DOCSLIB.ORG

Noise and Sensitivity in Cell Signalling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Noise and Sensitivity in Cell Signalling Noise and sensitivity in cell signalling Brendan A. Bicknell BSc (Hons) A thesis submitted to the University of Queensland for the degree of Doctor of Philosophy Queensland Brain Institute & School of Mathematics and Physics 2017 ii Abstract The ability of cells to receive and process chemical information is fundamental to the function of biological systems. Cell responses to salient chemical cues are characteristically reliable and precise, a striking example being the guidance of axons to their targets during brain develop- ment. However, chemical signalling pathways are subject to multiple sources of unavoidable noise, due to the random nature of molecular motion and interactions. This suggests that cellular systems may be optimised for transduction of noisy signals, which provides a guiding principle for understanding cell function at a biophysical level. In pursuit of this idea, we study three model problems, motivated by sensing and signalling in axon guidance. Our approach is to construct mathematical models, and through analysis and simulation, extract general prin- ciples and hypotheses about the quantitative nature of biological noise and mechanisms for sensitive chemosensation. First, we quantify the physical limits of chemosensation imposed by the random thermal motion of the molecules that need to be counted. In particular, we show how this depends on the dimension and spatial extent of the domain of diffusion. Although recurrent diffusion in 1d and 2d is detrimental to measurement precision, we find these effects are suppressed when sensing is performed within a confined space. Second, we study the stochastic behaviour of the inositol 1,4,5-trisphosphate receptor ion channel, which couples receptor activity at the membrane to the downstream calcium response that regulates axon growth and turning. By modelling the basic biophysical events that control ion channel opening, we introduce a new principle for understanding the origin of the multiple gating modes observed in single channel recordings. Third, we examine the finely-tuned response of dorsal root ganglia neurons to very shallow neurotrophin gradients. We show how paracrine signalling within the ganglion could explain this extreme sensitivity, as well as the currently unexplained biphasic dose response of many axon growth and guidance cues. Overall, this thesis gives new quantitative insights into chemical signalling in biological systems, across multiple stages of processing and spatial scales. Our models make testable predictions to motivate new experiments, and provide a strong foundation for further theoretical and computational study in both axon guidance and broader domains of biophysics. iii Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. iv Publications during candidature Bicknell, B.A. & Goodhill, G.J., (2016), Emergence of ion channel modal gating from inde- pendent subunit kinetics. Proc Natl Acad Sci USA, 113(36), E5288-E5297. Bicknell, B.A. , Dayan, P. & Goodhill, G.J., (2015), The limits of chemosensation vary across dimensions. Nat Comms, 6, 7468. Goodhill, G.J., Faville, R.A., Sutherland, D.J., Bicknell, B.A. Thompson, A.W., Pujic, Z., Sun, B., Kita, E.M. & Scott, E.K. (2015). The dynamics of growth cone morphology. BMC Biology, 13, 10. Publications included in this thesis Bicknell, B.A. & Goodhill, G.J., (2016), Emergence of ion channel modal gating from inde- pendent subunit kinetics. Proc Natl Acad Sci USA, 113(36), E5288-E5297. Incorporated as Chapter 3. B.A.B G.J.G. designed research 80 % 20 % performed research 100 % 0 % wrote manuscript 80 % 20 % Bicknell, B.A. , Dayan, P. & Goodhill, G.J., (2015), The limits of chemosensation vary across dimensions. Nat Comms, 6, 7468. Incorporated as Chapter 2. B.A.B P.D. G.J.G. designed research 70 % 10% 20% performed research 100 % 0 % 0 % wrote manuscript 80 % 10 % 10 % v Contributions by others to the thesis Contributions by others to chapters 2 and 3 are as listed in Publications included in this thesis. Zac Pujic performed the experiments reported in chapter 4, as described in Methods: Neurite growth assay, and advised on the associated