Stem Cell Therapeutics for Cancer E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 648

Veröffentlichungsjahr: 2013

Beschreibung

Stem Cell Therapeutics for Cancer covers the application of stem cells in various cancers, with an emphasis on the aspects of these strategies that are critical to the success of future stem cell-based therapies for cancer. Topics covered in the book include stem cell sources, tumor specificity, targeted therapeutics, visualizing the stem cell, and therapeutic agent pharmacokinetics. Each chapter contains a brief introduction to the cancer, followed by an exploration of how engineered stem cells have been utilized to cure the disease in mouse models and in early phase clinical trials.

• Comprises of sections on stem cell therapy in brain cancers, lung cancers, breast cancers, as well as stem cells in combination with other therapies
• Focuses on the practical applications of using stem cells as gene delivery agents to treat cancer
• Includes coverage of cutting-edge molecular imaging techniques in stem cell therapeutics for a variety of tumour types

Leseprobe

Contents

Contributors

Preface

Section 1 Introduction

Chapter 1 Stem Cell Sources and Their Potential for Cancer Therapeutics

Introduction

Adult Stem Cells

Prospects and Caveats on the Way to the Clinics

References

Section 2 Migration and Fate of Stem Cells

Chapter 2 The Role of CXCR4 as a Mediator of Glioma-Tropic Neural Precursor Cell Migration

Introduction

CXCR4

CXCR4 and NSC

Conclusion

References

Chapter 3 Tumor Tropism of Mesenchymal Stem Cells

Introduction

Homing of MSC to Tumors

GPCR in MSC Migration

Activation of MSC Migration by Cytokines and Growth Factors

Role of MMPs in MSC Migration

Crosstalk Between MMP-1/PAR-1 Axes with Other Signaling Pathway

Concluding Remarks

Acknowledgements

References

Section 3 Stem Cell Therapy in Brain Cancer

Chapter 4 Stem Cell-Mediated TRAIL Therapy for Highly Aggressive Brain Tumors

Introduction

Transplantation Route and Fate of Stem Cells

Genetic Modification of SC

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)

Stem cell–mediated delivery of TRAIL

Stem Cell–Mediated Delivery of TRAIL in Clinically Relevant Mouse Tumor Models

Resistance to TRAIL and Combination Therapies

Imaging of Death-Receptor Expression Levels Identifies Modulators of TRAIL Sensitivity

Combination of MS-275 and Stem Cell–Delivered TRAIL Reveals Efficacy in TRAIL-Resistant GBMs in Vivo

Conclusions and Perspectives

References

Chapter 5 Stem Cell-Mediated Prodrug Gene Therapy of High-Grade Brain Tumors

Introduction

Enzymes and Prodrugs in GDEPT for Cancer Treatment

Classification of Brain Tumors

Source of Mesenchymal Stem Cells for Therapeutic Use

Stem Cell–Mediated Prodrug Gene Therapy for Glioblastoma

Stem Cell–Driven Cytosine Deaminase/5-FC System

Stem Cell–Driven Herpes simplex virus Thymidine Kinase/Ganciclovir System

Stem Cell–Driven Rabbit Carboxylesterase/CPT-11 System

Stem Cell–Driven Therapeutic Cytokines and Proapoptotic Genes

Conclusions

Acknowledgements

References

Chapter 6 Role of Naïve Cord Blood Stem Cells in Glioma Therapy

Introduction

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells (hUCBSC)

Role of hUCBSC in Glioma Therapy

Future Insights on Cord Blood Stem Cell Therapy

Acknowledgements

References

Chapter 7 Stem Cell-Based Antiangiogenic Therapies for Brain Tumors

Introduction

Stem Cell–Based Antiangiogenic Therapies

Conclusions and Perspectives

References

Chapter 8 Treatment of Metastatic Neuroblastoma with Mesenchymal Stem Cell-Based Oncolytic Virotherapy

