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Author : Aubie Shaw
Publisher :
ISBN 13 :
Total Pages : 162 pages
Book Rating : 4.:/5 (891 download)
Download or read book Stromal-epithelial Hedgehog Signaling in Prostate Cancer written by Aubie Shaw and published by . This book was released on 2007 with total page 162 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : Yu-Ching Peng
Publisher :
ISBN 13 :
Total Pages : 232 pages
Book Rating : 4.:/5 (96 download)
Download or read book Hedgehog Signaling in Prostate Regeneration and Cancer written by Yu-Ching Peng and published by . This book was released on 2014 with total page 232 pages. Available in PDF, EPUB and Kindle. Book excerpt: Sonic hedgehog (SHH) signaling regulates adult stem cells in many self-renewing organs and its dysregulation has been linked to a variety of epithelial cancers. However, whether SHH signals to adult stem cells in the prostate and what cell types SHH signals to in prostate cancer have been unclear. In my thesis work, I found that in the adult mouse prostate SHH signals from prostate basal epithelial cells to adjacent stromal cells. Using molecular marker expression and cell location, I classified stoma cells into four subtypes. Furthermore, I showed that the SHH target gene Gli1 is preferentially expressed in the subtype closest to the epithelial source of SHH, namely subepithelial fibroblast-like cells. Using Genetic Inducible Fate Mapping (GIFM) to mark adult Gli1 - or Smooth muscle actin -expressing cells and follow their fate during regeneration, we found that Gli1 -expressing cells exhibit long-term self-renewal capacity during multiple rounds of androgen-mediated regeneration after castration-induced involution, and that smooth muscle cells depleted after castration are mainly replenished by preexisting smooth muscle cells. Based on these studies, I propose a model where in SHH signals to multiple stromal stem cells that are largely unipotent in vivo . We then characterized Gli1-expressing and Shh -expressing cells in two mouse models of prostate cancer. I found that Gli1 is expressed in cancer-associated stromal cells, with an enrichment in Cancer-Associated Fibroblasts (CAFs), whereas Shh is expressed in rare basal-like epithelial cells, indicating a paracrine mode of action of HH signaling in prostate cancer. Moreover, fate mapping demonstrated that a significant proportion of CAFs originate from smooth muscle cells. Since CAFs express a high degree of Gli1 , I tested whether aberrant activation of HH signaling in the stroma can alter stromal development and induce prostate cancer. I found that over-activation of HH signaling in the stroma is not sufficient to alter the epithelium and generate prostate cancer, although it does lead to disorganization of the smooth muscle layers with widened spaces between smooth muscle cells. In summary, my thesis research has revealed that HH signaling is active in stromal stem cells in the adult prostate and in CAFs in prostate cancer.
Author :
Publisher :
ISBN 13 :
Total Pages : 19 pages
Book Rating : 4.:/5 (318 download)
Download or read book Sonic Hedgehog Signaling in Normal Prostate Stem Cells and Prostate Cancer Stem Cells written by and published by . This book was released on 2008 with total page 19 pages. Available in PDF, EPUB and Kindle. Book excerpt: As an approach to identify potential Shh-responding stem cells in the mouse prostate, we used Genetic Inducible Fate Mapping (GIFM) to follow the fate of Shh-responding cells both during prostate development and during androgen-mediated regeneration of the gland in the adult, two processes that are driven by stem or progenitor cell expansion. As Gli1 expression is a sensitive readout of Shh signaling, we used a Gli1CreER allele and Rosa26 reporter to fate map Shh-responding cells. We show that Shh-responding cells do not expand over time in the normal homoeostatic prostate, but these same cells do expand massively after androgen-mediated regeneration, indicating that Shh-responding cells are normally quiescent, but retain the ability to expand in the adult prostate. The expansion of cells is confined to stromal fibroblasts and smooth muscle cells; no glandular epithelial cells are marked. These results indicate that Gli1 either specifically marks stromal stem cells that expand during regeneration to give rise to the two stromal cell types, or that fibroblasts and smooth muscle cells in general have a high capacity for proliferation even in the adult prostate. To determine whether the marked Shh-responding cells have the capacity for selfrenewal, we subjected Gli1CreER ; Rosa26 mice to eight cycles of prostate involution and regeneration. Cells marked before castration expand after 8 cycles of involution/regeneration, indicating that the initially marked Shh-responding cells are self-renewing. Additionally, using Gli1 null mutant mice, we demonstrate that Gli1 is required to drive stromal expansion during prostate regeneration. Based on our results, we propose a model wherein Shh is expressed in adult prostate epithelial cells, the signal is received by the adjacent stroma, which responds by expressing critical genes, including the transcription factor Gli1, that result in expansion of the two stromal cell types.
