|
1
|
Vasanthan KS, Srinivasan V, Mathur V, Agarwal P, Negi N, Kumari S. 3D Bioprinting for esophageal tissue regeneration: A review. JOURNAL OF MATERIALS RESEARCH 2022; 37:88-113. [DOI: 10.1557/s43578-021-00409-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/06/2021] [Indexed: 01/02/2025]
|
|
2
|
Gao Y, Jin SZ. Strategies for treating oesophageal diseases with stem cells. World J Stem Cells 2020; 12:488-499. [PMID: 32742566 PMCID: PMC7360987 DOI: 10.4252/wjsc.v12.i6.488] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/02/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
There is a wide range of oesophageal diseases, the most general of which are inflammation, injury and tumours, and treatment methods are constantly being developed and updated. With an increasingly comprehensive understanding of stem cells and their characteristics of multilineage differentiation, self-renewal and homing as well as the combination of stem cells with regenerative medicine, tissue engineering and gene therapy, stem cells are playing an important role in the treatment of a variety of diseases. Mesenchymal stem cells have many advantages and are most commonly applied; however, most of these applications have been in experimental studies, with few related clinical trials for comparison. Therefore, the methods, positive significance and limitations of stem cells in the treatment of oesophageal diseases remain incompletely understood. Thus, the purpose of this paper is to review the current literature and summarize the efficacy of stem cells in the treatment of oesophageal diseases, including oesophageal ulceration, acute radiation-induced oesophageal injury, corrosive oesophageal injury, oesophageal stricture formation after endoscopic submucosal dissection and oesophageal reconstruction, as well as gene therapy for oesophageal cancer.
Collapse
Affiliation(s)
- Yang Gao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Shi-Zhu Jin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| |
Collapse
|
|
3
|
Que J, Garman KS, Souza RF, Spechler SJ. Pathogenesis and Cells of Origin of Barrett's Esophagus. Gastroenterology 2019; 157:349-364.e1. [PMID: 31082367 PMCID: PMC6650338 DOI: 10.1053/j.gastro.2019.03.072] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023]
Abstract
In patients with Barrett's esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin, including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications.
Collapse
Affiliation(s)
- Jianwen Que
- Division of Digestive and Liver Diseases and Center for Human Development, Department of Medicine, Columbia University, New York, New York.
| | - Katherine S. Garman
- Division of Gastroenterology, Department of Medicine, Duke University School of Medicine. Durham, NC
| | - Rhonda F. Souza
- Center for Esophageal Diseases, Department of Medicine, Baylor University Medical Center at Dallas, and Center for Esophageal Research, Department of Medicine, Baylor Scott & White Research Institute, Dallas, TX
| | - Stuart Jon Spechler
- Center for Esophageal Diseases, Department of Medicine, Baylor University Medical Center at Dallas, Dallas, Texas; Center for Esophageal Research, Department of Medicine, Baylor Scott & White Research Institute, Dallas, Texas.
| |
Collapse
|
|
4
|
Epperly MW, Fisher R, Rigatti L, Watkins S, Zhang X, Hou W, Shields D, Franicola D, Bayir H, Wang H, Thermozier S, Henderson A, Donnelly C, Wipf P, Greenberger JS. Amelioration of Amyotrophic Lateral Sclerosis in SOD1 G93A Mice by M 2 Microglia from Transplanted Marrow. In Vivo 2019; 33:675-688. [PMID: 31028184 PMCID: PMC6559904 DOI: 10.21873/invivo.11526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 03/29/2019] [Accepted: 04/02/2019] [Indexed: 12/11/2022]
Abstract
Background/Aim: The cause of fatal neuromuscular amyotrophic lateral sclerosis (ALS) is not known. Materials and Methods: Ninety-day-old superoxide-dismutase-1 G93A (SOD1 G93A ) mice demonstrating level 1 paralysis, received 9.0 Gy total body irradiation (TBI) from a cesium source at 340 cGy per minute, and intravenous transplantation with 1×10 6 C57BL/6 green fluorescent protein (GFP)+ donor bone marrow cells. Results: Paralysis-free survival was prolonged in TBI and bone marrow-transplanted SOD1 G93A mice from 100 to over 250 days (p=0.0018). Other mice transplanted with SOD1 G93A marrow or marrow treated with the free-radical scavenger MMS350 showed no therapeutic effect. GFP+ macrophage-2 (M2) microglial cells of bone marrow origin, were seen at sites of degenerating anterior horn motor neurons. SOD1 G93A mice had a disruption in the blood-brain barrier permeability which was reversed by marrow transplant from C57BL/6 mice. SOD1 G93A marrow showed unexpected robust hematopoiesis in vitro, and radioresistance. Conclusion: After TBI, M2 microglial cells from transplanted donor marrow extended the paralysis-free interval in SOD1 G93A mice.
Collapse
Affiliation(s)
- Michael W Epperly
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Renee Fisher
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Lora Rigatti
- Division of Laboratory Animal Resources (DLAR), University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Simon Watkins
- Department of Cell Biology and Center for Images, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Xichen Zhang
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Wen Hou
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Donna Shields
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Darcy Franicola
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Hulya Bayir
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Hong Wang
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Stephanie Thermozier
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Andrew Henderson
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | | | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Joel S Greenberger
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A.
| |
Collapse
|
|
5
|
Zhang W, Wang DH. Origins of Metaplasia in Barrett's Esophagus: Is this an Esophageal Stem or Progenitor Cell Disease? Dig Dis Sci 2018; 63:2005-2012. [PMID: 29675663 PMCID: PMC6783253 DOI: 10.1007/s10620-018-5069-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The incidence of esophageal adenocarcinoma has been increasing in Western countries over the past several decades. Though Barrett's esophagus, in which the normal esophageal squamous epithelium is replaced with metaplastic intestinalized columnar cells due to chronic damage from gastroesophageal reflux, is accepted as the requisite precursor lesion for esophageal adenocarcinoma, the Barrett's esophagus cell of origin and the molecular mechanism underlying esophageal epithelial metaplasia remain controversial. Much effort has been dedicated towards identifying the Barrett's esophagus cell of origin since this could lead to more effective prevention and treatment strategies for both Barrett's esophagus and esophageal adenocarcinoma. Previously, it was hypothesized that terminally differentiated esophageal squamous cells might undergo direct conversion into specialized intestinal columnar cells via the process of transdifferentiation. However, there is increasing evidence that stem and/or progenitor cells are molecularly reprogrammed through the process of transcommitment to differentiate into the columnar cell lineages that characterize Barrett's esophagus. Given that Barrett's esophagus originates at the gastroesophageal junction, the boundary between the distal esophagus and gastric cardia, potential sources of these stem and/or progenitor cells include columnar cells from the squamocolumnar junction or neighboring gastric cardia, native esophageal squamous cells, native esophageal cuboidal or columnar cells from submucosal glands or ducts, or circulating bone marrow-derived cells. In this review, we focus on native esophageal specific stem and/or progenitor cells and detail molecular mediators of transcommitment based on recent insights gained from novel mouse models and clinical observations from patients.