Neuroblastoma

Oncolytic Virotherapy

Mesenchymal Stem Cell and Oncolytic Virotherapy

Conclusions and Perspectives

References

Section 4 Stem Cell Therapy in Brain Cancer

Chapter 9 Umbilical Cord Matrix Stem Cells for Cytotherapy of Breast Cancer

Introduction

MSC in Cancer Cytotherapy

Characteristics of UCMSC

UCMSC in cancer therapy

UCMSC Therapy in Breast Cancers

Future Studies

Conclusion

Acknowledgements

References

Chapter 10 Mesenchymal Stromal Cells as Effective Tumor Antigen-Presenting Cells in Cancer Therapeutics

Introduction

Medical Use of MSC in Treating Alloimmune Complications in the Context of GVHD in Non-Self-HSC-Transplanted Patients

Immune Plasticity of MSC

MSC and Cancer

Conclusion

Acknowledgements

References

Chapter 11 Diagnostic and Therapeutic Mesenchymal Stem Cells for Breast Cancer Treatment

Introduction

MSC Homing and Immune Regulation

Stem Cells that Have Combined Therapeutic and Diagnostic Functions

Perspectives

References

Chapter 12 Genetically Engineered Stem Cell Therapies Targeting Gastrointestinal Malignancy

Introduction

Genetic Modifications of Stem Cells to Target Gastrointestinal Malignancy

Genetically Engineering MSC to Target Gastrointestinal Malignancy: Transgene Products

Genetically Engineering MSC to Target Gastrointestinal Malignancy: Strategies to Enhance Tumor Selectively

Choice of Targeting Strategy Must Be Based on Thorough Understanding of Tumor Biology

Current Limitations of Genetically Engineered Stem Cell Cancer Therapy Targeting Gastrointestinal Malignancy

Conclusion

References

Chapter 13 Mesenchymal Stem Cells in Prostate Cancer: Clinical Opportunities

Background and Significance

Pathology of the Tumor Microenvironment: The MSC Connection

Recruitment of MSC to the Tumor Microenvironment

MSC in Prostate Cancer: An Update

Genetically Engineered MSC for the Treatment of Prostate Cancer

Clinical Prospects

Acknowledgements

References

Chapter 14 Primed Mesenchymal Stromal Cells for Cancer Therapy

Introduction

Priming Mesenchymal Stromal Cells with Paclitaxel

Testing PTX Uptake and Release

PTX-Uptake /Release Mechanism and Kinetics

In Vitro Antitumor Proliferation Activity

Antiangiogenic Properties of MSCPTX

Capacity of MSC-PTX to Inhibit In Vivo Tumor Growth

PTX Uptake Released by Stromal Cells from Different Species and Sources

Conclusions

References

Section 5 Combinatorial Stem Cell Therapies

Chapter 15 MicroRNA Adjuvants in Stem Cell-Based Cancer Therapy

Introduction

MicroRNAs: Biogenesis and Function

MicroRNAs and Cancer

MicroRNA Adjuvants in Cancer Research

MicroRNA-21: Target for Combinational Therapy

MicroRNAs: Regulators of TRAIL-Induced Apoptosis

Conclusion and Future Perspectives

References

Chapter 16 Stem Cell-Based Combination Therapies for Cancer: Systemic Delivery of a PI3K/mTOR Inhibitor (PI-103) and Stem Cell-Mediated Delivery of TRAIL in Brain Tumors

Introduction

Stem–Cell Based Combination Therapies in GBM

PI3K Signaling in GBM

PI3 Kinase Inhibitors

PI-103

PI3K Inhibition and TRAIL

PI-103 and Stem Cell–Delivered TRAIL

Concluding Remarks

References

Chapter 17 The Efficacy of Clinically Approved Agents with Stem Cell-Delivered Therapeutics for Cancer Therapy

Introduction

Conventional Therapy for Cancer and Glioblastoma

Combining Stem Cell Delivery of TRAIL with Chemotherapeutic Temozolomide

Combining Stem Cell Delivery of TRAIL with Radiation Therapy

Other Candidates to Combine with Stem Cell Delivery of Proapoptotic Molecule

Conclusions

References

Section 6 Tracking Stem Cells and Stem Cell-Based Therapeutics

Chapter 18 Imaging Migration and Fate of Stem Cells in Experimental Models of Cancer

Introduction

Optical Imaging as an Efficient Method for Imaging and Tracking Fate of Stem Cells

Conclusion

References

Chapter 19 Multifunctional Molecules for Interrogating Stem Cell-Based Therapeutics

Introduction

Conclusions

References

Chapter 20 Tracking Cancer-Targeted MSC with PET Imaging

Introduction

Principles of PET Imaging

Labeling Strategies for PET Imaging

Application of MSC Imaging with PET

Limitations

Future Perspectives

Conclusions

References

Supplemental Images

Index

Copyright © 2013 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Stem cell therapeutics for cancer / edited by Khalid Shah. p. ; cm. Includes bibliographical references and index.

