DOCSLIB.ORG

The Study of Epidermal Growth Factor Receptor, 99Mtechnetium

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Study of Epidermal Growth Factor Receptor, 99Mtechnetium The Study of Epidermal Growth Factor Receptor, 99m Technetium-depreotide, and Tumour Markers in the Management of Neuroendocrine Tumours by Tahir H Shah A thesis submitted to University College London for the degree of Doctor of Medicine (Res) January 2009 Neuroendocrine Tumour Unit & Department of Oncology Royal Free and University College Medical School & University College London 91 Riding House Street, London W1W 7B I, Tahir H Shah, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. ABSTRACT Purpose: Neuroendocrine Tumours (NETs) are rare and therefore poorly understood. Their slow progression and general poor response to standard chemotherapy regimes implies that their tumour biology is significantly different from most common cancers. There have been major advances in the past few decades in the diagnosis and management of these tumours which are perceived to be associated with improvements in quality and length of life. However, since most NETs have metastasised extensively by the time of diagnosis it is a major challenge indeed to try and effect tumour regression – the ultimate goal of any anti-cancer therapy. Chapters: 2 & 3: The epidermal growth factor receptor (EGFR) is commonly expressed in human tumours and provides an important target for therapy. Several classes of agents including small molecule inhibitors and antibodies are currently under clinical evaluation. These agents have shown interaction with chemotherapeutic agents in vitro and in vivo . However, the mechanisms of these interactions are not clearly understood, particularly in regards to NETs. The purpose of this study was to investigate the expression of EGFR in NET tissue and to determine its mechanisms of action, as well as the effects of modulation of EGFR activation. Experimental Design (Chapter 2): Paraffin-embedded tumour tissue was available from 98 patients with NETs (39 foregut, 42 midgut, four hindgut, five paragangliomas, and four of unknown origin). Immunohistochemical evaluation was performed for the expression of EGFR, p-EGFR, p-Akt, and p-ERK1/2. Results: Ninety-six percent of tumour samples were positive for EGFR expression; 63% were positive for activated EGFR; 76% were positive for activated Akt; and 96% were positive for activated ERK1/2. Importantly, the histological score for the activation of Akt and ERK1/2 correlated with the histological score for activated EGFR. These data provide a rationale for considering EGFR inhibitors in the treatment of NETs. Additionally, direct inhibition of Akt and ERK1/2 may provide further therapeutic options in the treatment of NETs in the future. Experimental Design (Chapter 3): The effects of the EGFR inhibitors gefitinib and erbitux were determined in several NET cell lines. The modulation of DNA-PK activity 1 by these agents was quantitated using a variety of techniques including immunoprecipitations, immunoblotting, cellular fraction extractions and immunohistochemistry. Results: Prolonged EGFR inhibition leads to reduction in DNAPK CS concentration in all tested NET cell lines except RIN, which displays the lowest levels of EGFR expression. This reduction in DNAPK CS is likely to lead to sensitisation of NET cells to ionising radiation, which causes double-strand DNA breaks, DNAPK CS being crucial to their repair. There are direct EGFR/DNAPK CS interactions in NET cell lines, which can be enhanced by EGFR inhibition. EGFR inhibition leads to transfer of DNAPK CS from the nucleus to the cytoplasm in SHP and BON cell lines but not in CRI, RIN, or NCI cell lines. This difference in the observed outcomes may be due to the lack of or mutations in intermediary proteins, though proof is needed for this hypothesis. The re-distribution of DNAPK CS is likely to lead to sensitisation of NET cells to ionising radiation, which causes double-strand DNA breaks, DNAPK CS being crucial to