Collapse
Affiliation(s)
- Wei Zhang
- Esophageal Diseases Center, Department of Internal Medicine and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - David H. Wang
- Esophageal Diseases Center, Department of Internal Medicine and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA,Medical Service, Dallas VA Medical Center, Dallas, Texas, USA
| |
Collapse
|
|
6
|
Zhang C, Zhang Y, Feng Z, Zhang F, Liu Z, Sun X, Ruan M, Liu M, Jin S. Therapeutic effect of dental pulp stem cell transplantation on a rat model of radioactivity-induced esophageal injury. Cell Death Dis 2018; 9:738. [PMID: 29970894 PMCID: PMC6030227 DOI: 10.1038/s41419-018-0753-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 05/09/2018] [Accepted: 05/22/2018] [Indexed: 01/14/2023]
Abstract
Dental pulp stem cell (DPSC) transplantation has been demonstrated to promote the regeneration and repair of tissues and organs and is a potentially effective treatment for radioactive esophageal injury. In this study, to explore the therapeutic effects of DPSCs on acute radiation-induced esophageal injury, DPSCs were cultured and transplanted into rats with acute radioactive esophageal injuries induced by radioactive 125I seeds in vivo. In the injured esophagus, PKH26-labeled DPSCs co-localized with PCNA, CK14, CD71, and integrin α6, and the expression levels of these four makers of esophageal stem cells were significantly increased. After DPSC transplantation, the injured esophagus exhibited a greater thickness. In addition, the esophageal function and inflammation recovered faster. The results demonstrated that transplanted DPSCs, which trans-differentiated into esophageal stem cells in vivo, could repair the damaged esophageal tissue.
Collapse
Affiliation(s)
- Chunwei Zhang
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Yichi Zhang
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Zhenning Feng
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Feifei Zhang
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Zishuai Liu
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Xiaoli Sun
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Mengting Ruan
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Mingna Liu
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China
| | - Shizhu Jin
- Department of Gastrointestinal and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, Harbin, China.
| |
Collapse
|
|
7
|
Zhuravleva M, Gilazieva Z, Grigoriev TE, Shepelev AD, Kh. Tenchurin T, Kamyshinsky R, Krasheninnikov SV, Orlov S, Caralogli G, Archipova S, Holterman MJ, Mavlikeev M, Deev RV, Chvalun SN, Macchiarini P. In vitroassessment of electrospun polyamide-6 scaffolds for esophageal tissue engineering. J Biomed Mater Res B Appl Biomater 2018; 107:253-268. [DOI: 10.1002/jbm.b.34116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 02/08/2018] [Accepted: 02/26/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Margarita Zhuravleva
- Laboratory of Bioengineering and Regenerative Medicine (BioReM); Kazan Federal University; Kazan Russia
| | - Zarema Gilazieva
- Laboratory of Bioengineering and Regenerative Medicine (BioReM); Kazan Federal University; Kazan Russia
| | | | | | | | | | | | - Sergei Orlov
- Scientific Research Institute of Medical Primatology; Sochi Russia
| | - Gina Caralogli
- Scientific Research Institute of Medical Primatology; Sochi Russia
| | - Svetlana Archipova
- Laboratory of Bioengineering and Regenerative Medicine (BioReM); Kazan Federal University; Kazan Russia
| | | | - Mikhail Mavlikeev
- Laboratory of Bioengineering and Regenerative Medicine (BioReM); Kazan Federal University; Kazan Russia
| | - Roman V. Deev
- Human Stem Cells Institute, Moscow, Russia; Ryazan State Medical University; Ryazan Russia
| | | | - Paolo Macchiarini
- Laboratory of Bioengineering and Regenerative Medicine (BioReM); Kazan Federal University; Kazan Russia
| |
Collapse
|
|
8
|
Hui YY, Chen X, Wang BM. Yesterday and today of Barrett's esophagus: Historical evolution and research hotspots. Shijie Huaren Xiaohua Zazhi 2016; 24:3077-3086. [DOI: 10.11569/wcjd.v24.i20.3077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
It has been more than 60 years since the concept of Barrett's esophagus (BE) was put forward, and over these a few decades, we have made great progress in the diagnosis and treatment of BE. BE does not cause clinical symptoms, but it attracts wide attention, because it is an important precursor lesion of esophageal adenocarcinoma. The purpose of this article is to review the process of the recognition of BE and the current research hotspots as well as to discuss the current status of esophageal adenocarcinoma screening in BE patients. We aim to provide clinicians with an overview of the ins and outs of the disease, which will help them improve the diagnosis and treatment of BE in clinical practice and provide patients with beneficial treatment.
Collapse
|
|
9
|
Wang DH, Souza RF. Transcommitment: Paving the Way to Barrett's Metaplasia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:183-212. [PMID: 27573773 DOI: 10.1007/978-3-319-41388-4_10] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Barrett's esophagus is the condition in which metaplastic columnar epithelium that predisposes to cancer development replaces stratified squamous epithelium in the distal esophagus. Potential sources for the cell or tissue of origin for metaplastic Barrett's epithelium are reviewed including native esophageal differentiated squamous cells, progenitor cells native to the esophagus located within the squamous epithelium or in the submucosal glands or ducts, circulating bone marrow-derived stem cells, and columnar progenitor cells from the squamocolumnar junction or the gastric cardia that proximally shift into the esophagus to fill voids left by damaged squamous epithelium. Wherever its source the original cell must undergo molecular reprogramming (i.e., either transdifferentiation or transcommitment) to give rise to specialized intestinal metaplasia. Transcription factors that specify squamous, columnar, intestinal, and mucus-secreting epithelial differentiation are discussed. An improved understanding of how esophageal columnar metaplasia forms could lead to development of effective treatment or prevention strategies for Barrett's esophagus. It could also more broadly inform upon normal tissue development and differentiation, wound healing, and stem cell biology.