ISBN 978-1-118-28242-7 (hardback : alk. paper) – ISBN 978-1-118-66033-1 – ISBN 978-1-118-66042-3 – ISBN 978-1-118-66049-2 (mobi) – ISBN 978-1-118-66062-1 I. Shah, Khalid. [DNLM: 1. Neoplasms–therapy. 2. Mesenchymal Stem Cell Transplantation–methods. 3. Mesenchymal Stromal Cells–physiology. 4. Stem Cells–physiology. QZ 266] RC271.C44 616.99′406–dc23

2013010437

Contributors

Giulio AlessandriDepartment of Cerebrovascular DiseasesFondazione IRCCS Neurological Institute Carlo BestaMilan, ItalyCestmir AltanerCancer Research InstituteSlovak Academy of SciencesBratislava, SlovakiaandCell Transplantation CentreSt. Elisabeth Oncological InstituteBratislava, SlovakiaMaarten C.J. AndereggAcademic Medical CenterDepartment of SurgeryAmsterdam, The NetherlandsTugba Bagci-OnderKoç University School of MedicineIstanbul, TurkeyDeepak BhereDepartment of RadiologyMassachusetts General HospitalHarvard Medical SchoolBoston, Massachusetts, USAArianna BonomiDepartment of Biomedical, Surgical, and Dental SciencesUniversity of MilanMilan, ItalyDiptiman ChandaDepartment of PathologyThe University of Alabama at BirminghamBirmingham, Alabama, USAClaudius ConradDepartment of Surgery/ Division of Surgical OncologyAffiliated Faculty Harvard Stem Cell InstituteMassachusetts General Hospital and Brigham and Women’s HospitalHarvard Medical SchoolBoston, Massachusetts, USAMaarten F. CorstenMeander Medical CenterDepartment of Internal MedicineAmersfoort, The NetherlandsVenkata Ramesh DasariDepartment of Cancer Biology and PharmacologyUniversity of Illinois College of Medicine at PeoriaPeoria, Illinois, USARóisín DwyerDiscipline of SurgerySchool of Medicine National University of Ireland Galway Galway, IrelandMoneeb EhteshamDepartment of Neurological SurgeryVanderbilt University Medical CenterNashville, Tennessee, USAJacques GalipeauDepartment of Hematology/Oncology and PediatricsWinship Cancer Institute of Emory UniversityAtlanta, Georgia, USAJavier García-CastroInstituto de Salud Carlos IIIMajadahonda, SpainShawn HingtgenUNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel Hill, North Carolina, USAIvy A. W. HoHumphrey Oei Institute of Cancer ResearchNational Cancer Centre of SingaporeSingaporeSusumu IshiguroDepartment of Anatomy and PhysiologyKansas State UniversityManhattan, Kansas, USARebecca KaslDepartment of Neurological SurgeryVanderbilt University Medical CenterNashville, Tennessee, USAAtsushi KawabataDepartment of Anatomy and PhysiologyKansas State UniversityManhattan, Kansas, USAEmily KeungDepartment of SurgeryBrigham and Women’s HospitalHarvard Medical SchoolBoston, Massachusetts, USAPaula Y. P. LamHumphrey Oei Institute of Cancer ResearchNational Cancer Centre of SingaporeSingaporeElliot MinDepartment of Neurological SurgeryVanderbilt University Medical CenterNashville, Tennessee, USAPeter J. NelsonMedizische Klinik und Poliklinik IVMunich, GermanyNaomi OhtaDepartment of Anatomy and PhysiologyKansas State UniversityManhattan, Kansas, USARoberto PalliniInstitute of NeurosurgeryCatholic University School of MedicineRome, ItalyEugenio ParatiDepartment of Cerebrovascular DiseasesFondazione IRCCS Neurological Institute Carlo BestaMilan, ItalyAugusto PessinaDepartment of Biomedical, Surgical, and Dental SciencesUniversity of MilanMilan, ItalySelvarangan PonnazhaganDepartment of PathologyThe University of Alabama at BirminghamBirmingham, Alabama, USAManuel RamírezPediatric Hematology and OncologyHospital Universitario Niño JesúsMadrid, SpainJasti S. RaoDepartments of Cancer Biology and Pharmacology and NeurosurgeryUniversity of Illinois College of Medicine at PeoriaPeoria, Illinois, USANavid RedjalDepartment of Radiology and NeurosurgeryMassachusetts General HospitalHarvard Medical SchoolBoston, Massachusetts, USAVéronique RoelantsUniversité catholique de LouvainInstitut de Recherche Expérimentale et CliniquePôle de Recherche Cardiovasculaire et Pôle d’Imagerie MoléculaireRadiothérapie et OncologieBrussels, BelgiumRaphaëlle Romieu-MourezThe Montreal Center for Experimental Therapeutics in CancerJewish General HospitalMcGill UniversityMontreal, Quebec, CanadaKhalid ShahDepartment of Radiology and NeurologyMassachusetts General HospitalHarvard Medical SchoolBoston, Massachusetts, USAMasaaki TamuraDepartment of Anatomy and PhysiologyKansas State UniversityManhattan, Kansas, USADeryl TroyerDepartment of Anatomy and PhysiologyKansas State UniversityManhattan, Kansas, USADeepthi UppalapatiDepartment of Anatomy and PhysiologyKansas State UniversityManhattan, Kansas, USAJean-Louis VanoverscheldeUniversité catholique de LouvainInstitut de Recherche Expérimentale et CliniquePôle de Recherche Cardiovasculaire et Pôle d’Imagerie MoléculaireRadiothérapie et OncologieBrussels, BelgiumKiran Kumar VelpulaDepartment of Cancer Biology and PharmacologyUniversity of Illinois College of Medicine at PeoriaPeoria, Illinois, USAHiroaki WakimotoDepartments of Radiology and NeurosurgeryMassachusetts General HospitalHarvard Medical SchoolBoston, Massachusetts, USA

