple cancer types.
Of note, C1orf116 is an unnamed gene of unknown function that is largely uncharacterized in any setting, including in cancer biology or in EMT.
To substantiate its potential role in EMT, we queried the NCI-60 cell line collection gene expression dataset and found that C1orf116 shared a similar expression pattern with epithelial marker genes (ESRP1, ESRP2, OVOL1, OVOL2) and a converse expression pattern to mesenchymal marker genes (CDH2, SNAI2, VIM). Moreover, we found that C1orf116 expression is decreased in metastatic prostate cancer tumors compared to localized disease (Oncomine), suggesting the potential for clinical translation.
To specifically interrogate the role of C1orf116 in EMT, we utilized the PC3 cell line, an in vitro model of prostate cancer EMT. We found that C1orf 116 expression was higher in an epithelial PC3 cell line (PC3-epi) compared to PC3 cells that had undergone a stable EMT (PC3-emt). Moreover, shRNA-mediated knockdown of C1orf116 expression in PC3-epi cells resulted in decreased gene expression of canonical epithelial markers (OVOL1, ESRP1, CDH1) and elevated expression of standard mesenchymal markers (CDH2, ZEB1, VIM), suggesting a role as a driver of the epithelial phenotype.
Interestingly, the sole publication specifically studying C1orf116 describes it as Specifically Androgen Regulated Gene (SARG). The authors demonstrate the presence of an androgen response element upstream of the C1orf116 start site the in androgen-responsive prostate cancer cell line LNCaP. Our data indicate a role for C1orf116 in the androgen receptor-negative prostate cancer cell line PC3, suggesting a non-androgen-mediated role for C1orf116 in prostate cancer.
In addition to elucidating its role in EMT, work is underway to characterize the RNA and protein products of C1orf116. Alternative splicing results in two transcripts of varying length that likely give rise to at least two protein product sizes. RNA sequencing and mass spectrometry will reveal transcript and protein identity and provide insight into potential isoform switching regulating EMT and other processes.
Citation Format: Sarah R. Amend, James Hernandez, Princy Parsana, Kenneth J. Pienta. C1orf116, a gene with unknown function, is a novel driver of epithelial phenotype in epithelial-to-mesenchymal transition in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 853. doi:10.1158/1538-7445.AM2017-853</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Abstract B06: Targeting M2-Tumor Associated Macrophages (M2-TAMs) in prostate cancer
No full textAbstract
Prostate cancer is a leading cause of cancer-related deaths of men in the U.S., and in the past year, over 30,000 men died from this disease. While localized prostate cancer is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Alternatively activated macrophages, also known as M2-macrophages, primarily scavenge debris and in the process, promote angiogenesis and wound repair. M2-macrophages are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors such as prostate cancer to facilitate epithelial to mesenchymal transition (EMT), tumor invasiveness, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. The purpose of this project is to develop novel therapeutics that will directly target M2-TAMs for destruction and subsequently attenuate prostate tumor growth, progression, and metastasis. Our hypothesis is to determine if targeting of M2-TAMs by using enriched surface antigens that are targeted by antibody-drug-conjugates (ADCs), be an effective therapy for lethal prostate cancer while simultaneously eliciting an immune response. To identify novel surface antigens expressed on M2-macrophages, we developed a novel method of creating homogenous populations of human macrophages from CD14+ monocytes in vitro. Our homogenous M1 macrophages secrete pro-inflammatory cytokines and our M2 macrophages secrete anti-inflammatory cytokines as well as VEGF. We then performed solid-phase extraction of N-linked glycopeptides (SPEG) followed by liquid chromatography-tandem Mass Spectrometry (LC-MS/MS) on our homogenous macrophage populations. We discovered six novel peptides that are enriched exclusively on M2-macrophages relative to M1 macrophages and CD14+ monocytes. Lastly, we determined if these surface antigens, found enriched on M2 macrophages, were also expressed in human metastatic castrate-resistant prostate cancer (mCRPC). Using mCRPC tissues from rapid autopsies supplied by the Departments of Urology and Surgical Pathology, we were able to determine M2-macrophage infiltration by using immunohistochemistry and flow cytometry. The studies described here outline a method of altering the tumor immune microenvironment. By identifying specific markers on M2-TAMs, we predict that this method of targeting will provide a better prognosis for patients who have been diagnosed with lethal prostate cancer.