Collapse
Affiliation(s)
- David H Wang
- Division of Hematology and Oncology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, Esophageal Diseases Center, Medical Service, VA North Texas Health Care System, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8852, USA.
| | - Rhonda F Souza
- Division of Digestive and Liver Diseases, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, Esophageal Diseases Center, Medical Service (111B1), VA North Texas Health Care System, University of Texas Southwestern Medical Center, 4500 S. Lancaster Road, Dallas, TX, 75216, USA
| |
Collapse
|
|
10
|
Kapoor H, Agrawal DK, Mittal SK. Barrett's esophagus: recent insights into pathogenesis and cellular ontogeny. Transl Res 2015; 166:28-40. [PMID: 25701368 DOI: 10.1016/j.trsl.2015.01.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 01/24/2015] [Accepted: 01/27/2015] [Indexed: 02/06/2023]
Abstract
Esophageal adenocarcinoma (EAC) has increased 6-fold in its incidence in the last 2 decades. Evidence supports the hypothesis of stepwise progression from normal squamous epithelium → reflux esophagitis → metaplasia (Barrett's esophagus, BE) → dysplasia → adenocarcinoma. The precursor, BE, stands as the bridge connecting the widespread but naive reflux disease and the rare but fatal EAC. The step of metaplasia from squamous to intestine-like columnar phenotype is perhaps pivotal in promoting dysplastic vulnerability. It is widely accepted that chronic inflammation because of gastroesophageal reflux disease leads to the development of metaplasia, however the precise molecular mechanism is yet to be discovered. Additionally, how this seemingly adaptive change in the cellular phenotype promotes dysplasia remains a mystery. This conceptual void is deterring further translational research and clouding clinical decision making. This article critically reviews theories on the pathogenesis of Barrett's esophagus and the various controversies surrounding its diagnosis. We further discuss unanswered questions and future directions, which are vital in formulating effective preventive and therapeutic guidelines for Barrett's esophagus.
Collapse
Affiliation(s)
- Harit Kapoor
- Esophageal Center, Department of Surgery, Creighton University School of Medicine, Omaha, Neb; Center for Clinical and Translational Sciences, Creighton University School of Medicine, Omaha, Neb
| | - Devendra K Agrawal
- Center for Clinical and Translational Sciences, Creighton University School of Medicine, Omaha, Neb
| | - Sumeet K Mittal
- Esophageal Center, Department of Surgery, Creighton University School of Medicine, Omaha, Neb.
| |
Collapse
|
|
11
|
Greenberger J, Kagan V, Bayir H, Wipf P, Epperly M. Antioxidant Approaches to Management of Ionizing Irradiation Injury. Antioxidants (Basel) 2015; 4:82-101. [PMID: 26785339 PMCID: PMC4665573 DOI: 10.3390/antiox4010082] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 01/12/2015] [Indexed: 11/25/2022] Open
Abstract
Ionizing irradiation induces acute and chronic injury to tissues and organs. Applications of antioxidant therapies for the management of ionizing irradiation injury fall into three categories: (1) radiation counter measures against total or partial body irradiation; (2) normal tissue protection against acute organ specific ionizing irradiation injury; and (3) prevention of chronic/late radiation tissue and organ injury. The development of antioxidant therapies to ameliorate ionizing irradiation injury began with initial studies on gene therapy using Manganese Superoxide Dismutase (MnSOD) transgene approaches and evolved into applications of small molecule radiation protectors and mitigators. The understanding of the multiple steps in ionizing radiation-induced cellular, tissue, and organ injury, as well as total body effects is required to optimize the use of antioxidant therapies, and to sequence such approaches with targeted therapies for the multiple steps in the irradiation damage response.
Collapse
Affiliation(s)
- Joel Greenberger
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Rm. 533, Pittsburgh, PA 15232, USA.
| | - Valerian Kagan
- Department of Environmental/Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
| | - Hulya Bayir
- Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA.
| | - Michael Epperly
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Rm. 533, Pittsburgh, PA 15232, USA.
| |
Collapse
|
|
12
|
Strategies for optimizing the response of cancer and normal tissues to radiation. Nat Rev Drug Discov 2013; 12:526-42. [PMID: 23812271 DOI: 10.1038/nrd4003] [Citation(s) in RCA: 328] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their treatment, and the majority of these patients are treated with curative intent. Despite recent advances in the planning of radiation treatment and the delivery of image-guided radiation therapy, acute toxicity and potential long-term side effects often limit the ability to deliver a sufficient dose of radiation to control tumours locally. In the past two decades, a better understanding of the hallmarks of cancer and the discovery of specific signalling pathways by which cells respond to radiation have provided new opportunities to design molecularly targeted therapies to increase the therapeutic window of radiation therapy. Here, we review efforts to develop approaches that could improve outcomes with radiation therapy by increasing the probability of tumour cure or by decreasing normal tissue toxicity.
Collapse
|
|
13
|
Tong JZ, Qu B, Wang YM, Jin SZ, Cui YL, Xin R, Wang BB, Jiang HY. Development of a rat model of intraluminal local radiation-induced acute radioactive esophageal injury. Shijie Huaren Xiaohua Zazhi 2013; 21:791-797. [DOI: 10.11569/wcjd.v21.i9.791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a rat model of acute radioactive esophageal injury by local irradiation of the esophagus with 125I seed chain and to explore its clinical application.
METHODS: 125I seed chain was used to locally irradiate the esophagus of SD rats. The rats were killed on days 3, 5 and 7 after irradiation to take the full-length esophageal tissue. Tissue samples were embedded in paraffin, sectioned, and subjected to HE staining for pathological analysis. Pathological changes in the full-length esophageal tissue at one week and two weeks and living status at two weeks after intraluminal irradiation with 0.8 mGi 125I seed chain (initial activity 0.8 mGi) were observed.
RESULTS: The chain of five 125I seeds, with an initial activity of > 0.6 mGi, could induce radioactive esophageal injury by intraluminally irradiating the esophagus for 5 d. Radioactive esophageal injury increased gradually with the increase in particle activity. 125I seed chain could be easily taken out postoperatively to avoid further esophageal injury. SD rats could gradually resume eating after intraluminal irradiation with 125I seed chain, and the injury tended to be repaired in two weeks.