Author : Sarah Ellen Wilkinson
Publisher :
ISBN 13 :
Total Pages : 538 pages
Book Rating : 4.:/5 (11 download)
Download or read book Stromal Hedgehog Signalling in Prostate Epithelial Cell Transformation written by Sarah Ellen Wilkinson and published by . This book was released on 2012 with total page 538 pages. Available in PDF, EPUB and Kindle. Book excerpt: The stromal microenvironment plays a key role in the normal development of the prostate and in the development of epithelial derived prostate cancer (PCa). A better understanding of how the stroma directs the correct differentiation of prostatic epithelium during development is therefore not only of interest to the developmental biologist, but vital in determining how the microenvironment may be effecting epithelium in diseases such as cancer. PCa can be treated in its early stages, however, many patients regress after treatment, and there is currently no cure for late stage disease. The aim of this thesis was to study the mechanisms of stromal mediated epithelial transformation in both development and disease, with the goal of informing better treatment options for PCa. The Hedgehog (Hh) signalling pathway is active during prostate development, and this thesis shows it is also involved in prostatic stromal mediated lineage transformation of adult epithelial stem cells. The Hh signalling pathway has also been implicated in PCa, however, the mechanisms of its involvement in this disease are still unclear. For this reason, subsequent studies in this thesis focused on the mechanisms of Hh signalling between the stromal and epithelial cellular compartments of the prostate and other tissues during non-malignant epithelial transformations, as well as in carcinogenesis. During epithelial transformation across a developmental germ layer boundary, paracrine Hh signalling occurs with increased downstream target gene expression in adjacent epithelium. On the other hand, Hh downstream target expression was found to be highly active in the PCa stroma, and may therefore be involved in the ability of PCa associated fibroblasts (known as CAFs) to promote epithelial tumours. This suggests a role for paracrine/stromal-epithelial Hh signalling in an opposite direction to that observed during epithelial transformation, but similar to the activity of Hh signalling in the developing prostate. Current PCa treatments are focused on removing and/or targeting the carcinogenic epithelial tissue in PCa. This thesis highlights the importance of the stroma and its paracrine signals in transforming adjacent epithelium and therefore adds impetus to notion that to treat and prevent recurrence and cancer we cannot just target the cancer itself, but must also target the microenvironment surrounding it. This thesis demonstrates that this microenvironment and its paracrine signals can both initiate epithelial transformations and also be conducive, if not instructive, to epithelial changes associated with malignancy. Implications of this work on PCa treatment may involve blocking stromal Hh signals after radical prostatectomy and/or chemotherapeutic adjuvant therapy of blocking stromal Hh may improve the prognosis of PCa sufferers. Future studies will need to test the efficacy of these approaches in the clinic.
Author : Yeok Loo Agnes Lim
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (886 download)
Download or read book Hedgehog Signaling in Urogenital Regeneration and Neoplasia written by Yeok Loo Agnes Lim and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The Hedgehog (Hh) signaling pathway functions in embryonic development to control cell growth, cell fate and pattern many aspects of the vertebrate body plan. The role of the pathway in adult tissue homeostasis, regeneration and cancer, however, is still emerging, especially in the context of epithelial/stromal interactions. Previous work on the adult bladder demonstrated the importance of stromal Hh pathway response in mediating homeostatic response to injury by eliciting production of stromal factors that act on the epithelium; in this dissertation I investigate the role of epithelial/stromal interactions involving the Hh pathway in prostate regeneration and bladder cancer. In the adult prostate, Hh pathway response occurs in a subset of stromal cells. Prostate regeneration involves the formation of new prostate branches, and I showed that stromal cells at the tips of nascent buds lacked Hh pathway response. Decreased pathway activity in stromal cells leads to increased branching, and this correlates with increased secretion of hepatocyte growth factor (Hgf), which acts on the epithelium to induce prostate branching. In regions that are not budding, stromal Hh pathway response down-regulates expression of Hgf. Hence, the spatial organization of stromal Hh pathway response in combination with the negative regulation of secreted hepatocyte growth factor (Hgf) levels by Hh pathway activity, together modulate branching morphogenesis during prostate regeneration. I also examined the role of Hh pathway activity in development of invasive urothelial carcinoma and find, despite its initial presence in the cancer cell of origin, that Sonic hedgehog (Shh) expression is lost during progression. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression. This cancer-protective effect is associated with Shh-induced stromal expression of BMP signals, which stimulate urothelial differentiation, and progression is reduced by pharmacological activation of BMP pathway activity. Taken together, the results of this dissertation highlight the importance, in regeneration and cancer, of epithelial/stromal interactions in which the Hh pathway is a key mediator. In both models examined, Hh ligand produced by the epithelium stiumates pathway response in the stroma, which regulates the secretion of factors that act on the epithelium. In a broader context, this work provides a conceptual framework for understanding epithelial/stromal interactions involving Hh signaling in other organ systems, a more detailed understanding of which will enable better therapeutic strategies for the treatment of disease.