their repair. Chapter 4: Surgery is at present the only therapy with the possibility of achieving a cure. Therefore optimising diagnostic modalities in order to discover the tumours early or to discover all the tumour lesions prior to surgery would be of use. The purpose of this project was to assess the role of 99m Tc-depreotide in patients with negative or weakly positive OctreoScan® (Krenning score ≤ 1; measured on a scale range 0-4). To determine the usefulness of 99m Tc-depreotide scintigraphy for highlighting lesions that may be missed by OctreoScan® and/or CT/MRI imaging. Experimental Design: Prospective analysis of 25 NET patients, with negative or weakly positive ¹¹¹In-pentetreotide scans, who were consecutively enrolled to undergo ¹¹¹In-pentetreotide and 99m Tc-depreotide imaging. The results were compared with either CT or MRI scans. Results: Histology was available for 20 of 25 patients: of these 40% had high grade tumours (cellular proliferation marker Ki67 score > 20%), a further 35% had intermediate grade tumours (Ki67 2-20%), and the remainder 25% had low grade tumours (Ki67<2%). 52% of patients had completely negative and 48% had weakly positive OctreoScan®. 32% of these same patients had significantly positive 99 mTc- 2 depreotide scans (Krenning score ≥ 2), with the histology demonstrating intermediate or high grade tumours. Chapter 5: Some NETs follow an indolent course compared to others which display a rapidly progressive course with only short-lived response to therapy. Being able to confidently predict the long-term prognosis is obviously desirable. The aims of this project were to determine the diagnostic and prognostic value of serum alpha- fetoprotein (AFP) and human chorionic gonadotrophin beta (hCG β) in NETs . Patients and methods: a database containing biochemical, histological, and survival data on 360 NET patients was constructed. This data was statistically assessed, using SPSS statistics package, to determine the utility of commonly measured tumour markers with particular emphasis on AFP and hCG β. Results: AFP and hCG β were raised in 9.5% and 12.3% of patients respectively, and jointly raised in 9.1% of patients in whom it was measured. AFP levels associated strongly and positively with tumour grade, serum CgA, hCG β levels and worse survival. hCG β levels also associated strongly and positively with serum CgA, AFP levels and worsening survival. 3 ACKNOWLEDGEMENTS The work carried out in this thesis was completed under the supervision of Dr Martyn Caplin at Royal Free Hospital and Professor Daniel Hochhauser at the Department of Oncology, UCL and was generously funded by the ‘Quiet Cancer Appeal’ of The Times Newspaper. I would like to thank Martyn and Daniel for their guidance over the two years I spent with them. I have benefited greatly from their mentorship and will continue to rely on their advice and guidance in the future. I would like to thank all my lab colleagues for their help and guidance and particularly Korsa Khan for her self-less attitude towards helping newcomers. 4 COMMUNICATIONS PRESENTATIONS European Neuroendocrine Tumour Society annual conference 2006: Effect of cisplatin and ionizing radiation on epidermal growth factor receptor in neuroendocrine tumor cell lines. PUBLICATIONS T. Shah, M. E. Caplin et al. The role of alpha fetoprotein and β-human chorionic gonadotrophin as tumour markers in neuroendocrine tumours. Br J Cancer. 2008; 99: 72-7. T Shah, D Hochhauser, R Frow, A Quaglia, A Dhillon, M Caplin. EGFR expression and activation in neuroendocrine tumours. J Neuroendocrinology 2006: 18; 355 – 360. T. Shah, J. Buscombe, D Hochhauser, M. Caplin. The role of 99 Tc-depreotide in neuroendocrine tumour imaging. Nuclear Medicine Communications 2008 May;29(5):436-40. B J Friedmann, M Caplin, B Savic, T Shah, C J Lord, A Ashworth, J A Hartley, D Hochhauser.Interaction of the epidermal growth factor receptor and the DNA-dependant protein kinase pathway following gefitinib treatment. Molecular Cancer Therapeutics 2006: 5(2); 209 – 217. AWAITING