Preface

Although they are a relatively new approach of therapeutics, stem cell-based therapies offer a huge potential in the practice of medicine. With the thorough understanding of stem cell biology and the advent of targeted therapeutics for cancer, stem cell-based therapeutic strategies are being explored in the treatment of various cancer types. This volume is focused on the application of stem cells in various cancers with emphasis on a number of aspects that are critical to the success of future stem cell-based therapies for cancer. The sections in this volume have been submitted by a range of experts working at the leading edge of the field, including oncologists, neurosurgeons, physicians, and research scientists. They cover a formidable array of topics in a concise way and offer differing scientific perspectives on specific aspects of stem cell-based cancer treatment.

The overarching theme of this text is not only to convey the facts, but also to spread a sense of excitement with a hint of challenge in stem cell research. Different sections of this volume are devoted to developing stem cell-based therapies for cancer with the main focus on tumoritrophic properties of stem cells, engineering targeted therapeutics, utilization of imaging techniques, and the recent combination studies that use currently employed drugs with stem cells. These sections are put together with the aim to make this text intellectually satisfying and to enable the users to appreciate the outstanding unanswered questions in the ocean of stem cell research with the focus on cancer therapeutics. This volume includes sufficient theoretical and practical details for students, established practitioners, and research fellows from different fields to become familiar with the potential of stem cell therapeutics in different cancer types.