CONCLUSION: The chain of five 125I seeds, with an initial activity of > 0.6 mGi, can induce radioactive esophageal injury by intraluminally irradiating the rat esophagus for five days. Intraluminal brachytherapy with low-energy radionuclide 125I seed chain may provide a clinical option for treatment of advanced esophageal cancer.
Collapse
|
|
14
|
Abstract
Airway epithelial healing is defined as restoration of health or soundness; to cure. Our research indicates that two types of progenitor cells participate in this process: the tissue-specific stem cell (TSC) and the facultative basal progenitor (FBP). The TSC restores the epithelium to its normal structure and function. Thus, the TSC regenerates the epithelium. In contrast, the FBP-derived epithelium is characterized by regions of cellular hyperplasia and hypoplasia. Since the FBP-derived epithelium deviates from normal, we term the FBP-mediated process repair. Our work indicates that the TSC responds to signals from other epithelial cells, including the FBP. These signals instruct the TSC to proliferate or to select one of several differentiation pathways. We interpret these data in the context of Stephen Padget's "seed and soil" paradigm. Therein, Padget explained that metastasis of a tumor, the seed, to a specific site, the soil, was determined by the growth and differentiation requirements of the tumor cell. By extending the seed and soil paradigm to airway epithelial healing, we suggest that proliferation and differentiation of the TSC, the seed, is determined by its interactions with other cell types, the soil. Based on this concept, we provide a set of suggestions for development of cell-based therapies that are directed toward chronic airways disease.
Collapse
|
|
15
|
Greenberger JS, Clump D, Kagan V, Bayir H, Lazo JS, Wipf P, Li S, Gao X, Epperly MW. Strategies for discovery of small molecule radiation protectors and radiation mitigators. Front Oncol 2012; 1:59. [PMID: 22655254 PMCID: PMC3356036 DOI: 10.3389/fonc.2011.00059] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 12/20/2011] [Indexed: 01/01/2023] Open
Abstract
Mitochondrial targeted radiation damage protectors (delivered prior to irradiation) and mitigators (delivered after irradiation, but before the appearance of symptoms associated with radiation syndrome) have been a recent focus in drug discovery for (1) normal tissue radiation protection during fractionated radiotherapy, and (2) radiation terrorism counter measures. Several categories of such molecules have been discovered: nitroxide-linked hybrid molecules, including GS-nitroxide, GS-nitric oxide synthase inhibitors, p53/mdm2/mdm4 inhibitors, and pharmaceutical agents including inhibitors of the phosphoinositide-3-kinase pathway and the anti-seizure medicine, carbamazepine. Evaluation of potential new radiation dose modifying molecules to protect normal tissue includes: clonogenic radiation survival curves, assays for apoptosis and DNA repair, and irradiation-induced depletion of antioxidant stores. Studies of organ specific radioprotection and in total body irradiation-induced hematopoietic syndrome in the mouse model for protection/mitigation facilitate rational means by which to move candidate small molecule drugs along the drug discovery pipeline into clinical development.
Collapse
Affiliation(s)
- Joel S. Greenberger
- Radiation Oncology Department, University of Pittsburgh Cancer InstitutePittsburgh, PA, USA
| | - David Clump
- Radiation Oncology Department, University of Pittsburgh Cancer InstitutePittsburgh, PA, USA
| | - Valerian Kagan
- Environmental and Occupational Health Department, University of PittsburghPittsburgh, PA, USA
| | - Hülya Bayir
- Critical Care Medicine Department, University of Pittsburgh Medical CenterPittsburgh, PA, USA
| | - John S. Lazo
- Pharmacology Department, University of VirginiaCharlottesville, VA, USA
| | - Peter Wipf
- Department of Chemistry, Accelerated Chemical Discovery Center, University of PittsburghPittsburgh, PA, USA
| | - Song Li
- Pharmaceutical Science Department, University of PittsburghPittsburgh, PA, USA
| | - Xiang Gao
- Pharmaceutical Science Department, University of PittsburghPittsburgh, PA, USA
| | - Michael W. Epperly
- Radiation Oncology Department, University of Pittsburgh Cancer InstitutePittsburgh, PA, USA
| |
Collapse
|
|
16
|
Kaur P, Hurwitz MD, Krishnan S, Asea A. Combined hyperthermia and radiotherapy for the treatment of cancer. Cancers (Basel) 2011; 3:3799-823. [PMID: 24213112 PMCID: PMC3763397 DOI: 10.3390/cancers3043799] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 09/23/2011] [Accepted: 09/23/2011] [Indexed: 12/25/2022] Open
Abstract
Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an integral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, cardiac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threatening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy.
Collapse
Affiliation(s)
- Punit Kaur
- Department of Pathology, Scott & White Hospital and the Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA; E-Mail:
| | - Mark D. Hurwitz
- Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, MA 02115, USA; E-Mail:
| | - Sunil Krishnan
- Department of Radiation Oncology, The University of Texas MD Anderson Medical Center, Houston, TX 77030, USA; E-Mail:
| | - Alexzander Asea
- Department of Pathology, Scott & White Hospital and the Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: or ; Tel: +1 (254) 743-0201; Fax: +1 (254) 743-0247
| |
Collapse
|
|
17
|
Jeon MS, Hong SS. [Preclinical experience in stem cell therapy for digestive tract diseases]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2011; 58:133-8. [PMID: 21960100 DOI: 10.4166/kjg.2011.58.3.133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Adult stem cells are multipotent and self-renewing cells that contain several functions; i) migration and homing potential: stem cells can migrate to injured and inflamed tissues. ii) differentiation potential: stem cells which migrated to injured tissues can be differentiated into multiple cell types for repairing and regenerating the tissues. iii) immunomodulatory properties: stem cells, especially mesenchymal stem cells can suppress immune system such as inflammation. All those characteristics might be useful for the treatment of the digestive tract diseases which are complex and encompass a broad spectrum of different pathogenesis. Preclinical stem cell therapy showed some promising results, especially in liver failure, pancreatitis, sepsis, and inflammatory bowel disease. If we can understand more about the mechanism of stem cell action, stem cell therapy can become a promising alternative treatment for refractory digestive disease in the near future. In this review, we summarized current preclinical experiences in diseases of the digestive tract using stem cells. (Korean J Gastroenterol 2011;58:133-138).
