664 research outputs found
Epigenetic Control of Gene Expression in the Normal and Malignant Human Prostate:A Rapid Response Which Promotes Therapeutic Resistance
No full textA successful prostate cancer must be capable of changing its phenotype in response to a variety of microenvironmental influences, such as adaptation to treatment or successful proliferation at a particular metastatic site. New cell phenotypes emerge by selection from the large, genotypically heterogeneous pool of candidate cells present within any tumor mass, including a distinct stem cell-like population. In such a multicellular model of human prostate cancer, flexible responses are primarily governed not only by de novo mutations but appear to be dominated by a combination of epigenetic controls, whose application results in treatment resistance and tumor relapse. Detailed studies of these individual cell populations have resulted in an epigenetic model for epithelial cell differentiation, which is also instructive in explaining the reported high and inevitable relapse rates of human prostate cancers to a multitude of treatment types
Stem cells and the role of ETS transcription factors in the differentiation hierarchy of normal and malignant prostate epithelium
No full textProstate cancer is the most common cancer of men in the UK and accounts for a quarter of all new cases. Although treatment of localised cancer can be successful, there is no cure for patients presenting with invasive prostate cancer and there are less treatment options. They are generally treated with androgen-ablation therapies but eventually the tumours become hormone resistant and patients develop castration-resistant prostate cancer (CRPC) for which there are no further successful or curative treatments. This highlights the need for new treatment strategies. In order to prevent prostate cancer recurrence and treatment resistance, all the cell populations in a heterogeneous prostate tumour must be targeted, including the rare cancer stem cell (CSC) population. The ETS transcription factor family members are now recognised as a common feature in multiple cancers including prostate cancer; with aberrant expression, loss of tumour suppressor function, inactivating mutations and the formation of fusion genes observed. Most notably, the TMPRSS2-ERG gene fusion is present in approximately 50% of prostate cancers and in prostate CSCs. However, the role of other ETS transcription factors in prostate cancer is less well understood. This review will describe the prostate epithelial cell hierarchy and discuss the evidence behind prostate CSCs and their inherent resistance to conventional cancer therapies. The known and proposed roles of the ETS family of transcription factors in prostate epithelial cell differentiation and regulation of the CSC phenotype will be discussed, as well as how they might be targeted for therapy
Cancer Stem Cells, Models of Study and Implications of Therapy Resistance Mechanisms
No full textThere is now compelling evidence for tumour initiating or cancer stem cells (CSCs) in human cancers. The current evidence of this CSC hypothesis, the CSC phenotype and methods of identification, culture and in vitro modelling will be presented, with an emphasis on prostate cancer. Inherent in the CSC hypothesis is their dual role, as a tumour-initiating cell, and as a source of treatment-resistant cells; the mechanisms behind therapeutic resistance will be discussed. Such resistance is a consequence of the unique CSC phenotype, which differs from the differentiated progeny, which make up the bulk of a tumour. It seems that to target the whole tumour, employing traditional therapies to target bulk populations alongside targeted CSC-specific drugs, provides the best hope of lasting treatment or even cure
Low temperature plasmas as emerging cancer therapeutics:the state of play and thoughts for the future
No full textThe field of plasma medicine has seen substantial advances over the last decade, with applications developed for bacterial sterilisation, wound healing and cancer treatment. Low temperature plasmas (LTPs) are particularly suited for medical purposes since they are operated in the laboratory at atmospheric pressure and room temperature, providing a rich source of reactive oxygen and nitrogen species (RONS). A great deal of research has been conducted into the role of reactive species in both the growth and treatment of cancer, where long-established radio- and chemo-therapies exploit their ability to induce potent cytopathic effects. In addition to producing a plethora of RONS, LTPs can also create strong electroporative fields. From an application perspective, it has been shown that LTPs can be applied precisely to a small target area. On this basis, LTPs have been proposed as a promising future strategy to accurately and effectively control and eradicate tumours. This review aims to evaluate the current state of the literature in the field of plasma oncology and highlight the potential for the use of LTPs in combination therapy. We also present novel data on the effect of LTPs on cancer stem cells, and speculatively outline how LTPs could circumvent treatment resistance encountered with existing therapeutics
Harvesting human prostate tissue material and culturing primary prostate epithelial cells
No full textIn order to fully explore the biology of a complex solid tumor such as prostate cancer, it is desirable to work with patient tissue. Only by working with cells from a tissue can we take into account patient variability and tumor heterogeneity. Cell lines have long been regarded as the workhorse of cancer research and it could be argued that they are of most use when considered within a panel of cell lines, thus taking into account specified mutations and variations in phenotype between different cell lines. However, often very different results are obtained when comparing cell lines to primary cells cultured from tissue. It stands to reason that cells cultured from patient tissue represents a close-to-patient model that should and does produce clinically relevant data. This chapter aims to illustrate the methods of processing, storing and culturing cells from prostate tissue, with a description of potential uses
Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer
No full textThe PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells. In contrast, when the AKT inhibitor AZD7328 was applied to patient-derived prostate cultures that retained expression of PTEN, activation of a compensatory Ras/MEK/ERK pathway was observed. Moreover, whilst autophagy was induced following treatment with AZD7328, cell viability was less affected in the patient-derived cultures than in cell lines. Surprisingly, treatment with a combination of both AZD7328 and two separate MEK1/2 inhibitors further enhanced phosphorylation of ERK1/2 in primary prostate cultures. However, it also induced irreversible growth arrest and senescence.Ex vivo treatment of a patient-derived xenograft (PDX) of prostate cancer with a combination of AZD7328 and the mTOR inhibitor KU-0063794, significantly reduced tumour frequency upon re-engraftment of tumour cells.The results demonstrate that single agent targeting of the PI3K/AKT/mTOR pathway triggers activation of the Ras/MEK/ERK compensatory pathway in near-patient samples. Therefore, blockade of one pathway is insufficient to treat prostate cancer in man
Building Breastfeeding Research Relations and Beyond: An Interview With Fiona Dykes
No full textProfessor Fiona Dykes is Professor Emerita of Maternal and Infant Health at the University of Central Lancashire in the United Kingdom (UCLAN). Fiona has a particular interest in the global, sociocultural, and political influences upon infant and young child feeding practices; her methodological expertise is in ethnography and other qualitative research methods. She founded the Maternal and Infant Nutrition and Nurture Unit (MAINN) in 2000 which she led until she retired from her full-time professorship in 2020. Fiona established the associated MAINN Conference in 2007. The MAINN conference is a 3 day, international, peer reviewed event held bi-annually in the United Kingdom and, more recently, in alternate years overseas (Sydney, Australia; Falun, Dalarna, Sweden; and Florida, United States). The conference draws together key researchers in the field of infant and young child feeding from around the world. Fiona was a founding member of the journal Maternal and Child Nutrition. She is author of Breastfeeding in Hospital: Mothers, Midwives and the Production Line (Routledge) and co-author, with Dr Tanya Cassidy, of Banking on Milk: An Ethnography of Donor Human Milk Relations (Routledge). She is also joint editor of several books including Infant and Young Child Feeding: Challenges to Implementing a Global Strategy (Wiley-Blackwell) and Ethnographic Research in Maternal and Child Health (Routledge). This interview was conducted on April 20, 2023, by Dr. Tanya Cassidy, and is based on a verbatim transcription and edited for readability
Effects on prostate cancer cells of targeting RNA polymerase III
No full textRNA polymerase (pol) III occurs in two forms, containing either the POLR3G subunit or the related paralogue POLR3GL. Whereas POLR3GL is ubiquitous, POLR3G is enriched in undifferentiated cells. Depletion of POLR3G selectively triggers proliferative arrest and differentiation of prostate cancer cells, responses not elicited when POLR3GL is depleted. A small molecule pol III inhibitor can cause POLR3G depletion, induce similar differentiation and suppress proliferation and viability of cancer cells. This response involves control of the fate-determining factor NANOG by small RNAs derived from Alu short interspersed nuclear elements. Tumour initiating activity in vivo can be reduced by transient exposure to the pol III inhibitor. Untransformed prostate cells appear less sensitive than cancer cells to pol III depletion or inhibition, raising the possibility of a therapeutic window
Handbook of biochemistry and molecular biology / edited by Roger L. Lundblad, Fiona M. Macdonald.
No full textIncludes bibliographical references and index.Book fair 2013.xvii, 1080 p. :Edited by renowned protein scientist and bestselling author Roger L. Lundblad, with the assistance of Fiona M. Macdonald of CRC Press, this fourth edition of the Handbook of Biochemistry and Molecular Biology represents a dramatic revision -- the first in two decades -- of one of biochemistry's most referenced works. This edition gathers a wealth of information not easily obtained, including information not found on the web." "Offering a molecular perspective not available 20 years ago, it provides physical and chemical data on proteins, nucleic acids, lipids, and carbohydrates. Presented in an organized, concise, and simple-to-use format, this popular reference allows quick access to the most frequently used data. Covering a wide range of topics, from classical biochemistry to proteomics and genomics, it also details the properties of commonly used biochemicals, laboratory solvents, and reagents." "Just a small sampling of the wealth of information found inside the handbook" : "Buffers and buffer solutions" -- "Heat capacities and combustion levels" -- "--Reagents for the chemical modification of proteins" -- "Comprehensive classification system for lipids" -- "Biological characteristics of vitamins" -- "A huge variety of UV data" -- "Recommendations for nomenclature and tables in biochemical thermodynamics" -- "Guidelines for NMR measurements for determination of high and low pka values" -- "Viscosity and density tables" -- "Chemical and physical properties of various commercial plastics" -- "Generic source-based nomenclature for polymers" -- "Therapeutic enzyme
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