SUBMISSION Expression of ErbB family of receptors in neuroendocrine tumour tissue. Srirajaskanthan R, Shah T , Caplin ME. Consequences of EGFR activation and their relation to survival outcomes in neuroendocrine tumour patients. Shah T , Srirajaskanthan R, Caplin ME. 5 TABLE OF CONTENTS ABSTRACT 1 ACKNOWLEDGEMENTS 4 COMMUNICATIONS 5 TABLE OF CONTENTS 6 INDEX OF FIGURES 11 INDEX OF TABLES 13 ABBREVIATIONS 14 CHAPTER 1 INTRODUCTION 16 1.1 Neuroendocrine Tumours 17 1.1.1 Incidence and Mortality 19 1.2 Diagnosis 22 1.2.1 Tumour markers 22 1.2.2 Imaging 22 1.2.3.1 Imaging in suspected primary 22 1.2.2.2 Imaging for detecting the primary tumour when 23 the patient has already presented with metastases 1.3 Management 24 1.3.1 Biotherapy 26 1.3.1.1 Somatostatin analogues 26 1.3.1.2 IFN alpha treatment in NETs 27 1.3.2 Chemotherapy 28 1.3.2.1 Well differentiated neuroendocrine tumours of 28 the pancreas 1.3.2.2 Well differentiated tumours of the gastrointestinal tract 29 1.3.2.3 Poorly differentiated tumours of the gastrointestinal 29 tract 1.3.3 Somatostatin receptor targeted radionuclide therapy 30 1.3.4 Chemoembolisation of liver metastases 32 1.3.5 Sequential hepatic artery embolization 33 1.3.6 Trans-catheter arterial chemoembolization (TACE) 33 1.4 Promising fields for study in the management of NETs: 34 6 Modulation of DNA-damage repair mechanisms through better understanding of EGFR/DNA-PK CS interactions 1.4.1 Intrinsic causes of DNA Damage 34 1.4.2 DNA-Interactive Chemotherapeutic Agents 34 1.4.3 Cellular Response to DNA Damage 35 1.4.4 DNA-Dependent Protein Kinase (DNA-PK) and 36 its role in NHEJ 1.5 Epidermal Growth Factor Receptor (EGFR) 39 1.5.1 ErbB receptors are activated by ligand-induced dimerization 39 1.5.2 Growth Factor Ligands that Regulate the Four 40 ErbB Receptors 1.5.3 Domain Organisation and Relationships with the ErbB 40 Receptor Family 1.5.4 ErbB Receptor Signalling 41 1.5.5 System Controls of the ErbB Signalling Network 43 1.5.5.1 Positive-feedback loops.
Load more

Recommended publications
  • ISSN: 2320-5407 Int. J. Adv. Res. 8(06), 797-810
    ISSN: 2320-5407 Int. J. Adv. Res. 8(06), 797-810 Journal Homepage: - www.journalijar.com Article DOI: 10.21474/IJAR01/11159 DOI URL: http://dx.doi.org/10.21474/IJAR01/11159 RESEARCH ARTICLE GROWTH FACTORS - PERIODONTAL REGENERATION: CURRENT OPINIONS IN PERIODONTOLOGY Dr. Kousain Sehar1, Dr. Nadia Irshad2, Dr. Navneet kour1, Dr. Manju Verma2 and Dr. Mir Tabish Syeed3 1. MDS Dept of Periodontology and Implantology, BRS Dental College and Hospital Sultanpur Panchkula. 2. MDS Dept of Paedontics and Preventive Dentistry, BRS Dental College and Hospital Sultanpur Panchkula. 3. MDS Dept of Paedontics and Preventive Dentistry, Swami Devi Dayal Hospital and Dental College, Barwala, Panchkula. …………………………………………………………………………………………………….... Manuscript Info Abstract ……………………. ……………………………………………………………… Manuscript History Periodontal tissue has the capacity for repair and regeneration. Received: 10 April 2020 Periodontal regeneration definition implies the formation of new bone, Final Accepted: 12 May 2020 new cementum and a functionally oriented periodontal ligament. Published: June 2020 Key words:- Periodontal, Repair, Regeneration Copy Right, IJAR, 2020,. All rights reserved. …………………………………………………………………………………………………….... Introduction:- Periodontitis, evoked by the bacterial biofilm (dental plaque) that forms around teeth, progressively destroys the periodontal tissues supporting the teeth, including the periodontal ligament, cementum, alveolar bone and gingiva1. Thus, the rationale of periodontal therapy is to eradicate the inflammation of the periodontal tissues, to arrest the destruction of soft tissue and bone caused by periodontal disease, and regenerates the lost tissue2. Periodontal surgical procedures have focused on the removal of hard and soft tissue defects by regenerating new attachment3.Periodontal wound-healing studies, however, indicate that conventional periodontal therapy most commonly results in repair rather than regeneration4, 5.