Citation Format: Jelani C. Zarif, James R. Hernandez, Weiming Yang, Hui Zhang, Kenneth J. Pienta. Targeting M2-Tumor Associated Macrophages (M2-TAMs) in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B06.</jats:p
Abstract 4945: Axl-hi DTCs in the bone marrow of a genetically engineered mouse model of prostate cancer exhibit decreased proliferation
No full textAbstract
The majority of prostate cancer (PCa) deaths are attributed to bone metastases, which may not arise until years after the primary tumor has been removed. Disseminated tumor cells (DTCs) have been shown to already be present in the bone marrow of patients at the time of prostatectomy, and it is thought that they undergo a period of dormancy, allowing them to remain undetected for years before manifesting into clinically detectable metastases. It is not known what allows PCa DTCs to undergo and persist in this dormant state, but it is likely that factors in the bone marrow niche play an essential role. Previously our group has shown that one of these niche factors, Gas6, can regulate growth of PCa cells. The growth restraining effects of Gas6 on PCa cells is likely mediated through the tyrosine kinase receptor Axl, whose expression was found to be increased on dormant DTCs compared to proliferating metastases in a xenograft mouse model. Here, we utilized the TRAMP model, a genetically engineered mouse model of spontaneous PCa progression, to compare the frequency of Axl-hi and Axl-low bone marrow DTCs that are proliferating versus non-proliferating. Further, we also compared Axl expression and proliferation in matched primary tumors. To investigate the functional significance of Gas6/Axl signaling in mediating PCa dormancy, we have generated Axl knockout PCa cells to test the requirement of Axl in maintaining dormancy, and Axl overexpressing PCa cells to test the sufficiency of Axl in mediating dormancy. Determining the role of Axl and any other regulatory mechanisms of PCa DTC dormancy will be crucial in efforts to prevent lethal and incurable metastasis.
Citation Format: Haley D. Axelrod, Kenneth C. Valkenburg, Brian W. Simons, Kenneth J. Pienta. Axl-hi DTCs in the bone marrow of a genetically engineered mouse model of prostate cancer exhibit decreased proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4945. doi:10.1158/1538-7445.AM2017-4945</jats:p
Abstract 3053: Stability and stemness of the hybrid epithelial-mesenchymal phenotype
No full textAbstract
Transitions between epithelial and mesenchymal phenotypes – EMT and MET – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During these transitions, cells can also adopt a hybrid epithelial/mesenchymal (hybrid E/M) phenotype enabling them to migrate collectively as observed during gastrulation, wound healing, and clusters of Circulating Tumor Cells (CTCs). The hybrid E/M phenotype has largely been tacitly assumed to be 'metastable', i.e. transient state. Here, we integrate mathematical modeling with in vitro experiments to identify certain 'phenotypic stability factors' (PSFs) - GRHL2, OVOL2 and ΔNP63α that can stabilize a hybrid E/M phenotype. We show that H1975 (NSCLC cell line) cells can display a hybrid E/M phenotype stably and migrate collectively, a behavior that is impaired by knockdown of GRHL2 or OVOL2. Further, our computational model predicts that these PSFs can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of one or more of these PSFs may predict poor patient outcome. Overall, our results suggest that a hybrid E/M phenotype need not be 'metastable', and bolster the notion that a hybrid E/M phenotype, but not necessarily full EMT, associates with aggressive tumor progression.
Citation Format: Mohit Kumar Jolly, Dongya Jia, Satyendra C. Tripathi, Steve Mooney, Muge Celiktas, Samir M. Hanash, Sendurai A. Mani, Kenneth J. Pienta, Eshel Ben-Jacob, Herbert Levine. Stability and stemness of the hybrid epithelial-mesenchymal phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3053. doi:10.1158/1538-7445.AM2017-3053</jats:p
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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