Author :
Publisher :
ISBN 13 :
Total Pages : 61 pages
Book Rating : 4.:/5 (227 download)
Download or read book Sonic Hedgehog Signaling Promotes Tumor Growth written by and published by . This book was released on 2005 with total page 61 pages. Available in PDF, EPUB and Kindle. Book excerpt: We have shown that the Sonic hedgehog (Shh) signaling pathway is absolutely required for normal prostate development and our studies performed with the support of the DOD New Investigator award indicate that Shh signaling promotes tumor growth. This proposal addresses the hypothesis that Sonic hedgehog signaling promotes tumor growth by activating stromal cell gene expression. To address this hypothesis, we have developed the DLP(lacZ-LNCaP) xenograft, a model that provides us with the opportunity to selectively assay gene expression in the stromal and epithelial compartments of the tumor using species specific PCR primers and to make specific modifications in stromal cell gene expression. We will use this model to: (1) determine whether Shh promotes tumor growth by activating expression of Gli-1 in the tumor stromal cells; (2) characterize the mechanisms by which tumor growth is promoted; and (3) examine the action of a specific stromal Shh target genes in tumor growth.
Author :
Publisher :
ISBN 13 :
Total Pages : 46 pages
Book Rating : 4.:/5 (318 download)
Download or read book Identification of Sonic Hedgehog-Induced Stromal Factors That Stimulate Prostate Tumor Growth written by and published by . This book was released on 2007 with total page 46 pages. Available in PDF, EPUB and Kindle. Book excerpt: We will determine the mechanism by which Shh signaling accelerates prostate tumor growth, identify Shh targets in prostate tumor stroma, and test the effect of individual target genes on tumor growth. The purpose of the report is to evaluate the second year of research. We reduced autocrine signaling in LNShh cells and found that this does not disrupt increased growth of LNShh tumors. This shows that autocrine Shh signaling is not involved in tumor growth. We evaluated Shh signaling in human prostate tumors. In our mouse model system, we have identified 9 stromal genes that may be involved in tumor growth that is stimulated by Shh Only one gene is over-expressed in prostate cancer compared to normal prostate. Since Shh signaling is present in tumor stromal cells, we evaluated the role of different stromal phenotype in Shh signaling. Human benign and cancer samples were stained for myofibroblasts. We found that increased numbers of myofibroblasts relates to expression of each of the nine genes we identified in the xenograft model. Tumors with reactive stroma also have increased proliferation. These data may assist in predicting prostate tumor recurrence.