Collapse
Affiliation(s)
- Myung Shin Jeon
- Clinical Research Center, School of Medicine, Inha University, Incheon, Korea
| | | |
Collapse
|
|
18
|
Abstract
Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. The dose of ionizing radiation that can be given to the tumour is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumour or to decrease the effects on normal tissues. These aims must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumour in the second approach. Two factors have made such approaches feasible: namely, an improved understanding of the molecular response of cells and tissues to ionizing radiation and a new appreciation of the exploitable genetic alterations in tumours. These have led to the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumour or normal tissue, leading to improvements in efficacy.
Collapse
Affiliation(s)
- Adrian C Begg
- Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
| | | | | |
Collapse
|
|
19
|
Cao X, Wu X, Frassica D, Yu B, Pang L, Xian L, Wan M, Lei W, Armour M, Tryggestad E, Wong J, Wen CY, Lu WW, Frassica FJ. Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells. Proc Natl Acad Sci U S A 2011; 108:1609-14. [PMID: 21220327 PMCID: PMC3029740 DOI: 10.1073/pnas.1015350108] [Citation(s) in RCA: 193] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Radiation therapy can result in bone injury with the development of fractures and often can lead to delayed and nonunion of bone. There is no prevention or treatment for irradiation-induced bone injury. We irradiated the distal half of the mouse left femur to study the mechanism of irradiation-induced bone injury and found that no mesenchymal stem cells (MSCs) were detected in irradiated distal femora or nonirradiated proximal femora. The MSCs in the circulation doubled at 1 week and increased fourfold after 4 wk of irradiation. The number of MSCs in the proximal femur quickly recovered, but no recovery was observed in the distal femur. The levels of free radicals were increased threefold at 1 wk and remained at this high level for 4 wk in distal femora, whereas the levels were increased at 1 wk and returned to the basal level at 4 wk in nonirradiated proximal femur. Free radicals diffuse ipsilaterally to the proximal femur through bone medullary canal. The blood vessels in the distal femora were destroyed in angiographic images, but not in the proximal femora. The osteoclasts and osteoblasts were decreased in the distal femora after irradiation, but no changes were observed in the proximal femora. The total bone volumes were not affected in proximal and distal femora. Our data indicate that irradiation produces free radicals that adversely affect the survival of MSCs in both distal and proximal femora. Irradiation injury to the vasculatures and the microenvironment affect the niches for stem cells during the recovery period.
Collapse
Affiliation(s)
- Xu Cao
- Departments of Orthopaedic Surgery
| | - Xiangwei Wu
- Departments of Orthopaedic Surgery
- Shihezi Medical College, Shihezi University, Shihezi Xinjiang 832002, China; and
| | | | - Bing Yu
- Departments of Orthopaedic Surgery
| | - Lijuan Pang
- Departments of Orthopaedic Surgery
- Shihezi Medical College, Shihezi University, Shihezi Xinjiang 832002, China; and
| | | | - Mei Wan
- Departments of Orthopaedic Surgery
| | | | - Michael Armour
- Radiation Oncology Medical Physics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Erik Tryggestad
- Radiation Oncology Medical Physics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - John Wong
- Radiation Oncology Medical Physics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Chun Yi Wen
- Department of Orthopaedics, University of Hong Kong, Hong Kong 999777, China
| | - William Weijia Lu
- Department of Orthopaedics, University of Hong Kong, Hong Kong 999777, China
| | | |
Collapse
|
|
20
|
Abstract
The past few years have brought new advances in our understanding of the molecular mechanisms underlying the development of Barrett's esophagus and esophageal adenocarcinoma. Although knowledge of the genetic basis for these conditions has not yet translated into clinically useful biomarkers, the current pace of biomedical discovery holds endless possibilities for molecular medicine to improve the diagnosis and management of patients with these conditions. This article provides a useful conceptual basis for understanding the molecular events involved in the making of Barrett metaplasia and in its neoplastic progression, and provides a rationale for evaluating studies on the application of molecular medicine to the diagnosis and management of patients with Barrett's esophagus and esophageal adenocarcinoma.
Collapse
Affiliation(s)
- David H. Wang
- Assistant Professor, Departments of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, and the Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
| | - Rhonda F. Souza
- Associate Professor, Departments of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, and the Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
| |
Collapse
|
|
21
|
Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, Catena R, Collantes M, Peñuelas I, Díaz-González JA, Calvo A. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer 2010; 10:188. [PMID: 20459769 PMCID: PMC2883966 DOI: 10.1186/1471-2407-10-188] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Accepted: 05/11/2010] [Indexed: 11/28/2022] Open
Abstract
Background There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC). Methods We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out. Results Lapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001). Conclusion Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.
Collapse
Affiliation(s)
- Roque Diaz
- Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Niu Y, Wang H, Wiktor-Brown D, Rugo R, Shen H, Huq MS, Engelward B, Epperly M, Greenberger JS. Irradiated esophageal cells are protected from radiation-induced recombination by MnSOD gene therapy. Radiat Res 2010; 173:453-61. [PMID: 20334517 PMCID: PMC2872095 DOI: 10.1667/rr1763.1] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Radiation-induced DNA damage is a precursor to mutagenesis and cytotoxicity. During radiotherapy, exposure of healthy tissues can lead to severe side effects. We explored the potential of mitochondrial SOD (MnSOD) gene therapy to protect esophageal, pancreatic and bone marrow cells from radiation-induced genomic instability. Specifically, we measured the frequency of homologous recombination (HR) at an integrated transgene in the Fluorescent Yellow Direct Repeat (FYDR) mice, in which an HR event can give rise to a fluorescent signal. Mitochondrial SOD plasmid/liposome complex (MnSOD-PL) was administered to esophageal cells 24 h prior to 29 Gy upper-body irradiation. Single cell suspensions from FYDR, positive control FYDR-REC, and negative control C57BL/6NHsd (wild-type) mouse esophagus, pancreas and bone marrow were evaluated by flow cytometry. Radiation induced a statistically significant increase in HR 7 days after irradiation compared to unirradiated FYDR mice. MnSOD-PL significantly reduced the induction of HR by radiation at day 7 and also reduced the level of HR in the pancreas. Irradiation of the femur and tibial marrow with 8 Gy also induced a significant increase in HR at 7 days. Radioprotection by intraesophageal administration of MnSOD-PL was correlated with a reduced level of radiation-induced HR in esophageal cells. These results demonstrate the efficacy of MnSOD-PL for suppressing radiation-induced HR in vivo.
