Use of IPs cell derived neural stem cells as a cellular vehicle for glioma and breast cancer therapy

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Use of IPs cell derived neural stem cells as a cellular vehicle for glioma and breast cancer therapy

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USE OF iPS CELL-DERIVED NEURAL STEM CELL AS A CELLULAR VEHICLE FOR GLIOMA AND BREAST CANCER THERAPY ESTHER LEE XING WEI (B,Biomed Sci., University of Melbourne) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILISOPHY DEPARTMENT OF BIOLOGICAL SCIENCES NATIONAL UNIVERSITY OF SINGAPORE & INSTITUTE OF BIOENGINEERING AND NANOTECHNOLOGY (A*STAR) 2011 ACKNOWLEDGEMENTS First and foremost I would like to thank A/P Wang Shu for his scientific support and guidance The members of our lab: Ghayathri Balasundaram, Xiaoying Bak, Yukti Choudhury, Timothy Kwang, Dang Hoang Lam, Jiakai Lin, Seong Loong Lo, Yovita Ida Purwanti, Chrishan Julian Alles Ramachandra, Mohammad Shahbazi, Chunxiao Wu, Kai Ye, Ying Zhao, Jieming Zeng and Detu Zhu have been invaluable resources, not only for their technical help, tips and advices but also the camaraderie I am grateful for my family, especially my husband and son who have been with me through the tough times They have been nothing but supportive in all my endevaours Finally and most importantly,I would also like to thank God for His countless grace LIST OF PUBLICATIONS E X W Lee, D.H Lam and S.Wang iPS-cell derived Neural Stem Cell for Glioma Therapy Poster presentation World Stem Cell Summit, Detriot, USA, 2010 X Y Bak, D H Lam, J Yang, K Ye, E X W Lee, S K Lim and S Wang, "Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells as Cellular Delivery Vehicles for Prodrug Gene Therapy of Glioblastoma," Human Gene Therapy, (2011) E X W Lee, D.H Lam, C.X Wu, J Yang, C.K Tham, W.H Ng and S Wang Glioma Gene Therapy Using Induced Pluripotent Stem Cell Derived Neural Stem Cells Molecular Pharmaceutics , Oct 3;8(5):1515-24Jul 22,2011 E X W Lee, Y Kai, G Balasundaram, F Tay, S.Goh, S Wang Comparison of three suicide gene/prodrug systems in cancer gene therapy mediated by baculovirus-transduced neural stem cells derived from human pluripotent stem cells Poster presentation Stem Cell Society Singapore Symposium 2011 TABLE OF CONTENTS Introduction 1.1 Glioblastoma 13 1.2 Breast cancer 13 1.3 Gene therapy: the methods of gene transfer 1.3.1 Viral vectors 14 14 1.3.1.1 Adenovirus 15 1.3.1.2 Retrovirus 16 1.3.1.3 Baculovirus 16 1.3.2 Synthetic vectors 18 1.3.3 Molecular approach for cancer gene therapy 18 1.3.3.1 Prodrug converting/suicide gene therapy 18 1.3.3.2 Expression of molecules that affect angiogenesis, tumor invasion and metastasi 20 1.3.3.3 RNA interference (RNAi) targeting approach 21 1.3.4 Immunomodulation approach to cancer gene therapy 21 1.3.5 Current status of gene therapy for glioma and breast cancer 22 1.4 Stem cells 1.4.1 Adult stem cells 1.4.1.1 Neural stem cells 1.4.2 Induced pluripotent stem cells 1.5 Stem cell as a vehicle for cancer gene therapy 1.5.1 Stem cell based cancer gene therap 23 24 24 25 26 26 1.5.2 Cancer tropism of stem cells 27 1.5.3 Route of administration of stem cell 28 1.5.4 Clinical trials with stem cell based cancer gene therapy 28 1.5.5 Future of stem cell based cancer gene therapy 30 Aims and objective 31 Material and methods 33 3.1 Cell culture 33 3.2 Mouse iPSC-derived NSC for glioma therapy 34 3.2.1 Lentivirus preparation, reprogramming and maintenance of mouse iPSC 34 3.2.2 Alkaline phosphatase staining 36 3.2.3 Generation of mouse iPSC-derived NSC (msiPSC-NSC) 36 3.2.4 Characterization of msiPSC-NSC 37 3.2.5 RT2 profiler PCR array 38 3.2.6 Baculoviral vector construction and transduction 40 3.2.7 Cytotoxicity assay 40 3.2.8 In vitro migration assay 3.2.9 In vitro sensitivity of TK expressing-neural stem cells (msiPSCNSCtk) to GCV 42 3.2.10 In vitro tumoricidal effect in glioma cells 42 3.2.11 Animal study design: the use of msiPSC-derived NSC for glioma therapy 42 3.3 Comparison of different delivery methods of stem cells in breast cancer mouse