Author : Maribella Domenech
Publisher :
ISBN 13 :
Total Pages : 153 pages
Book Rating : 4.:/5 (745 download)
Download or read book Compartmentalized Microchamber Platform for the Study of Tumor-stroma Interactions written by Maribella Domenech and published by . This book was released on 2010 with total page 153 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author :
Publisher :
ISBN 13 : 9789461825452
Total Pages : 191 pages
Book Rating : 4.8/5 (254 download)
Download or read book Opening New Doors written by and published by . This book was released on 2015 with total page 191 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author :
Publisher :
ISBN 13 :
Total Pages : 21 pages
Book Rating : 4.:/5 (742 download)
Download or read book An Embryonic Growth Pathway is Reactivated in Human Prostate Cancer written by and published by . This book was released on 2005 with total page 21 pages. Available in PDF, EPUB and Kindle. Book excerpt: Epithelial-mesenchymal interactions in prostate cancer represent a promising target for drug therapies to arrest or slow tumor growth. For this potential to be realized, it is necessary to identify one specific epithelial-mesenchymal interaction which is critical for tumor growth. We have shown that Sonic hedgehog (Shh) signaling pathway is absolutely required for normal prostate development. Our preliminary studies show this pathway is expressed at very low levels in the normal adult prostate but reactivated in human prostate cancer. This research postulates that prostate cancer cells commandeer this normal epithelial-mesenchymal signaling pathway to recruit stromal cells to support abnormal tumor growth and tests the hypothesis that Shh signaling promotes prostate tumor growth. The primary goal of the study is to establish the concept that prostate tumor growth is promoted by re-activation of the Shh-Gli pathway and identify this as a novel target for drug treatment to slow or arrest prostate cancer growth.
Author :
Publisher :
ISBN 13 :
Total Pages : 8 pages
Book Rating : 4.:/5 (742 download)
Download or read book Targeting Stromal Recruitment by Prostate Cancer Cells written by and published by . This book was released on 2005 with total page 8 pages. Available in PDF, EPUB and Kindle. Book excerpt: Sonic hedgehog(shh)overexpression in LNCaP cells accelerates tumor growth. To characterize the contributions of each Gli gene to Shh-induced tumor growth, Gli1, Gli2 and Gli3 knockout UGS-M cells have been isolated and UGSM-2 cells were transfected with the Gli expression vectors. Gli1 and Gli2 gene were overexpressed in the cell line, and we have confirmed activation of the downstream target genes Patch and Hip in the Gli2 overexpressed cells. Experiments using those cell lines in the xenograft model are currently being done.
Author :
Publisher :
ISBN 13 :
Total Pages : 39 pages
Book Rating : 4.:/5 (227 download)
Download or read book The Role of the Sonic Hedgehog Pathway for Prostate Cancer Progression written by and published by . This book was released on 2006 with total page 39 pages. Available in PDF, EPUB and Kindle. Book excerpt: The hedgehog pathway plays a critical role in the development of prostate. In the previous funding period, we reported activation of hedgehog signaling in advanced and metastatic tumors. Here we report molecular mechanisms by which activated hedgehog signaling alter cell functions. In one cancer cell line, NCI-H209, we detected promoter methylation of Su(Fu). Ectopic expression of Su(Fu) in NCI-H209 cells down-regulates hedgehog target gene expression and leads to inhibition of BrdU incorporation, a marker for cell proliferation. Thus, inactivation of Su(Fu) is a mechanism by which hedgehog signaling is activated in human cancer. We also investigated the molecular basis by which PKA affects Gli1 activity. We find that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1. Mutation analysis identifies T374 as a major PKA site determining Gli1 protein localization. In the three dimension structure, T374 resides adjacent to the basic-residue cluster of the nuclear localization signal (NLS). Mutation of this residue to Asp (Gli1/T374D) results in more cytoplasmic Gli1 whereas a mutation to Lys (Gli1/T374K) leads to more nuclear Gli1. These data provide evidence to support a model that PKA regulates Gli1 localization, in part, through modulating the NLS function.
Author :
Publisher :
ISBN 13 : 9789462596290
Total Pages : 162 pages
Book Rating : 4.5/5 (962 download)
Download or read book Intestinal Hedgehog Signaling in Tumors and Inflammation written by and published by . This book was released on 2015 with total page 162 pages. Available in PDF, EPUB and Kindle. Book excerpt: "In this thesis we investigated the role of Hedgehog signaling in tumors and inflammation. By using an inducible Indian Hedgehog (Ihh) knockout mouse we show that Ihh signals via the mesenchyme to the proliferating cells in the crypt to attenuate proliferation. Despite its anti-proliferative role in intestinal homeostasis, we show that Ihh is mandatory for Apc mutant adenoma formation in mice. It seems that tumor epithelial cells need to secrete Ihh in order to maintain an intestinal stromal phenotype that is required for adenoma development. In the next study, we used mouse models where we can either activate or inactivate the Hedgehog pathway conditionally. Analysis of gene arrays of colons from these mice show that Hedgehog regulates the expression of the Interferon response target genes. This finding can explain why Ihh mutant mice are more prone to develop a more severe colitis. The next question is how Hedgehog regulates the interferon response? This question touches upon an issue that has been in the field for years; what cell is the Hedgehog target cell in the intestine? We exclude that the Hedgehog target cell is a myeloid cell and show by characterization of known mesenchymal markers that the Hedgehog target cell is a stromal cell. Furthermore, we show that Hedgehog's effect on the expression of the Interferon response mediated genes, including chemokines seems to act via the stromal cells. Together, this thesis gives us more insight in the role of Hedgehog in homeostasis, inflammation and adenoma formation."--Samenvatting auteur.