Collapse
Affiliation(s)
- Yunyun Niu
- Departments of Radiation Oncology and Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Coppes RP, van der Goot A, Lombaert IMA. Stem cell therapy to reduce radiation-induced normal tissue damage. Semin Radiat Oncol 2009; 19:112-21. [PMID: 19249649 DOI: 10.1016/j.semradonc.2008.11.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Normal tissue damage after radiotherapy is still a major problem in cancer treatment. Stem cell therapy may provide a means to reduce radiation-induced side effects and improve the quality of life of patients. This review discusses the current status in stem cell research with respect to their potential to reduce radiation toxicity. A number of different types of stem cells are being investigated for their potential to treat a variety of disorders. Their current status, localization, characterization, isolation, and potential in stem cell-based therapies are addressed. Although clinical adult stem cell research is still at an early stage, preclinical experiments show the potential these therapies may have. Based on the major advances made in this field, stem cell-based therapy has great potential to allow prevention or treatment of normal tissue damage after radiotherapy.
Collapse
Affiliation(s)
- Rob P Coppes
- Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | | | | |
Collapse
|
|
24
|
Abstract
The recovery of tissues and organs from ionizing irradiation is critically dependent on the repopulation of resident stem cells, defined as the subset of cells with capacity for both self-renewal and differentiation. Stem cells of both hematopoietic and epithelial origin reside in defined areas of the cellular microenvironment (recently defined as the stem cell "niche"). Experiments using serial repopulation assays in serial generations of total body irradiated mice receiving transplanted marrow and in continuous bone marrow cultures both identified specific microanatomic sites that comprise the bone marrow stem cell niche. Supportive cells of the hematopoietic microenvironment not only contribute to stem cell repopulation capacity but also to the maintenance of their quiescent or nonproliferative state, which allows the most primitive hematopoietic stem cells to stay in a noncycling state protected from both direct ionizing radiation-induced cell-cycle phase-specific killing and indirect cytokine and free radical mediated killing. Recent evidence has defined both cell contact and humoral mechanisms of protection of hematopoietic stem cells by stromal cells. There is also recent evidence for multilineage differentiation capacity of cells of the hematopoietic microenvironment termed bone marrow stromal cells (mesenchymal stem cells). Both hematopoietic stem cells and mesenchymal stem cell populations have been shown to be involved in the repair of ionizing irradiation damage of distant epithelial as well as other hematopoietic sites through their capacity to migrate through the circulation. The radiobiology of these 2 bone marrow stem cell populations is the subject of intense investigation. This review defines the status of research in the areas of stem cell quiescence, niche contact, and migratory responses to ionizing irradiation.
Collapse
Affiliation(s)
- Joel S Greenberger
- Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
| | | |
Collapse
|
|
25
|
Zani A, Pierro A, Elvassore N, De Coppi P. Tissue engineering: an option for esophageal replacement? Semin Pediatr Surg 2009; 18:57-62. [PMID: 19103424 DOI: 10.1053/j.sempedsurg.2008.10.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Esophageal replacement is required in several pediatric surgical conditions, like long-gap esophageal atresia. Although several techniques have been described to bridge the gap, all of them could be followed by postoperative complications. Esophageal tissue engineering could represent a valid alternative thanks to the recent advances in biomaterial science and cellular biology. Numerous attempts to shape a new esophagus in vitro have been described in the last decade. Herein, we review the main studies on the experimental use of nonabsorbable and absorbable materials as well as the development of cellularized patches. Furthermore, we describe the future perspectives of esophageal tissue engineering characterized by the use of stem cells seeded on new biopolymers. This opens to the construction of a functional allograft that could allow an anatomical replacement that grows with the children and does not severely impair their anatomy.
Collapse
Affiliation(s)
- Augusto Zani
- Department of Paediatric Surgery, Institute of Child Health & Great Ormond St Hospital, London, United Kingdom
| | | | | | | |
Collapse
|
|
26
|
Gharaibeh B, Lu A, Tebbets J, Zheng B, Feduska J, Crisan M, Péault B, Cummins J, Huard J. Isolation of a slowly adhering cell fraction containing stem cells from murine skeletal muscle by the preplate technique. Nat Protoc 2008; 3:1501-9. [PMID: 18772878 DOI: 10.1038/nprot.2008.142] [Citation(s) in RCA: 247] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This protocol details a procedure, known as the modified preplate technique, which is currently used in our laboratory to isolate muscle cells on the basis of selective adhesion to collagen-coated tissue culture plates. By employing this technique to murine skeletal muscle, we have been able to isolate a rapidly adhering cell (RAC) fraction within the earlier stages of the process, whereas a slowly adhering cell (SAC) fraction containing muscle-derived stem cells is obtained from the later stages of the process. This protocol outlines the methods and materials needed to isolate RAC and SAC populations from murine skeletal muscle. The procedure involves mechanical and enzymatic digestion of skeletal muscle tissue with collagenase XI, dispase and trypsin followed by plating the resultant muscle slurry on collagen type I-coated flasks where the cells adhere at different rates. The entire preplate technique requires 5 d to obtain the final preplate SAC population. Two to three additional days are usually required before this population is properly established. We also detail additional methodologies designed to further enrich the resultant cell population by continuing the modified preplating process on the SAC population. This process is known as replating and requires further time.
Collapse
Affiliation(s)
- Burhan Gharaibeh
- Stem Cell Research Center, 4100 Rangos Research Center, 3460 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Esophageal stem cells--a review of their identification and characterization. ACTA ACUST UNITED AC 2008; 4:261-8. [PMID: 18679835 DOI: 10.1007/s12015-008-9031-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2008] [Indexed: 12/13/2022]
Abstract
The incidence of adenocarcinoma of the esophagus has increased faster than any other internal malignancy over the last 40 years. Despite this, surprisingly little is known about the basic biology of this tissue, particularly with regards to the organization of cell proliferation within the epithelium. This is a matter of crucial importance for our understanding of the pathogenesis of esophageal cancer. Nevertheless, significant advances have recently been made in the identification and functional characterization of both murine and human esophageal stem cells and their progeny in recent years. This places investigators in an exciting position to gain further insights into the processes of tissue renewal and repair on the one hand and the development of dysplasia and malignancy on the other.
