The Role of Prostate Specific Membrane Antigen in Prostate Cancer and Pathologic Angiogenesis in Vivo PDF Download
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Author: Christina Lee Grant
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages :
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Book Description
The Prostate Specific Membrane Antigen (PSMA) transmembrane peptidase is highly expressed on endothelial cells of tumor vasculature and on epithelial cells in advanced and metastatic prostate carcinoma where its expression correlates with tumor progression. While the expression pattern of PSMA makes it a potentially attractive target for therapeutic development, the precise function of PSMA in either tumor associated endothelium or prostate epithelial cells is not clear. PSMA has been shown to be significantly and universally up-regulated on the vasculature of solid tumors, while it is absent in normal, quiescent vessels suggesting it may play a role in pathologic angiogenesis. Inhibiting the enzymatic activity of PSMA leads to a decrease in endothelial cell adhesion, invasion and migration in vitro, processes which are necessary for angiogenesis. Taken together, these findings suggest that PSMA may play a role in angiogenesis in vivo. We examined tumor initiation, growth and metastasis in a transgenic model of tumor progression in wild-type and PSMA-null animals. We also investigated the relative contribution of tumor vs. endothelial PSMA expression using PSMA positive tumor allografts into wild type or PSMA null mice, and show that PSMA expression on endothelial cells is necessary for tumor angiogenesis. We also showed that PSMA contribution to pathologic angiogenesis was not restricted to tumor angiogenesis, using a mouse model of retinopathy of prematurity to show that PSMA function changes outcome in this model. Understanding the contribution of PSMA to angiogenesis progression will further understanding of diseases involving pathologic blood vessel growth. While angiogenesis occurs during normal development and in healing wounds, it is also involved in processes which involve the growth of new blood vessels, such as tumor growth and metastasis and the pathologic overgrowth of vessels into the eye which often results in blindness. Better understanding of the molecules regulating this process may lead to new therapies for tumor metastasis and for diseases involving detrimental angiogenesis.
Author: Christina Lee Grant
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages :
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Book Description
The Prostate Specific Membrane Antigen (PSMA) transmembrane peptidase is highly expressed on endothelial cells of tumor vasculature and on epithelial cells in advanced and metastatic prostate carcinoma where its expression correlates with tumor progression. While the expression pattern of PSMA makes it a potentially attractive target for therapeutic development, the precise function of PSMA in either tumor associated endothelium or prostate epithelial cells is not clear. PSMA has been shown to be significantly and universally up-regulated on the vasculature of solid tumors, while it is absent in normal, quiescent vessels suggesting it may play a role in pathologic angiogenesis. Inhibiting the enzymatic activity of PSMA leads to a decrease in endothelial cell adhesion, invasion and migration in vitro, processes which are necessary for angiogenesis. Taken together, these findings suggest that PSMA may play a role in angiogenesis in vivo. We examined tumor initiation, growth and metastasis in a transgenic model of tumor progression in wild-type and PSMA-null animals. We also investigated the relative contribution of tumor vs. endothelial PSMA expression using PSMA positive tumor allografts into wild type or PSMA null mice, and show that PSMA expression on endothelial cells is necessary for tumor angiogenesis. We also showed that PSMA contribution to pathologic angiogenesis was not restricted to tumor angiogenesis, using a mouse model of retinopathy of prematurity to show that PSMA function changes outcome in this model. Understanding the contribution of PSMA to angiogenesis progression will further understanding of diseases involving pathologic blood vessel growth. While angiogenesis occurs during normal development and in healing wounds, it is also involved in processes which involve the growth of new blood vessels, such as tumor growth and metastasis and the pathologic overgrowth of vessels into the eye which often results in blindness. Better understanding of the molecules regulating this process may lead to new therapies for tumor metastasis and for diseases involving detrimental angiogenesis.
Author: Christina Lee Grant
Publisher:
ISBN:
Category :
Languages : en
Pages : 228
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Book Description
Author: Ravikumar Aalinkeel
Publisher: Nova Science Publishers
ISBN: 9781611229752
Category : Neovascularization
Languages : en
Pages : 0
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Book Description
Prostate specific antigen (PSA) is a serine protease present in an enzymatically inactive form in human serum at a concentration of nanograms/ml; serum PSA (S-PSA) is used widely as a surrogate marker in the diagnosis and management of prostate cancer (CaP). However, the vast majority of PSA produced in the prostate is secreted as active enzyme into the seminal fluid or is sequestered within the prostate tissue microenvironment. This book examines the role of the prostate-specific antigen in prostate tumour growth.