    [Show full text]
  • From Pathway to Population–A Multiscale Model of Juxtacrine
    BMC Systems Biology BioMed Central Research article Open Access From pathway to population – a multiscale model of juxtacrine EGFR-MAPK signalling DC Walker*1, NT Georgopoulos2 and J Southgate2 Address: 1Department of Computer Science, University of Sheffield, Kroto Research Institute, North Campus, Broad Lane, Sheffield, S3 7HQ, UK and 2Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York YO10 5YW, UK Email: DC Walker* - [email protected]; NT Georgopoulos - [email protected]; J Southgate - [email protected] * Corresponding author Published: 26 November 2008 Received: 3 June 2008 Accepted: 26 November 2008 BMC Systems Biology 2008, 2:102 doi:10.1186/1752-0509-2-102 This article is available from: http://www.biomedcentral.com/1752-0509/2/102 © 2008 Walker et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Most mathematical models of biochemical pathways consider either signalling events that take place within a single cell in isolation, or an 'average' cell which is considered to be representative of a cell population. Likewise, experimental measurements are often averaged over populations consisting of hundreds of thousands of cells. This approach ignores the fact that even within a genetically-homogeneous population, local conditions may influence cell signalling and result in phenotypic heterogeneity. We have developed a multi-scale computational model that accounts for emergent heterogeneity arising from the influences of intercellular signalling on individual cells within a population.
    [Show full text]
  • Role of Patched-1 Intracellular Domains in Canonical and Non-Canonical Hedgehog Signalling Events
    Role of Patched-1 Intracellular Domains in Canonical and Non-Canonical Hedgehog Signalling Events by Malcolm Harvey A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Laboratory Medicine & Pathobiology University of Toronto © Copyright by Malcolm Harvey 2013 Role of Patched-1 Intracellular Domains in Canonical and Non- Canonical Hedgehog Signalling Events Malcolm Harvey Master of Science Department of Laboratory Medicine & Pathobiology University of Toronto 2013 Abstract Patched-1 (Ptch1) is the primary receptor for Hedgehog (Hh) ligands and mediates both canonical and non-canonical Hh signalling. Previously, our lab identified that mice possessing a Ptch1 C-terminal truncation display blocked mammary gland development at puberty that is overcome by overexpression of activated c-src. Testing the hypothesis that this involves a direct interaction between Ptch1 and c-src, we identified through co-immunoprecipitation that Ptch1 and c-src associate in an Hh-dependent manner, and that the Ptch1 C-terminus regulates activation of c-src in response to Hh ligand. Since the effects of Ptch1 intracellular domain deletions on canonical Hh signalling are ill-defined, we assayed this through luciferase reporter assays and qRT-PCR. Transient assays revealed that the Ptch1 middle intracellular loop is required for response to ligand, while qRT-PCR from primary cells showed that C-terminal truncation impairs canonical Ptch1 function. Together, this indicates that the intracellular domains of Ptch1 mediate distinct canonical and non-canonical functions. ii Acknowledgments First, I would like to thank my supervisor Dr. Paul A. Hamel for offering me the opportunity to pursue graduate studies in his lab and for his guidance, advice, support, and patience along the way.
