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The CD49d+/high subpopulation from isolated human breast sarcoma spheres possesses tumor-initiating ability
DC Field | Value | Language |
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dc.contributor.advisor | 노동영 | - |
dc.contributor.author | 이경민 | - |
dc.date.accessioned | 2017-07-14T01:14:45Z | - |
dc.date.available | 2017-07-14T01:14:45Z | - |
dc.date.issued | 2012-08 | - |
dc.identifier.other | 000000004983 | - |
dc.identifier.uri | https://hdl.handle.net/10371/121760 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 협동과정 종양생물학전공, 2012. 8. 노동영. | - |
dc.description.abstract | Primary breast sarcomas that arise from mammary stroma are very rare, highly aggressive tumors with a heterogeneous phenotype and are associated with high risk of recurrence and poor prognosis. Despite significant advances in medical and surgical management, these tumors have no suitable therapeutic modalities. Tumor-initiating cells (TICs) or cancer stem cells (CSCs) have been recently implicated in the pathogenesis of other heterogeneous, highly malignant tumors. I demonstrate here the existence of a small subpopulation of self-renewing primary breast sarcoma cells that are capable of forming suspended spherical, also called sarcospheres (designated NDY-1 sarcospheres), in anchorage-independent, serum-starved conditions from primary breast sarcoma tissue. Sarcospheres able to initiate and sustain tumor growth in immune-deficient NOD/SCID mice, to express stemness genes, including Notch 4, Bmi-1 and ABCG2, and to differentiate into mesenchymal lineages, such as osteoblasts and adipocytes. In addition, I observed a distribution of ALDH+ stem-like cells activity NDY-1 sarcospheres compared to the adherent cells. Through the screening for various markers and analysis of gene expression profiles in both sarcospheres and adherent cells, revealed a marked decrease in CD49d expression in corresponding adherent cells from NDY-1 sarcospheres. The CD49d+/high subpopulation sorted from NDY-1 spheres displayed higher cell viability and sphere-forming ability than CD49d-/low population in vitro. Moreover, the CD49d+/high population displayed high tumor initiating ability in limiting dilution transplantation to NOD/SCID mice, and the xenotransplanted CD49dhigh/+ population recapitulated the complexity of the original primary tumors. Moreover, greater doxorubicin resistance was exhibited by the CD49d+/high population, compared with the CD49d-/low population. Therefore, my results support the extension of the CSCs hypothesis to include tumors of mesenchymal lineage, breast sarcoma and highlight CD49d as a pivotal marker for identification of these cells. This is the first study to identify CSCs from primary breast sarcoma and this may be of primary importance in the development of new therapeutic strategies and new prognostic procedures against highly aggressive breast sarcoma. | - |
dc.description.tableofcontents | ABSTRACT i
TABLE OF CONTENTS iv LIST OF FIGURES vi LIST OF TABLES vii LIST OF ABBREVIATIONS ix INTRODUCTION 1 1. Primay breast sarcoma 1 2. Cancer stem cells 2 3. Implications CSCs theory in primary breast sarcoma 6 4. Integrin and CD49d 7 4. Purpose of this study 9 MATERIALS AND METHODS 10 1. Patients 10 2. Primary cell isolation and in vitro expansion 10 3. Sphere formation assay 11 4. Differentiation assay 11 5. Flow cytometry analysis 12 6. Fluorescence-activated cell sorting (FACS) 13 7. Aldeflour dehydrogenase activity (ALDH) assay 14 8. RNA extraction, cDNA synthesis, and PCR 14 9. Illumina microarray analysis 15 10. Ingenuity Pathways Analysis (IPA) 16 11. Western blot analysis. 17 12. Proliferation and cytotoxicity 18 13. In vivo xenograft experiments. 18 14. H&E stain and immunohistochemistry (IHC). 19 15. Statistical analysis. 20 RESULTS 21 1. Patient characteristics 21 2. Establishment of sarcospheres from primary human breast sarcoma and self-renewal ability 21 3. Characterization of NDY-1 sarcospheres 24 4. Biological differences between NDY-1 sarcospheres and adherent cells in vitro and in vivo 30 5. Modulation of gene expression profile. 42 6. In vitro and in vivo characterization of CD49d+/high cells from NDY-1 spheres. 46 7. Doxorubicin resistance of CD49d+/high cells 55 DISCUSSION 58 REFERENCES 67 ABSTRACT IN KOREA 79 | - |
dc.format | application/pdf | - |
dc.format.extent | 3576326 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Breast sarcoma | - |
dc.subject | Cancer stem cells | - |
dc.subject | sarcoma initiating cells | - |
dc.subject | CD49d | - |
dc.title | The CD49d+/high subpopulation from isolated human breast sarcoma spheres possesses tumor-initiating ability | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.citation.pages | ix, 82 | - |
dc.contributor.affiliation | 의과대학 협동과정 종양생물학전공 | - |
dc.date.awarded | 2012-08 | - |
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