Khalid Shah

Section 1

Introduction

Chapter 1

Stem Cell Sources and Their Potential for Cancer Therapeutics

Khalid Shah

Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

Introduction

Stem cells are the natural sources of embriogenetic tissue generation and continuous regeneration throughout adult life. In embryogenesis, cells from the inner cell mass (ICM) of the gastrula are known as embryonic stem cells, and their multilineage potential is generally referred to as pluripotent.1 The gastrular ICM cells commence formation of the three germ layers: endoderm, mesoderm, and ectoderm, each committed to generating specified tissues of the forming body, and thus containing stem cells with more restricted potential than pluripotent stem cells.2 Tissue-specific stem cells, such as mesenchymal stem cells (mesoderm), hematopoietic stem cells (mesoderm), and neural stem cells (ectoderm), have been identified as present and active for virtually every bodily tissue and are hierarchically situated between their germ layer progenitors and differentiated end-organ tissues.2

Stem cells can be isolated in three ways: from the ICM of the gastrula (embryonic stem cells), from fetal cord blood, and from adult tissues or blood (adult/somatic stem cells). It is not entirely clear whether adult stem cells harbor intrinsic differences from embryonic stem cells. Embryonic stem cells display indefinite self-renewal capacity due to high telomerase expression. In contrast, telomerase activity in adult stem cells seems to be lower, limiting their perpetuation capacity in the long run.3 Adult stem cells have been studied extensively and are already a successful source of FDA-approved treatments for nine human diseases, such as Parkinson’s disease and juvenile diabetes, currently applied in clinical centers.4 Though not as highly pluripotent and self-renewing as their embryonic counterparts, adult stem cells are much safer with respect to postgrafting tumor formation. Further, whereas the isolation of adult stem cells from specific parts of the body—such as brain or heart—is complicated, the advent of transdifferentiation techniques and ongoing discovery of unexpectedly plastic and versatile stem cells might provide autologous stem cells resembling these clonal subtypes.5,6 Namely, the long held dogma of differentiation as a rigid and ­nonreversible process has been challenged over the past decade by a vast amount of studies claiming to show transdifferentiation or even de-differentiation of committed cells. Mesenchymal stem cells (MSC), muscle stem cells, and neural stem cells all seem to possess the potential of converting to tissue types of other lineages, both within or across germ lines.7–9 The highest degree of lineage plasticity has been imputed to bone marrow–derived MSC, which appear capable of giving rise to virtually all cell types following implantation into early blastocysts and are relatively easy to handle in vitro.8,10 Recent reports have shown that pluripotent stem cells could be generated from murine fibroblasts11 as well as from ­several human organs, such as heart, skin,12 and bone marrow.5 Also, researchers seem ­progressively to be able to guide differentiation of pluripotent stem cells into cell types of interest.13,14 These studies indicate that controlled transformation of naïve or committed adult cells from dispensable tissue into desired cell types for autologous transplantation might become reality in the near future.

Adult Stem Cells

Mesenchymal Stem Cells

The ability of MSC to develop into various cell types, and the ease with which they can be expanded in culture, have led to a great deal of interest in their use as therapeutic agents to treat a wide range of diseases. They can be isolated from adult human tissues, have the ­capability for self-renewal, and can differentiate into mesenchymal lineages—osteocytic, chondrocytic, and adipogenic. They can be expanded and manipulated in vitro and subsequently regrafted. Following reimplantation, they have been found to suppress the immune system, reintegrate into tissue architecture, and give rise to progeny consisting of both stem cells and lineage-restricted daughter cell types.15 Most importantly, MSC exhibit potent pathotropic migratory properties, rendering them attractive for use as targeted delivery ­vectors in tumor therapy.15,16

MSC have been successfully isolated from a number of organs including brain, liver, kidney, lung, bone marrow, muscle, thymus, pancreas, skin, adipose tissue, fetal tissues, umbilical cord, Wharton’s jelly, and placenta.17–20 The highest degree of lineage plasticity has been imputed to bone marrow–derived MSC, which are capable of giving rise to virtually all cell types following implantation into early blastocysts and are relatively easy to handle in vitro.8,10 Most of the preclinical studies to date have been performed with bone marrow–derived MSC, which might not be the most practical source available for the clinical settings. The harvesting of bone marrow requires an invasive procedure that yields a small number of cells, and the number, differentiation potential, and lifespan of bone marrow–derived MSC decline with patient age.21–23 Two alternate sources for harvesting MSC that have received considerable attention in recent years are adipose tissue and umbilical cord blood. Adipose tissue obtained from subcutaneous tissue represents the most abundant potential source for harvesting MSC reliably using simple techniques. The expansion potential, differentiation capacity, and immunophenotype of MSC derived from adipose tissue are nearly identical to those isolated from bone marrow.22 Umbilical cord blood, obtained after removal of the placenta, is a rich source of hematopoietic stem cells24,25 and has been shown to be also a rich source of MSC.26 Mononuclear cells can be separated and cultured from the cord blood, and cells in the heterogenous adherent layer have been shown to have a fibroblastoid morphology and express the same markers as bone marrow–derived MSC, namely CD13, CD29, CD49e, CD54, CD90, but not CD14, CD31, CD34, CD45, CD49d, or CD106, among others.27 Umbilical cord blood–derived MSC expand at a higher rate as compared to bone marrow and adipose-derived MSC,22,28 which may be due in part to higher telomerase activity.29 All three type of cells differentiate into osteocytes and chondrocytes,22,27,30,31 which is consistent with the properties of MSC.