    [Show full text]
  • (Cell-Cell Communication) and Entropy Change of the Cellular System
    American Journal of Applied Bio-Technology Research (AJABTR) Vol: 1, Pg: 1-6, Yr: 2020-AJABTR Cell Signalling (cell-cell communication) and entropy change of the cellular system S Das Chaudhury1, S Ghosh1 and Gargi Sardar2* 1Center for Rural and Cryogenic Technologies, Jadavpur University Campus, Kolkata -700032 2Department of Zoology, Baruipur College, W.B. 743610, India Corresponding E-mail: [email protected] Abstract diseases may be treated effectively and, theoretically, artificial tissues may be Cell signalling is a complex process of regenerated. communication among cells and organs that governing cellular activities and 1. Introduction cooperative cellular function. The ability In a living organism cells are always of cells to perceive and correctly respond dynamic particles secreting different to their microenvironment is the basis of chemical (enzymes etc.) which development like tissue repair, immunity changes when the cell is diseased. as well as normal tissue homeostasis. We Entropy of the disordered cell is higher have attempted to show that cell signalling than the corresponding normal cells [1- (or information transmission) is associated 3]. Moreover, in a living organism, with the entropy change of the cellular signalling [4] between different cells system. Disordered (higher entropy) occurs either through release into the diseased cells produce error signals in extracellular space which might be , cellular information processing. Error over short distances (paracrine signals are responsible for diseases such as signaling) and over long distances cancer, autoimmunity, and diabetes and (endocrine signalling), or by juxtacrine what not. Every disorder for any internal signalling ( known as direct signalling . or external reason is associated with the Signalling information is transmitted to entropy change of the system.
    [Show full text]
  • Emerging Role of Contact-Mediated Cell Communication in Tissue Development and Diseases
    Histochemistry and Cell Biology (2018) 150:431–442 https://doi.org/10.1007/s00418-018-1732-3 REVIEW Emerging role of contact-mediated cell communication in tissue development and diseases Benjamin Mattes1 · Steffen Scholpp1 Accepted: 18 September 2018 / Published online: 25 September 2018 © The Author(s) 2018 Abstract Cells of multicellular organisms are in continuous conversation with the neighbouring cells. The sender cells signal the receiver cells to influence their behaviour in transport, metabolism, motility, division, and growth. How cells communicate with each other can be categorized by biochemical signalling processes, which can be characterised by the distance between the sender cell and the receiver cell. Existing classifications describe autocrine signals as those where the sender cell is identical to the receiver cell. Complementary to this scenario, paracrine signalling describes signalling between a sender cell and a different receiver cell. Finally, juxtacrine signalling describes the exchange of information between adjacent cells by direct cell contact, whereas endocrine signalling describes the exchange of information, e.g., by hormones between distant cells or even organs through the bloodstream. In the last two decades, however, an unexpected communication mechanism has been identified which uses cell protrusions to exchange chemical signals by direct contact over long distances. These signalling protrusions can deliver signals in both ways, from sender to receiver and vice versa. We are starting to understand the morphology and function of these signalling protrusions in many tissues and this accumulation of findings forces us to revise our view of contact-dependent cell communication. In this review, we will focus on the two main categories of signalling protrusions, cytonemes and tunnelling nanotubes.