model 43 3.3.1 Derivation, maintenance of iPSC-NSC 43 3.3.2 Characterization of iPSC-NSC 44 3.3.3 Fluorescence labelling and biocompatibility analysis 45 3.3.4 Animal study design: comparison of different delivery methods 45 3.4 Comparison of suicide gene systems: HSVtk, Fcy and CodA 3.4.1 Baculovirus preparation and cell transduction 46 46 3.4.2 In vitro sensitivity of HSVtk, Fcy and CodA-expressing iPSC-NSC 47 3.4.3 Animal study design: comparison of prodrug systems in 4T1 breast cancer mouse models 49 Results 4.1 Use of msiPSC-NSC in glioma therapy 4.1.1 Aim 50 50 4.1.2 Reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells and the derivation of neural stem cells 50 4.1.3 msiPSC-NSC display migratory behavior to glioma 57 4.1.4 msiPSC-NSC can be successfully transduced with baculovirus 59 4.1.5 msiPSC-NSCtk generated by baculoviral transduction display bystander killing effects on glioma cells in vitro 65 4.1.6 Gene therapy using HSVtk-expressing NSCs in glioma mouse model successfully reduces tumor growth rate 67 4.2 Comparison of different stem cell delivery methods in breast cancer mouse model 67 4.2.1 Aim 67 4.2.2 DiR labeled iPSC-NSC as a tool for tracking stem cell migration in vivo 67 4.2.3 iPSC-NSC injected intravenously exhibits observable but limited migration to mammary fatpad tumor in vivo 69 4.2.4 Baculovirus successfully transduces iPSC-NSC iPSCNSCtk/GCV exhibits breast cancer therapeutic effect 4.3 Comparison of suicide gene systems: HSVtk, Fcy and CodA 4.3.1 Aim 73 76 76 4.3.2 iPSC-NSC transduced with baculovirus carrying herpes simplex virus thymidine kinase or cytoskine deaminase are sensitive to GCV and 5’-FC respectively 76 4.3.3 A small population of suicide gene carrying cells is sufficient to elicit bystander mediated killing effect 80 4.3.4 CD/5-FC system shows slightly better therapeutic effect in 4T1 breast cancer mouse in vivo Discussion 5.1 Use of msiPSC-NSC in glioma therapy 82 86 86 5.1.1 NSCs as a suitable gene delivery vehicle for glioma therapy 86 5.1.2 The population size of NSC is a limiting factor for gene delivery 87 5.1.3 Using baculoviral vector for gene transfer 89 5.1.4 The immunomodulatory effects of NSCs 90 5.1.5 The suitability of U87 glioblastoma model as a tool for studying glioma therapy in vivo 92 5.2 Comparison of different stem cell delivery methods in breast cancer mouse model 92 5.2.1 Issues regarding the different methods of stem cell administration 93 5.2.2 DiR as a suitable label for in vivo tracking of iPSC-NSC 94 5.3 Comparison of suicide gene systems: HSVtk, Fcy and CodA 95 5.3.1 HSVtk/GCV and CD/5-FC mediates bystander effect by different methods 96 5.3.2 Tumor growth rates were reduced but no complete eradication of cancer was observed 98 5.3.3 Possible strategies to improve therapeutic efficiency 98 5.3.4 Possible cytotoxic side effects from prodrug treatment 100 Conclusion 101 Future Direction 106 Summary Using neural stem cells with tumor tropic migratory capacity to deliver therapeutic genes is an attractive strategy in eliminating metastatic or disseminated tumor Different methods have been studied and developed to isolate or generate NSCs, but it has not been assessed whether induced pluripotent stem cells (iPSCS), a type or pluripotent stem cells that hold great potential for regenerative medicine, can be used as a source for derivation of NSCs with tumor tropism In this study, we used a conventional lentivirus transduction method to derive both mouse and human iPSCs from embryonic fibroblasts and then generated NSCs from these iPSCs To investigate whether the iPSC-derived NSCs can be used in the treatment of disseminated brain tumor and metastatic breast cancer, the cells were transduced with baculoviral vector containing the herpes simplex virus thymidine kinase or the cytosine deaminase suicide gene In the glioma study, the mouse iPSC-NSCtk were injected contralaterally to tumor inoculation site in a mouse intracranial human glioma xenograft model In the breast cancer study, the human iPSC-NSCtk, iPSC-NSCFcy, iPSC-NSCCodA were injected