Neural Stem Cells (NSC)

NSC isolated from both embryonic and adult human tissues have emerged as attractive candidates for delivering therapeutic proteins that specifically target glioma cells. These cells can be expanded and manipulated in vitro, and re-engrafed following transplantation. NSC have shown the ability to migrate extensively to sites of different pathologies and reintegrate into tissue architecture to give rise to progeny consisting of both stem cells and lineage-restricted terminal cell types.1,32,33 For therapeutic purposes, NSC must be derived, in a ­substantial number, from safe, consistent, and reliable sources and must meet the criterion of plasticity. Both embryonic stem cells (ESC) and adult NSC can be obtained in substantial amounts and have the intrinsic ability to adapt their specification fate in response to different environmental cues.34 Recent advances in the in vitro expansion of human ESC culture involve the characterization of defined factors that negate the use of feeder layers (often of murine origin), thus eliminating the problems of xenogeneic cell contamination and possible viral transmission.35,36 Adult NSC are multipotent cells that can be obtained from embryonic, fetal, neonatal, or adult central nervous system (CNS) tissue. These cells are found in abundance during embryonic development and their numbers and developmental potential dwindle as development progresses and exist only in small numbers and in specialized niches in the adult organism. In the adult CNS, these cells are especially enriched in the subventricular zone and the subgranular zone of the hippocampal dentate gyrus. Also, NSC have been isolated from the human postnatal cerebellum and adult brain.37,38 In humans, fetal NSC were originally isolated from the germinal zones in the subventricular region of a fetal telencephalon.39 Difference in developmental plasticity between embryonic, fetal, and adult stem cells could be either due to intrinsic cellular difference or disparity in the surrounding microenvironment but is most likely a combination of the two.40,41 This abrogation of developmental plasticity could also explain for the limited ability for tissue repair seen in the adult organism. Non-CNS–derived multipotent somatic stem cells, such as mesenchymal stem cells,42 placental cord blood stem cells,43 skin stem cells,44 and adipose tissue stem cells45 have recently been shown to have the potential to become NSC.

Therapeutic applications of NSC require a substantial number of cells that can be propagated in vitro in serum-free condition in the presence of epidermal growth factor (EGF) and β-fibroblast growth factor (FGF) as multicellular free-floating spheres or neurospheres. Withdrawal of growth factors promotes the spontaneous differentiation into mature cells (astrocytes, oligodendrocytes, and neurons) within the neurospheres. Regular ­disaggregations of neurospheres ensure the healthy propagation of NSC in vitro and numerical expansion of NSC. This, however, is time consuming and does not yield the large numbers of cells required for most experimental and clinical trials. Immortalization of primary NSC offers a solution to the above problem and can be achieved via the transduction of oncogenes such as the simian virus 40 large T antigen or the v-myc gene.46,47 These cells behave similarly as nonimmortalized NSC with the capability to migrate extensively in the developing and mature CNS. Ectopic expression of telomerase has also been shown to prolong the undifferentiated stemlike property of the NT2 neural progenitor cells.48,49

Apart from ethical considerations, the therapeutic use of ESC is constrained by some key issues—such as feeder-dependent growth expansion. As mentioned previously, this vexing problem, especially in the in vitro propagation of human ESC, is gradually being solved with the characterization of factors responsible for maintenance of the differentiated state of the ESC. In addition, better understanding of developmental kinetics of stem cells helps to increase the yield of ESC-derived NSC. However, additional guidelines need to be instituted, especially with respect to avoidance of in vivo teratocarcinoma formation associated with ESC. Practical issues pertaining to these matters are discussed in a review by Martino and Pluchino.50