    [Show full text]
  • Transgenic Stem Cells in Hydra Reveal an Early Evolutionary Origin for Key Elements Controlling Self-Renewal and Differentiation
    Developmental Biology 309 (2007) 32–44 www.elsevier.com/developmentalbiology Transgenic stem cells in Hydra reveal an early evolutionary origin for key elements controlling self-renewal and differentiation Konstantin Khalturin 1, Friederike Anton-Erxleben 1, Sabine Milde 1, Christine Plötz 1, ⁎ Jörg Wittlieb 1, Georg Hemmrich, Thomas C.G. Bosch Zoological Institute, Christian-Albrechts-University, Olshausenstrasse 40, 24098 Kiel, Germany Received for publication 28 March 2007; revised 15 June 2007; accepted 15 June 2007 Available online 22 June 2007 Abstract Little is known about stem cells in organisms at the beginning of evolution. To characterize the regulatory events that control stem cells in the basal metazoan Hydra, we have generated transgenics which express eGFP selectively in the interstitial stem cell lineage. Using them we visualized stem cell and precursor migration in real-time in the context of the native environment. We demonstrate that interstitial cells respond to signals from the cellular environment, and that Wnt and Notch pathways are key players in this process. Furthermore, by analyzing polyps which overexpress the Polycomb protein HyEED in their interstitial cells, we provide in vivo evidence for a role of chromatin modification in terminal differentiation. These findings for the first time uncover insights into signalling pathways involved in stem cell differentiation in the Bilaterian ancestor; they demonstrate that mechanisms controlling stem cell behaviour are based on components which are conserved throughout the animal kingdom. © 2007 Elsevier Inc. All rights reserved. Keywords: Hydra; Evolution of development; Stem cells; Stem cell niche; Wnt; Notch; Polycomb group proteins Introduction relationships. Insects and vertebrates, however, all derive from the “Bilateria” clade of metazoans (Fig.
    [Show full text]
  • The Regulation of Self-Renewal in Normal Human Urothelial Cells
    The Regulation of Self-Renewal in Normal Human Urothelial Cells Lisa A. Kirkwood PhD University of York Department of Biology April 2012 Abstract The urinary tract is lined by a mitotically-quiescent, but highly regenerative epithelium, the urothelium. The mechanisms regulating urothelial regeneration are incompletely understood although autocrine stimulation of the Epidermal Growth Factor Receptor (EGFR) signalling pathway has been implicated. The hypothesis developed in this thesis is that urothelial homeostasis is regulated through resolution of interactive signal transduction networks downstream of local environmental cues, such as cell:cell contact. Here, canonical Wnt signalling was examined as a candidate key pathway due to the pivotal role of β-catenin in both nuclear transcription and intercellular adherens junctions. Normal human urothelial (NHU) cells isolated from surgical biopsies were grown as finite cell lines in monolayer culture. mRNA analysis from proliferating cultures inferred all components for a functional autocrine-activated canonical Wnt cascade were present. In proliferating cells, β-catenin was nuclear and Axin2 expression provided an objective hallmark of β-catenin/TCF transcription factor activity. This endogenous activity was not mediated by Wnt receptor activation, as Wnt ligand was produced in inactive (non-palmitylated) form in serum-free culture, but instead -catenin activation was driven via EGFR- mediated phosphorylation of GSK3 and inhibition of the β-catenin destruction complex. In quiescent, contact–inhibited cultures, β-catenin was seen to re- localise to the adherens junctions and GSK3β activity was re-established. Knock-down of β-catenin using RNA interference led to significant changes in p-ERK and p-AKT activity as well as an increase in E-cadherin protein expression.
    [Show full text]
  • 0008-5472.CAN-15-3490.Full.Pdf
    Published OnlineFirst February 15, 2017; DOI: 10.1158/0008-5472.CAN-15-3490 Cancer Tumor and Stem Cell Biology Research Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in Mammary Gland Tumors Giovanni Valenti1, Hazel M. Quinn1, Guus J.J.E. Heynen1, Linxiang Lan1, Jane D. Holland1, Regina Vogel1, Annika Wulf-Goldenberg2, and Walter Birchmeier1 Abstract Many tumors display intracellular heterogeneity with sub- activation of Hedgehog signaling. CAFs subsequently secrete sets of cancer stem cells (CSC) that sustain tumor growth, factors that promote expansion and self-renewal of CSCs. recurrence, and therapy resistance. Cancer-associated fibro- In vivo treatment of tumors with the Hedgehog inhibitor blasts (CAF) have been shown to support and regulate CSC vismodegib reduce CAF and CSC expansion, resulting in an function. Here, we investigate the interactions between CSCs overall delay of tumor formation. Our results identify a novel and CAFs in mammary gland tumors driven by combined intracellular signaling module that synergistically regulates activation of Wnt/b-catenin and Hgf/Met signaling in mouse CAFs and CSCs. Targeting CAFs with Hedgehog inhibitors mammary epithelial cells. In this setting, CSCs secrete the may offer a novel therapeutic strategy against breast cancer. Hedgehog ligand SHH, which regulate CAFs via paracrine Cancer Res; 77(8); 1–14. Ó2017 AACR. Introduction and skin (10, 11). Mesenchymal stem cells (MSC) and immune cells establish permissive growing conditions for CSCs in gastric Tumor heterogeneity is believed to be dependent on a distinct and intestinal tumors (12, 13). In breast cancer, a number of subset of tumor cells that possess the capacity to sustain tumor cellular components of the microenvironment have been growth, referred to as cancer stem cells (CSC) or tumor-initiating reported to regulate CSCs, such as MSCs, macrophages, and cells (1).