Author : Manfred Wirth
Publisher : Walter de Gruyter
ISBN 13 : 3110807270
Total Pages : 220 pages
Book Rating : 4.1/5 (18 download)
Download or read book Molecular Biology of Prostate Cancer written by Manfred Wirth and published by Walter de Gruyter. This book was released on 2013-05-22 with total page 220 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : David A. Frank
Publisher : Springer Science & Business Media
ISBN 13 : 1402073402
Total Pages : 358 pages
Book Rating : 4.4/5 (2 download)
Download or read book Signal Transduction in Cancer written by David A. Frank and published by Springer Science & Business Media. This book was released on 2002-12-31 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."
Author : Mohit Kumar Jolly
Publisher : MDPI
ISBN 13 : 3039367242
Total Pages : 512 pages
Book Rating : 4.0/5 (393 download)
Download or read book Epithelial-Mesenchymal Plasticity in Cancer Metastasis written by Mohit Kumar Jolly and published by MDPI. This book was released on 2020-12-29 with total page 512 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recent studies have highlighted that epithelial-mesenchymal transition (EMT) is not only about cell migration and invasion, but it can also govern many other important elements such as immunosuppression, metabolic reprogramming, senescence-associated secretory phenotype (SASP), stem cell properties, therapy resistance, and tumor microenvironment interactions. With the on-going debate about the requirement of EMT for cancer metastasis, an emerging focus on intermediate states of EMT and its reverse process mesenchymal-epithelial transition (MET) offer new ideas for metastatic requirements and the dynamics of EMT/MET during the entire metastatic cascade. Therefore, we would like to initiate discussions on viewing EMT and its downstream signaling networks as a fulcrum of cellular plasticity, and a facilitator of the adaptive responses of cancer cells to distant organ microenvironments and various therapeutic assaults. We hereby invite scientists who have prominently contributed to this field, and whose valuable insights have led to the appreciation of epithelial-mesenchymal plasticity as a more comprehensive mediator of the adaptive response of cancer cells, with huge implications in metastasis, drug resistance, tumor relapse, and patient survival.
Author : Leland W. K. Chung
Publisher : Springer Science & Business Media
ISBN 13 : 1597452246
Total Pages : 512 pages
Book Rating : 4.5/5 (974 download)
Download or read book Prostate Cancer written by Leland W. K. Chung and published by Springer Science & Business Media. This book was released on 2007-11-10 with total page 512 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate Cancer: Biology, Genetics, and the New Therapeutics, Second Edition, reviews new, valuable approaches to the treatment of prostate cancer in men. The latest edition contains new material on molecular imaging, new treatments for prostate cancer, molecular targets, cell signaling pathways, bioinformatics, and pathogenomics. The book details the latest innovations and advances in prostate cancer and may be used as a rapid reference text for readers. The volume profiles the latest advances in cancer research and treatment and includes profound studies in prostate stem cells, cancer-host interactions, hedgehog signaling in development and cancer, cholesterol and cell signaling, gene therapy for advanced prostate cancer, and noninvasive strategies such as molecular imaging to visualize gene expression. This new edition also investigates expression profiling and somatic alterations in prostate cancer progression and linkage studies of prostate cancer families to identify susceptibility genes. The issues of racial differences in prostate cancer mortality, radiotherapy for the treatment of locally advanced prostate cancer, recombinant antibody candidates for treatment, taxane-based chemotherapy, lethal phenotypes, and novel and efficient translation clinical trials are also presented in great depth. Prostate Cancer: Biology, Genetics, and the New Therapeutics, Second Edition, provides readers with a general reference for prostate cancer from prevention to therapy and will be of value to clinicians, scientists, and administrators who strive to solve the cancer problem.