Author: Rebecca Elisabeth Conway
Publisher:
ISBN: 9781109909265
Category :
Languages : en
Pages : 147
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Book Description
Prostate Specific Membrane Antigen (PSMA), a transmembrane peptidase classically expressed in prostate cancer, is also up-regulated in the vasculature of solid tumors. However, its functional contribution to angiogenesis has not been previously studied. Therefore, we investigated whether PSMA is required for angiogenesis in vivo. We demonstrate that growth factor-induced neovascularization is drastically reduced in PSMA-null animals compared to wild type littermates in the Matrigel implant model, suggesting that PSMA is necessary during angiogenesis. To elucidate the mechanisms governing this process, we assessed endothelial cell function in response to loss of PSMA activity or expression; we find that PSMA specifically regulates endothelial cell invasion by modulating laminin-specific integrin activity. Signaling pathways downstream of integrins are also modulated by PSMA, including activation of focal adhesion kinase (FAK) and p21-activated kinase (PAK-1). Interestingly, we find that mechanism during endothelial cell invasion. We hypothesize that the actin binding protein filamin A mechanistically links PAK to PSMA regulation; our data support this idea, as PSMA interacts with filamin A in endothelial cells to regulate invasion. Because filamin A is a known substrate of PAK, and phosphorylation of filamin modulates its interaction with cell-surface proteins, we propose that PSMA-activated PAK phosphorylates filamin A. PAK-mediated filamin A phosphorylation could result in reduced interaction with PSMA, thus decreasing PSMA activity and supporting productive motility by carefully modulating activation of the migratory machinery of the cell. The results of the current study implicate PSMA as an important contributor to angiogenesis and describe a novel mechanism for PSMA in this process.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 21
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Book Description
Prostate Specific Membrane Antigen, PSMA is a type II transmembrane glycoprotein, overexpressed in prostate carcinoma (PCa) including androgen sensitive and independent disease, increased in expression with early relapse following therapy. PSMA is a carboxypeptidase with two important enzymatic functions, namely, folate hydrolase and NAALADase. We have used in vitro invasion assays to explore the possible role of PSMA in PCa cells. Androgen dependent PCa lines, which express PSMA endogenously (e.g., LNCaP, CWR22) are less invasive compared to androgen independent PSMA negative PC3 or DU145 cells. Ectopic expression of PSMA in PC3 cells reduced the invasiveness of these cells, suggesting that this reduction in the invasion capability of PSMA expressing cells is due to PSMA expression, not due to intrinsic properties of different cell lines. Expression of PSMA mutants lacking carboxypeptidase activity reduced the impact of PSMA expression on invasiveness. Thus it appears that the enzymatic activity is associated with PSMA's effect on cellular invasiveness. To test our experimental results in vivo, we have further co-expressed PSMA and luciferase reporter gene in highly invasive PC3MM2 lines. We obtained several expressors with high luciferase and PSMA expression. Tumor formation ability and metastatic potential of these lines will be tested in mice.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 38
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Book Description
It is fundamentally important to understand the underlying mechanisms regulating prostate caner (PCa) metastasis. Despite the increased PSMA expression found in more advanced stage of PCa, little is known about the functional role of PSMA in PCa progression. With this founding from the Department of Defense Prostate Cancer Research Program, we have achieved each of these tasks during the course of this project. We have been able to (1) monitor PSMA expression in live PCa cells, (2) examine its function in cell adhesion, (3) establish its role in cell migration, (4) identify fibronetin as a specific extracellular matrix for enhanced PSMA-positive cell attachment, (5) determine the association of PSMA with integrin, a key signaling molecule known to controlling cancer progression and metastasis and (6) characterize its enzymatic activity in regulation of cell attachment and migration. Our work has contributed to new insight into the role of PSMA in PCa progression. Knowledge of PSMA in cell adhesion and migration will have a direct impact on the design of targeted treatment for patients suffering metastatic PCa.