    [Show full text]
  • Reciprocal Network Between Cancer Stem-Like Cells and Macrophages
    Published OnlineFirst April 24, 2018; DOI: 10.1158/1078-0432.CCR-18-0461 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer Hai Huang1, Chao Wang1, Fei Liu1, Hui-Zhen Li1, Guang Peng1, Xu Gao1, Ke-Qin Dong1, Hong-Ru Wang1, De-Pei Kong1, Min Qu1, Li-He Dai1, Kai-Jian Wang1, Zhe Zhou1, Jun Yang1, Ze-Yu Yang1, Yan-Qiong Cheng1, Qin-Qin Tian1, Dan Liu1, Chuan-Liang Xu1, Dan-Feng Xu2, Xin-Gang Cui3,4, and Ying-Hao Sun1 Abstract Purpose: Cancer stem-like cells (CSC) contribute to the pro- Results: Autophagy-related gene 7 (ATG7) facilitated the gression and androgen deprivation therapy (ADT) resistance transcription of OCT4 via b-catenin, which binds to the OCT4 of prostate cancer. As CSCs depend on their specificniche, promoter, promoting CSC characteristics in prostate cancer, including tumor-associated macrophages (TAM), elucidating including self-renewal, tumor initiation, and drug resistance. the network between CSCs and TAMs may help to effectively In addition, CSCs remodeled their specific niche by educating inhibit the progression and ADT resistance of prostate cancer. monocytes/macrophages toward TAMs, and the CSC-educat- Experimental Design: The underlying intracellular ed TAMs reciprocally promoted the stem-like properties of mechanism that sustains the stem-like characteristics of CSCs, progression and ADT resistance of prostate cancer via CSCs in prostate cancer was assessed via RNA sequencing, IL6/STAT3. Furthermore, the combined targeting of CSCs and co-immunoprecipitation, chromatin immunoprecipitation, their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 and other assays.
    [Show full text]
  • Cytonemes Extend Their Reach
    The EMBO Journal (2013), 1–2 www.embojournal.org Cytonemes extend their reach Thomas B Kornberg Cardiovascular Research Institute, University of California, San Francisco, CA, USA. Correspondence to: [email protected] The EMBO Journal advance online publication, 14 May 2013; doi:10.1038/emboj.2013.115 Cytonemes are specialized filopodia, first described in the functionally diverse, with a subset dedicated and designed Drosophila wing imaginal disc, that were proposed to for juxtacrine signalling between distant cells. The term mediate long distance signalling during development. A cytoneme was coined to highlight this specialized function- recent report from Barna and colleagues (Sanders et al, ality (Ramirez-Weber and Kornberg, 1999). Filopodia with 2013) published in Nature shows that cytonemes in the apparent sensory function had been observed previously in chick limb bud carry SHH signalling proteins out to signal various contexts: thin, dynamic filopodia extend across sea receiving cells, thus highlighting their evolutionarily urchin embryos, appearing to explore and perhaps pattern conserved roles in cell–cell communication. distant sheets of cells (reviewed in McClay, 1999), and Our textbooks inform us that long distance signalling by anthropomorphic descriptions of neuronal growth cone animal cells is carried out in either of two ways. One, specific for neurons, involves signal exchange at sites of direct con- tact. The cell body of a neuron can be far from target cells (even metres away), but neurons extend processes that can bridge the distance to the target cell. Non-neuronal cells, in contrast, are hemmed in by their neighbours, their contacts limited to nearest neighbours, and they use the other Chick limb bud Receptors mode: signal release at the surface of signal-producing cells, followed by dispersion in extracellular fluid so that released SHH target cells signals eventually bind to receptors on target cells.