Induced Pluripotent Stem Cells (iPSC)

Induced pluripotent stem cells are created by causing differentiated cells to express genes that are specific to embryonic stem cells. iPSC share many characteristics of embryonic stem cells, including the ability to differentiate into cells of all organs and tissues. The idea of being able to restore pluripotency to somatic cells by coexpression of specific reprogramming factors has created powerful new opportunities for modeling human diseases and offers hope for personalized regenerative cell therapies.51,52 iPSC have been shown to have the capacity to redifferentiate into almost any human cell type.

iPSC are a novel and practical tool for human disease modeling and correction, and in theory could serve as a limitless stem cell source for patient-specific cellular therapies.53Pluripotency refers to the ability of stem cells to grow indefinitely in culture while maintaining the potential to give rise to any of the three germ layers: endoderm, mesoderm, and ectoderm. Somatic cells can be reprogrammed to a stem cell–like state by transferring their nuclear content into oocytes or by fusion with ESC, indicating that unfertilized eggs and ESC contain factors that can confer pluripotency to somatic cells.52,53 Takahashi and Yamanaka hypothesized that the factors that play important roles in the maintenance of ESC identity also play pivotal roles in the induction of pluripotency in somatic cells.11 A screen of 24 candidate genes led to the triumphant description of a tetrad of transcription factors—Oct4, Sox2, Klf4, and cMyc—sufficient to reprogram tail-tip fibroblasts of mice into iPSC.52,53 This contribution stimulated an overwhelming number of follow-up studies, with successful reprogramming quickly translated to human ­fibroblasts12,54,55 and then to a wide variety of other cell types, including pancreatic β cells,56 neural stem cells,57,58 mature B cells,59 stomach and liver cells,60 melanocytes,61 adipose stem cells,62 and keratinocytes,63 demonstrating the seemingly universal capacity to alter cellular identity.

Other Stem Cell Sources

Dental Pulp Stem Cells

The potential use of adult dental pulp as a source of MSC has also been explored and validated. Dental pulp (DP) is a vascular connective tissue similar to mesenchymal tissue. The dental pulp–derived stem cells (DP-MSC) have a phenotype similar to the adult bone marrow–derived MSC (BM-MSC), and these cells also express mesenchymal progenitor-related antigens SH2, SH3, SH4, CD166, and CD29 with a cellular homogeneity of 90%–95%. Also, the DP-MSC and BM-MSC populations have a similar gene expression profile.64,65 In contrast to BM-MSC, DP-MSC have presented a higher proliferation pattern and lower differentiation ability. The most evident difference is the inability of DP-MSC to differentiate towards chondrogenesis. This may indicate either that BM- and DP-MSC are present at different stages of commitment and differentiation, not marked by phenotypical characteristics, or that different humoral networks are involved in each microenvironment.64

In short, the dental pulp–derived stem cells are obtained from a very accessible tissue resource, which is further expandable by using deciduous teeth, and possess stem cell–like qualities, including very good self-renewal and multilineage differentiation. Their capacity to induce osteogenesis64,66 could be of great clinical application in implantology. Moreover, these cells also could have potential clinical application in autologous in vivo stem cell ­transplantation for calcified tissue reconstruction. Their proven immunomodulatory activity makes them suitable for suppression of T-cell–mediated reaction in the setting of allogeneic bone marrow transplantation.64

Menstrual Blood Stem Cells

Menstrual blood from the uterine lining has been recognized as a novel source of stem cells67,68 with high regenerative capability after the menstrual cycle.67,69 Additionally, stromal cells derived from menstrual blood (MenSC) can be acquired without invasive procedures and avoid any ethical controversies. These cells display stem cell–like phenotypic markers, a propensity for self-renewal, high proliferative potential in vitro, and the ability to differentiate towards diverse cell lineages.