Author: Ushma Doshi
Publisher:
ISBN:
Category :
Languages : en
Pages : 78
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Book Description
Background: Prostate-specific antigen (PSA) is extensively used as a biomarker for early diagnosis and management of prostate cancer. The physiological function of PSA in liquefying the seminal clot is well understood. However, the role of PSA in growth and progression of prostate cancer still remains unknown. PSA has been reported to have anti-angiogenic and anti-tumorigenic activities in both in vitro and in vivo studies. The aim of this study is to examine the effects of PSA on angiogenic growth factor expression in epithelial and endothelial cells. Methods: Column chromatography was used to purify free-PSA (f-PSA) from human seminal plasma. Confluent monolayers of prostate cancer epithelial cell line, PC-3M and endothelial cells, HUVEC were treated with f-PSA at different concentrations and for various time periods. q-PCR studies were performed to determine the changes in expression of various genes that are known to regulate tumor growth and metastasis. The following genes were examined for the above studies: VEGF, KDR, FGF-2, Ang-1, FAK, Twist-1, p38 MAPK, Pim-1 and PTEN. Gene expression studies in PC-3M cells were validated by determining the changes in secreted VEGF protein on f-PSA treatment by ELISA. Results: Treatment with f-PSA suppressed the expression of pro-angiogenic and pro-migratory genes in both cell lines. The optimum treatment conditions in PC-3M cells included 1℗æM or 10℗æM f-PSA treatment for 48 hours. Gene expression in HUVEC cells was significantly inhibited after 24 hours treatment with 10℗æM f-PSA. Dose-dependent response was gene specific. In contrast to VEGF gene expression, there was an increase in secreted VEGF protein on f-PSA treatment. However, this anomaly needs further investigation. Conclusion: f-PSA affects the expression of angiogenic growth factors and genes involved in migration and metastasis in both tumor epithelial cells and vasculature cells. The concentration of f-PSA used for the experiments is relevant since it is similar to PSA concentrations in the extracellular fluid of the prostate and in primary prostate cancer. This study supports the hypothesis that PSA potentially has anti-angiogenic and anti-metastatic activities in prostate cancer.
Author: Carolyn A. Staton
Publisher: John Wiley & Sons
ISBN: 047002934X
Category : Medical
Languages : en
Pages : 410
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Book Description
Angiogenesis, the development of new blood vessels from the existing vasculature, is essential for physiological growth and over 18,000 research articles have been published describing the role of angiogenesis in over 70 different diseases, including cancer, diabetic retinopathy, rheumatoid arthritis and psoriasis. One of the most important technical challenges in such studies has been finding suitable methods for assessing the effects of regulators of eh angiogenic response. While increasing numbers of angiogenesis assays are being described both in vitro and in vivo, it is often still necessary to use a combination of assays to identify the cellular and molecular events in angiogenesis and the full range of effects of a given test protein. Although the endothelial cell - its migration, proliferation, differentiation and structural rearrangement - is central to the angiogenic process, it is not the only cell type involved. the supporting cells, the extracellular matrix and the circulating blood with its cellular and humoral components also contribute. In this book, experts in the use of a diverse range of assays outline key components of these and give a critical appraisal of their strengths and weaknesses. Examples include assays for the proliferation, migration and differentiation of endothelial cells in vitro, vessel outgrowth from organ cultures, assessment of endothelial and mural cell interactions, and such in vivo assays as the chick chorioallantoic membrane, zebrafish, corneal, chamber and tumour angiogenesis models. These are followed by a critical analysis of the biological end-points currently being used in clinical trials to assess the clinical efficacy of anti-angiogenic drugs, which leads into a discussion of the direction future studies should take. This valuable book is of interest to research scientists currently working on angiogenesis in both the academic community and in the biotechnology and pharmaceutical industries. Relevant disciplines include cell and molecular biology, oncology, cardiovascular research, biotechnology, pharmacology, pathology and physiology.
Author: Manfred Wirth
Publisher: Walter de Gruyter
ISBN: 3110807270
Category : Medical
Languages : en
Pages : 220
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Book Description
Author: Gary Cook
Publisher: Springer
ISBN: 3319576240
Category : Medical
Languages : en
Pages : 73
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Book Description
This pocket book explains the significant and well-documented impact that PET/CT can have on the management of prostate cancer through the provision of high-quality evidence regarding function and structure. Up-to-date information is supplied on the relevance of PET/CT to diagnosis, treatment planning, and therapy, including the emerging role of PET/CT with PSMA. Readers will also find clear explanation of the relation of the clinical and pathological background to imaging and the value of PET/CT compared with conventional radiological imaging. The book will be an excellent asset for referring clinicians, nuclear medicine/radiology physicians, radiographers/technologists, and nurses who routinely work in nuclear medicine and participate in multidisciplinary meetings. It is published within the Springer series Clinicians’ Guides to Radionuclide Hybrid Imaging, which presents contributions from professionals worldwide who share a common purpose in promoting nuclear medicine as an important imaging specialty for the diagnosis and management of oncological and non-oncological conditions.