immunostaining and microscopy. Geoff Goodhill and Peter Dayan contributed to the design and writing of the research presented in chapter 4. Statement of parts of the thesis submitted to qualify for the award of another degree None. Research involving human or animal subjects Experiments involving animals were conducted in accordance with the Animal Care and Pro- tection Act Qld (2002), and the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, 8th edition (2013). Ethics approval was obtained from the University of Queensland Ethics Committee, Approval Number QBI/548/16. The approval certificate is included as appendix A. vi Acknowledgements I am very grateful to Geoff Goodhill, whose guidance throughout every stage of this process has been a wonderful privilege. My time in the lab has been formative, and I go forward with broadened horizons and heightened zeal for brain research. I very much appreciate all of the encouragement and opportunities, and for the timely reminders of the forest while wandering amongst the trees. And to Peter Dayan, whose incisive comments and questions were invalu- able, and whose generosity is an inspiration. Thank you Zac Pujic, for introducing me to the combination of technique, time and superstition required for successful experimental work, and other Goodhill lab members, for their feedback and entertaining discussions throughout. Outside the lab, there are many people I would like to thank. A non-exhaustive selection: Isobel, for the selfless support and patience for which I will be forever grateful. There is a long list of adventures postponed by this endeavour, which I now look forward to working through with you. My family, for their unwavering support and encouragement, and for their essential and expert counsel on matters mathematical, musical, whimsical and bicycle. Finally, James, Kim and Tristan for the welcome extracurricular noise. vii Financial support This research was supported by an Australian Postgraduate Award. Keywords cell signalling, chemosensation, diffusion, ion channel, inositol 1,4,5-trisphosphate receptor, axon guidance, nerve growth factor Australian and New Zealand Standard Research Classifi- cations (ANZSRC) ANZSRC code: 010202, Biological Mathematics (40 %) ANZSRC code: 029901, Biological Physics (40 %) ANZSRC code: 110905, Peripheral Nervous System (20 %) Fields of Research (FoR) Classification FoR code: 0102, Applied Mathematics (40 %) FoR code: 0299, Other Physical Sciences (40 %) FoR code: 1109, Neurosciences (20 %) viii Contents List of Figures xiii List of Tables xv 1 Introduction 1 1.1 Thesis outline . .4 2 The limits of chemosensation vary across dimensions 7 2.1 Introduction . .8 2.2 Results . 10 2.2.1 Derivation of theoretical results . 10 2.2.2 Simulations . 14 2.2.3 Biological implications . 17 2.3 Discussion . 20 2.4 Methods . 21 2.4.1 Simulations . 21 2.5 Supplementary Information . 22 2.5.1 Evaluation of sums . 22 2.5.2 Derivation without spatial averaging . 28 2.5.3 Ring of receptors in 2D . 29 2.5.4 Supplementary figures . 31 3 Emergence of ion channel modal gating from independent subunit kinetics 35 3.1 Introduction . 36 3.2 Results . 37 3.2.1 Bursting motif . 38 3.2.2 Timescale separation . 40 3.2.3 Modal gating motif . 41 3.2.4 Simulations . 43 ix x Contents 3.2.5 Full model . 45 3.2.6 Model fitting . 47 3.2.7 Modal gating analysis . 48 3.3 Discussion . 52 3.3.1 Model assumptions . 53 3.3.2 Role of IP3R modal gating in Alzheimer's disease . 55 3.3.3 Application to other ion channels . 56 3.4 Methods . 57 3.5 Supplementary Information . 57 3.5.1 Conditional mean open time . 57 3.5.2 Supplementary figures . 59 3.5.3 Supplementary tables . 64 4 Control of neurite growth and guidance by an inhibitory cell-body signal 65 4.1 Introduction . 66 4.2 Results . 67 4.2.1 Growth inhibition at high concentration is neither single-cell intrinsic, nor due to fasciculation . 67 4.2.2 Biased outgrowth in shallow gradients implies remarkable sensitivity . 71 4.2.3 A mathematical model of inhibitory growth control . 71 4.2.4 Coupled growth and gradient detection . 77 4.2.5 Model predictions .
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]
  • 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.
    [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]