The utilization of human MenSC as a potential source for reprogramming into iPSC offers several advantages. First, MenSC may be more easily reprogrammed than terminally differentiated fibroblasts. Second, the procedure for isolating MenSC is relatively simple, fast, and safe, and does not pose any ethical concerns. Third, it is convenient to obtain a large quantity of MenSC as the starting population for reprogramming. Fourth, because the reprogramming process requires only two factors, opportunities for insertional mutagenesis are minimized. Furthermore, obviating the requirement for KLF4 and c-MYC reduces the risk of inducing tumorigenesis. However, there is one obvious limitation for MenSC in that they are only obtained from menstrual blood samples of women of reproductive age, which may narrow their applications. However, if iPSC indeed have memory of the donor tissue,67,70 MenSC-iPSC should be the best candidate for producing MenSC to treat uterus-related problems.67,68

Prospects and Caveats on the Way to the Clinics

Stem cell research is one of the most rapidly developing areas of science and medicine. The ability of adult stem cells, to preferentially migrate towards local and disseminated malignant disease and to interact with different tissue environments, present them as most attractive ­candidates for cell-based therapies in humans. For translation of promising pre-clinical studies into clinics, it is critical to develop a greater understanding of stem and progenitor cell characteristics, single-cell heterogeneity and their fate in mouse models that recapitulate more closely clinical settings. The type of stem cells used for a particular type of cancer in clinics will depend on their isolation efficiency and their pre-requirement as an allogeneic transfer. For example, the clinical translation of umbilical cord blood–derived MSC will be limited by their unreliable and often low isolation efficiency and requires ­allogeneic transfer. In contrast, allogeneic transfer is not necessary for adipose or bone ­marrow-derived MSC, in which case an autograft can easily be harvested from any patient. The advantage of using autologous stem cells is mainly their immunological ­compatibility, which has been shown to have a profound effect on cell survival after ­transplantation. For most of the stem cell based therapeutics for cancer, genetic manipulation of cells to combat the disease process will be required prior to transplantation. Before modification of the stem cells with a tumor specific transgene, a thorough understanding of the altered signaling pathways in different cancer types is necessary. This will ensure the specificity of the stem cell based targeted therapeutics. The safety of the transplanted stem cells is a major concern in clinical setting. Importantly, nonimmortalized adult stem cells do not confer the same danger as immortalized adult stem cells and may be used without posing risk to the patient. A number of clinical trials utilizing stem cells for cancer have not reported any major adverse events to date [NCT 00027820, NCT 00392886, NCT 00005799; www.clinicaltrials.gov]. There are also a number of ongoing clinical trials that are utilizing stem cells for cancer therapy; and the results of any adverse effect from such trials are still awaited. When the malignant transformation of transplanted stem cells is suspected, it would be desirable to selectively eradicate MSC by incorporating activatable cellular suicide genes into transplanted MSC or to selectively turn off gene expression. Possible mechanisms that allow for such controls are stem cell–conferred prodrug converting enzymes and transgenes that require additional in vivo cues for expression and the use of tetracyclin-regulatable ­promoters to turn off gene expression.

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Section 2

Migration and Fate of Stem Cells

Chapter 2

The Role of CXCR4 as a Mediator of Glioma-Tropic Neural Precursor Cell Migration

Moneeb Ehtesham, Elliot Min, and Rebecca Kasl

Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA

Introduction

Despite significant advances in surgical and adjuvant therapies, the prognosis for patients with high-grade gliomas remains dismal. For patients diagnosed with glioblastoma multiforme (GBM), the most common and aggressive subtype of glioma, median survival remains less than a year, while five-year survival hovers at less than 10%. Such statistics demonstrate the nature of gliomas as resilient and challenging therapeutic targets. Gliomas originate as primary invasive neoplasms from glia throughout the CNS and include astrocytomas, oligodendrocytomas, and ependymomas. Furthermore, the tendency of high-grade gliomas to metastasize via invasive microsatellites that infiltrate deeply into normal brain tissue makes most current therapies unlikely to significantly improve patient outcomes. However, the heterogeneity of cell populations that make up these tumors, specifically glioma progenitor cells, provides a potential target for more specialized treatment. Traditionally, tumors were considered grossly as a homogeneous cell population. More recent research has provided support for a cancer stem cell hypothesis in which a small subset of cells serve as progenitors to induce tumor growth and invasion.