Collapse
|
|
28
|
Sarosi G, Brown G, Jaiswal K, Feagins LA, Lee E, Crook TW, Souza RF, Zou YS, Shay JW, Spechler SJ. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus. Dis Esophagus 2008; 21:43-50. [PMID: 18197938 DOI: 10.1111/j.1442-2050.2007.00744.x] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus develops when refluxed gastric juice injures the esophageal squamous lining and the injury heals through a metaplastic process in which intestinal-type columnar cells replace squamous ones. The progenitor cell that gives rise to Barrett's metaplasia is not known, nor is it known why the condition is predisposed to malignancy. We studied the contribution of bone marrow stem cells to the development of Barrett's esophagus in an animal model. Twenty female rats were given a lethal dose of irradiation followed by tail vein injection of bone marrow cells from male rats. Ten days later, the female rats were randomly assigned to undergo either esophagojejunostomy, a procedure that causes reflux esophagitis with intestinal metaplasia, or a sham operation. The rats were killed at 8 weeks and serial sections of the snap-frozen esophagi were cut and mounted on slides. The first and last sections were used for histological evaluation and the intervening sections were immunostained for cytokeratin to identify epithelial cells and analyzed for Y chromosome by fluorescence in situ hybridization (FISH). Histological evaluation of the esophagi from rats that had esophagojejunostomy revealed ulcerative esophagitis and multiple areas of intestinal metaplasia. FISH analyses showed that some of the squamous epithelial cells and some of the columnar epithelial cells lining the glands of the intestinal metaplasia were positive for Y chromosome. These observations suggest that multi-potential progenitor cells of bone marrow origin contribute to esophageal regeneration and metaplasia in this rat model of Barrett's esophagus.
Collapse
Affiliation(s)
- G Sarosi
- Dallas VA Medical Center, Dallas, Texas 75216, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Niu Y, Epperly MW, Shen H, Smith T, Wang H, Greenberger JS. Intraesophageal MnSOD-plasmid liposome enhances engraftment and self-renewal of bone marrow derived progenitors of esophageal squamous epithelium. Gene Ther 2007; 15:347-56. [PMID: 18097469 DOI: 10.1038/sj.gt.3303089] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We evaluated whether the improved esophageal radiation tolerance following Manganese Superoxide Dismutase (MnSOD)-Plasmid Liposomes was explained by improved engraftment of bone marrow-derived progenitors. C57BL/6NHsd female mice pretreated with intraesophageal MnSOD-PL were irradiated to 29 Gy to the esophagus and intravenously transplanted with marrow from male B6. 129S7-Gt (ROSA) 26S OR/J ROSA (Lac-Z+, G418-resistant) mice. After 14 days, esophagi were removed and side population and non-side population cells evaluated for donor multilineage (endothelin/vimentin/F480) positive esophageal cells. Serial intravenous transplantability was tested in second generation 29 Gy esophagus-irradiated mice. Esophagi from recipients receiving swallowed MnSOD-PL 24 h prior to irradiation demonstrated significantly increased esophageal repopulation with donor bone marrow-derived Lac-Z+, G418+, Y-probe+ multilineage cells (37.8+/-1.8>50 cell Lac-Z+ foci per esophagus) compared to irradiated controls (19.8+/-1.8) P<0.0001. Serial transfer to second-generation irradiated C57BL/6NHsd mice of intravenously injected SP or NSP first generation recipient esophagus cells was also significantly enhanced by MnSOD-PL intraesophageal pretreatment (74.4+/-3.6 SP-derived Lac-Z+ foci per esophagus, 48.6+/-5.4 NSP-derived) compared to irradiation controls (23.4+/-1.8 SP, 6.0+/-3.0 NSP), P<0.0001. Thus, intraesophageal MnSOD-PL administration enhances engraftment of marrow-derived progenitors.
Collapse
Affiliation(s)
- Y Niu
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
| | | | | | | | | | | |
Collapse
|
|
30
|
Păunescu V, Deak E, Herman D, Siska IR, Tănasie G, Bunu C, Anghel S, Tatu CA, Oprea TI, Henschler R, Rüster B, Bistrian R, Seifried E. In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J Cell Mol Med 2007; 11:502-8. [PMID: 17635641 PMCID: PMC3922356 DOI: 10.1111/j.1582-4934.2007.00041.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Our study examined whether human bone marrow-derived MSCs are able to differentiate, in vitro, into functional epithelial-like cells. MSCs were isolated from the sternum of 8 patients with different hematological disorders. The surface phenotype of these cells was characterized.To induce epithelial differentiation, MSCs were cultured using Epidermal Growth Factor, Keratinocyte Growth Factor, Hepatocyte Growth Factor and Insulin-like growth Factor-II. Differentiated cells were further characterized both morphologically and functionally by their capacity to express markers with specificity for epithelial lineage. The expression of cytokeratin 19 was assessed by immunocytochemistry, and cytokeratin 18 was evaluated by quantitative RT-PCR (Taq-man). The data demonstrate that human MSCs isolated from human bone marrow can differentiate into epithelial-like cells and may thus serve as a cell source for tissue engineering and cell therapy of epithelial tissue.
Collapse
Affiliation(s)
- Virgil Păunescu
- Department of Physiology and Immunology, University of Medicine and Pharmacy Victor Babes Timisoara, Romania.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
Cytotoxic exposure of bone marrow and other non-hematopoietic organs containing self-renewing stem cell populations is associated with damage to the supportive microenvironment. Recent evidence indicates that radical oxygen species resulting from the initial oxidative stress persist for months after ionizing irradiation exposure of tissues including oral cavity, esophagus, lung and bone marrow. Antioxidant gene therapy using manganese superoxide dismutase plasmid liposomes has provided organ-specific radiation protection associated with delay or prevention of acute and late toxicity. Recent evidence has suggested that manganese superoxide dismutase transgene expression in cells of the organ microenvironment contributes significantly to the mechanism of protection. Incorporating this knowledge into designs of novel approaches for stem cell protection is addressed in the present review.