    [Show full text]
  • Role of the Microenvironment in Regulating Normal and Cancer Stem Cell Activity: Implications for Breast Cancer Progression and Therapy Response
    cancers Review Role of the Microenvironment in Regulating Normal and Cancer Stem Cell Activity: Implications for Breast Cancer Progression and Therapy Response Vasudeva Bhat 1,2 , Alison L. Allan 3,4 and Afshin Raouf 1,2,* 1 Department of Immunology, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada 2 Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada 3 London Regional Cancer Program, London Health Science Centre, London, ON N6A 5W9, Canada 4 Department of Anatomy & Cell Biology and Oncology, Western University, London, ON N6A 3K7, Canada * Correspondence: [email protected]; Tel.: +1-204-975-7704 Received: 26 July 2019; Accepted: 19 August 2019; Published: 24 August 2019 Abstract: The epithelial cells in an adult woman’s breast tissue are continuously replaced throughout their reproductive life during pregnancy and estrus cycles. Such extensive epithelial cell turnover is governed by the primitive mammary stem cells (MaSCs) that proliferate and differentiate into bipotential and lineage-restricted progenitors that ultimately generate the mature breast epithelial cells. These cellular processes are orchestrated by tightly-regulated paracrine signals and crosstalk between breast epithelial cells and their tissue microenvironment. However, current evidence suggests that alterations to the communication between MaSCs, epithelial progenitors and their microenvironment plays an important role in breast carcinogenesis. In this article, we review the current knowledge regarding the role of the breast tissue microenvironment in regulating the special functions of normal and cancer stem cells. Understanding the crosstalk between MaSCs and their microenvironment will provide new insights into how an altered breast tissue microenvironment could contribute to breast cancer development, progression and therapy response and the implications of this for the development of novel therapeutic strategies to target cancer stem cells.
    [Show full text]
  • Α-Cell Signalling in Glucose- Regulated Glucagon Secretion
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1478 α-Cell signalling in glucose- regulated glucagon secretion QIAN YU ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0387-1 UPPSALA urn:nbn:se:uu:diva-356478 2018 Dissertation presented at Uppsala University to be publicly examined in B21, Biomedical Centre, Husargatan 3, Uppsala, Thursday, 13 September 2018 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor David W Piston (Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, U.S.A). Abstract Yu, Q. 2018. α-Cell signalling in glucose-regulated glucagon secretion. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1478. 49 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0387-1. Glucagon is a blood glucose-elevating hormone released from α-cells in the islets of Langerhans during hypoglycaemia. Glucagon is critical for glucose homeostasis and inappropriate regulation of its secretion underlies both impaired counter-regulation of hypoglycaemia and chronic hyperglycaemia in diabetes patients. The mechanisms by which glucose controls glucagon secretion are poorly understood, but have been suggested to involve both direct effects of the sugar on α-cells and indirect effects mediated by paracrine factors released within the islet, including insulin and gamma-hydroxybutyrate (GHB) from β-cells, and somatostatin from δ-cells. This thesis addresses the role of the intracellular messengers ATP, Ca2+ and cAMP in glucose-regulated glucagon secretion. Various fluorescence microscopy techniques were used to monitor changes of these messengers in single, dispersed α-cells and those in situ within intact islets, and glucagon secretion from islets was measured with an immunoassay.
    [Show full text]