either intravenously or directly into the tumor site We observed that NSCs expressing the suicide gene were, in the presence of respective prodrugs ganciclovir or 5fluorocytosine, effective with varying extents in inhibiting the cancer development of the glioma xenograft and breast cancer metastatic model and prolonging the survival of tumor-bearing mice Our findings provide evidence for the feasibility of using iPSC derived NSCs as a vehicle for targeted anticancer gene therapy LIST OF TABLES Table RT-PCR primer sequences for pluripotent stem cell “stemness”-specific and neural stem cell-specific markers 57 Table Changes in expression of embryonic stem cell-specific markers and embryonic stem cell differentiation/lineage marker genes between msiPSCs and MEFs 58 10 for glioblastoma Cancer Gene Ther 15: 605-615 Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K (2008) Generation of Human Induced Pluripotent Stem Cells from Dermal Fibroblasts PNAS 105: 2883-2888 Maherali N., Sridharan R., Xie W., Utikal J, Eminli S, Arnold K, Staftfeld M, Yachechko R, 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relative to mouse embryonic fibroblasts Description Fold change Functional Gene Grouping (I) Forkhead box D3 15 ESC-specific genes GATA binding protein Gastrulation brain homeobox ESC-specific genes 51 ESC-specific genes 273 ESC-specific genes 151 ESC-specific genes 14 ESC-specific genes 2018 ESC-specific genes 218 ESC-specific genes Nanog homeobox Nuclear receptor subfamily 5, group A, member Nuclear receptor subfamily 6, group A, member POU domain, class 5, transcription factor SRY-box containing gene Transcription factor CP2-like Undifferentiated embryonic cell transcription factor 229 ESC-specific genes 1195 ESC-specific genes Zinc finger protein 42 1107 ESC-specific genes COMM domain containing Cellular retinoic acid binding protein II ESC-specific genes ESC-specific genes Endothelin receptor type B ESC-specific genes Fibroblast growth factor 347 ESC-specific genes Fibroblast growth factor Gamma-aminobutyric acid (GABA) A receptor, subunit beta ESC-specific genes ESC-specific genes Galanin Growth factor receptor bound protein ESC-specific genes 27 ESC-specific genes ESC-specific genes 27 ESC-specific genes ESC-specific genes 36 ESC-specific genes 213 ESC-specific genes 287 ESC-specific genes ESC-specific genes 41 ESC-specific genes Hemopoietic cell kinase Interferon induced transmembrane protein Interleukin signal transducer Kit oncogene Left right determination factor Left-right determination factor Leukemia inhibitory factor receptor Nodal Functional Gene Grouping (II) Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Transcription factors maintaining "stemness" Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal 124 Noggin Numb gene homolog (Drosophila) Phosphatase and tensin homolog Secreted frizzled-related protein Teratocarcinoma-derived growth factor Brix domain containing CD9 antigen Diaphanous homolog (Drosophila) DNA methyltransferase 3B Interferon induced transmembrane protein Insulin-like growth factor mRNA binding protein Lin-28 homolog (C elegans) Podocalyxin-like RE1-silencing transcription factor Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A Telomerase reverse transcriptase Growth differentiation factor ESC-specific genes ESC-specific genes ESC-specific genes ESC-specific genes 897 1 ESC-specific genes ESC-specific genes ESC-specific genes Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal Signalling molecules required for pluripotency and self-Renewal other ESC-specific genes other ESC-specific genes 16 ESC-specific genes ESC-specific genes other ESC-specific genes other ESC-specific genes ESC-specific genes other ESC-specific genes 101 35 ESC-specific genes ESC-specific genes ESC-specific genes other ESC-specific genes other ESC-specific genes other ESC-specific genes ESC-specific genes other ESC-specific genes ESC-specific genes other ESC-specific genes ESC-specific genes other ESC-specific genes 48 ESC-specific genes ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage other ESC-specific genes Alpha fetoprotein Serine (or cysteine) peptidase inhibitor, clade A, member 1a Caudal type homeo box Eomesodermin homolog (Xenopus laevis) 26 Glial cells missing homolog (Drosophila) Keratin Fibronectin Laminin, alpha 21 Laminin B1 subunit Laminin, gamma visceral endoderm markers visceral endoderm markers Trophoblast markers Trophoblast markers Trophoblast markers Trophoblast markers Parietal endoderm marker Parietal endoderm marker Parietal endoderm marker Parietal endoderm marker 130 SRY-box containing gene 17 Glucagon Islet amyloid polypeptide Insulin II Paired box gene Pancreatic and duodenal homeobox Somatostatin Oligodendrocyte transcription factor Tyrosine aminotransferase Nestin Neurogenic differentiation 27 Paired box gene 6 Desmin Myogenic factor 5 Myogenic differentiation 1 Brachyury 97 Wilms tumor homolog DEAD (Asp-Glu-Ala-Asp) box polypeptide Synaptonemal complex protein 140 GATA binding protein markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers Parietal endoderm marker Pancreas Pancreas Pancreas Pancreas Pancreas Pancreas other differentiation/lineage marker other differentiation/lineage marker Neural Neural Neural Muscle Muscle Muscle Mesoderm marker Mesoderm marker Germ cell Germ cell Extra-embryonic endoderm markers 131 Pancreas specific transcription factor, 1a Forkhead box A2 CD34 antigen Cadherin FMS-like tyrosine kinase Platelet/endothelial cell adhesion molecule 79 Collagen, type I, alpha Runt related transcription factor Hemoglobin X, alpha-like embryonic chain in Hba complex Hemoglobin Y, beta-like embryonic chain 5 ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers ESC differentiaiton/lineage markers Extra-embryonic endoderm markers Extra-embryonic endoderm markers Endothelial Endothelial Endothelial Endothelial Bone Bone Blood Blood 132 Figure A2 Measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and urine creatinine levels 4T1 breast cancer mice were injected with iPSC-NSCtk, iPSC-NSCFcy and IPSCNSCCodA and thereafter ip GCV and 5FC treatment respectively After week of treatment , sera and urine samples were collected from animals per group AST, ALT assays (Biovision; Ca, USA) and creatinine assays (R&D Systems) were conducted according to manufacturer’s protocol Liver function tests usually includes both AST and ALT measurements and altered creatinine levels are often an indicator of kidney dysfunction After week of 5FC treatment, no significant elevations were observed in AST, ALT and creatinine levels in the iPSCNSCFcy/5FC and iPSCNSCtk/GCV group as compared to control breast cancer group The AST and creatinine levels in the iPSCNSCCodA/5-FC group was comparable to the others but the ALT levels were significantly higher, suggesting possible liver toxicity 128 Figure A3 Biodistribution of DiR labeled hESC-derived NSCs and MSCs NSG immunodeficient mice were intravenously injected with x 106 DiR labeled hESC-derived NSCs and MSCs and fluorescence signal from DiR labeled cells was monitored by imaging the mice 24 hours, days, days and 12 days post injection As expected, the hESC derived cells when introduced intravenously, was maintained mainly in the lungs initially, then migrated towards the liver However the fluorescent signal diminished very rapidly after days Hence DiR labeled cells would only be a reliable tool for biodistribution analysis for a short period of time 129 ... status of gene therapy for glioma and breast cancer 22 1.4 Stem cells 1.4.1 Adult stem cells 1.4.1.1 Neural stem cells 1.4.2 Induced pluripotent stem cells 1.5 Stem cell as a vehicle for cancer. .. primers as follows: was performed using the forward and reverse CodA, GCGGAATTCATGAGCAATAACGCTTTAC -3’ (forward) and 5’ACGCTCGAGTCAACGTTTGTAATCGA -3’ (reverse), size:1.2kb; Fcy 5’-AGGAATTCATGGTGACAGGGGGAATG... potential benefit As these cancers have a high risk of relapse, irrespective of grade and stage, they account for a large proportion of metastatic breast cancers (Irvin WJ and Carey 2008) 4T1 mammary

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