Collapse
Affiliation(s)
- J S Greenberger
- Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2532, USA.
| |
Collapse
|
|
32
|
De Ruysscher D, Dehing C, Bremer RH, Bentzen SM, Koppe F, Pijls-Johannesma M, Harzée L, Minken A, Wanders R, Hochstenbag M, Dingemans AM, Boersma L, van Haren E, Geraedts W, Pitz C, Simons J, Wouters B, Rosier JF, Lambin P. Maximal neutropenia during chemotherapy and radiotherapy is significantly associated with the development of acute radiation-induced dysphagia in lung cancer patients. Ann Oncol 2007; 18:909-16. [PMID: 17322546 DOI: 10.1093/annonc/mdm005] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Acute dysphagia is a distressing dose-limiting toxicity after concurrent chemoradiation or high-dose radiotherapy for lung cancer. We therefore identified factors associated with the occurrence of acute dysphagia in lung cancer patients receiving radiotherapy alone or combined with chemotherapy. PATIENTS AND METHODS Radiotherapy, chemotherapy and patient characteristics were analyzed using ordinal regression analysis as possible predictors for acute dysphagia (CTCAE 3.0) in 328 lung cancer patients treated with curative intent. RESULTS The most significant association was seen between the maximal grade of neutropenia during chemoradiation and dysphagia, with an odds ratio increasing from 1.49 [95% confidence interval (CI) 0.63-3.54, P = 0.362] for grade 1-2 neutropenia to 19.7 (95% CI 4.66-83.52, P < 0.001) for patients with grade 4 neutropenia. Twice-daily schedule, mean esophageal dose and administration of chemotherapy were significant predictive factors. By combining these factors, a high-performance predictive model was made. On an individual patient level, 64% of patients were correctly classified and only 1.2% of patients were misclassified by more than one grade. CONCLUSIONS The maximal neutrophil toxicity during concurrent chemotherapy and radiotherapy is strongly associated with the development of acute dysphagia. A multivariate predictive model was developed.
Collapse
Affiliation(s)
- D De Ruysscher
- Department of Radiotherapy, MAASTRO clinic, GROW, University Hospital Maastricht, Maastricht, The Netherlands.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Li Y, Wo JM, Ellis S, Ray MB, Jones W, Martin RCG. Morphological transformation in esophageal submucosa by bone marrow cells: esophageal implantation under external esophageal perfusion. Stem Cells Dev 2007; 15:697-705. [PMID: 17105405 DOI: 10.1089/scd.2006.15.697] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Accumulating clinical and experimental studies indicate that Barrett's esophagus might arise through multipotential stem cells under the stress of gastroesophageal reflux. Previously, we have presented a novel external pump perfusion rat model and demonstrated that perfusion with both acid and bile can induce severe esophagitis in 1 week with a similarly pathological change seen in humans. The aim of this study was to investigate the histological changes of esophagus after bone marrow cell engraftment with bile and acid perfusion. The external pump perfusion procedure involved implantation of a microosmotic pump for esophageal perfusion. Bone marrow cells were obtained by flushing of the femur marrow, and the cell suspension was injected between the esophageal muscular and inner mucosa layer. Histological changes were determined after 4 weeks of perfusion. Proliferating cell nuclear antigen, 8-hydroxy-deoxyguanosine, manganese superoxide dismutase, and apoptosis were measured by immunohistochemical staining and TUNEL assay, respectively. Severe esophagitis was seen in both acid and bile perfusion. Bone marrow engraftment and potentiation was seen in both the acid and bile perfusion, when compared to saline controls. Glandular-like cells in submucosa, consistent with intestinal metaplasia, confirmed by Alcin Blue-PAS staining were observed after bone marrow esophageal implantation along with bile perfusion, but not with acid perfusion and controls. Bone marrow implantation in conjunction with esophageal reflux injury contributes to abnormal histological changes consistent with early Barrett's esophageal changes. Engrafted bone marrow cells proliferate under oxidative stress conditions with bile perfusion.
Collapse
Affiliation(s)
- Yan Li
- Division of Surgical Oncology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | | | | | | | | | | |
Collapse
|
|
34
|
Epperly MW, Cao S, Goff J, Shields D, Zhou S, Glowacki J, Greenberger JS. Increased longevity of hematopoiesis in continuous bone marrow cultures and adipocytogenesis in marrow stromal cells derived from Smad3(-/-) mice. Exp Hematol 2005; 33:353-62. [PMID: 15730859 DOI: 10.1016/j.exphem.2004.11.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2004] [Revised: 11/12/2004] [Accepted: 11/18/2004] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To determine the role of Smad3 in modulating hematopoiesis, continuous bone marrow cultures were established from Smad-/- mice, and the longevity of hematopoiesis and extent of adipogenesis in the supportive hematopoietic microenvironment were compared to those from cultures of control, Smad3+/+ or heterozygous Smad3+/- mice. MATERIALS AND METHODS Long-term bone marrow cultures (LTBMCs) were established from Smad3+/+, Smad3+/-, or Smad3-/- mice. On a weekly basis, the number of cobblestone islands, number of nonadherent cells, confluence of the adherent cells, or CFU-GEMM colonies was determined. Bone marrow stromal cell lines were established and cobblestone island production on these cell lines determined in the presence of nonadherent cells from week-42 Smad3-/- or week-4 C57BL/6J LTBMCs. RESULTS Initial proliferative capacity of the LTBMCs was similar in all groups through week 20, at which time there was an increase in cobblestone islands and production of nonadherent cells and CFU-GEMM colonies in the Smad3-/- group. By week 28, only the Smad3-/- LTBMCs had significantly maintained increased production of these parameters. Maintenance of cobblestone islands indicative of the most primitive hematopoietic progenitor cells persisted past 45 weeks in Smad3-/- cultures. The Smad3-/- stromal cell line also demonstrated increased support of cobblestone island production when incubated with nonadherent cells from week-42 Smad3-/- or week-4 C57BL/6J LTBMCs. Evaluation of adipocytogenesis in stromal cells showed significantly greater accumulation of adipocytes in lines from Smad3-/- than from Smad3+/+ mice. CONCLUSIONS These data provide evidence for a significant effect of deletion of the Smad3 signaling pathway in increased hematopoiesis in LTBMCs and support the negative regulatory influence of TGFbeta signaling on adipocytogenesis and long-term hematopoiesis in vitro.
Collapse
Affiliation(s)
- Michael W Epperly
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
| | | | | | | | | | | | | |
Collapse
|