Identification and Characterization of CD90+ Cancer Stem Cells in Hepatocellular Carcinoma PDF Download

Author: Wing-yuen Ho
Publisher:
ISBN:
Category : Cancer cells
Languages : en
Pages : 464

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Author: Wing-Yuen Ho
Publisher: Open Dissertation Press
ISBN: 9781361007433
Category : Medical
Languages : en
Pages : 258

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This dissertation, "Identification and Characterization of CD90⁺ Cancer Stem Cells in Hepatocellular Carcinoma" by Wing-yuen, Ho, 何永源, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Hepatocellular carcinoma (HCC) is one of the most devastating malignancies worldwide with increasing incidences in both developed and developing countries. Survival rates have not been significantly improved over the past decades in spite of advances in detection and therapies for this disease, suggesting that current treatments may target the wrong cells, and miss the cancer stem cells (CSCs). The cancer stem cell hypothesis presents that tumor formation, proliferation and propagation are driven by a rare subpopulation of chemoresistant CSCs that are not killed by conventional therapies and go on to cause disease relapse. The objective of this study was to identify and characterize CSCs in HCC cell lines and human liver tumor specimens using CD90 as a potential marker. The number of CD90+ cells present in HCC cell lines was found to positively correlate with tumorigenicity potentials. Injection of as few as 2,000 sorted CD90+ cells from HCC cell lines resulted in the formation of tumor nodules in nude mice, whereas no tumors formed for CD90ˉcells in the same model. The tumor xenograft generated by injection of CD90+ cells sorted from previous xenograft in a serial xenotransplantation assay exhibited recapitulation of tumor heterogeneity to original primary tumor and consistent proportion of CD90+ and CD90ˉ cells which demonstrated self-renewal and differentiation capacities of CD90+CSCs. CD45ˉCD90+ cells were detected (0.03%-6.2%) in human liver tumor specimens, but were only present in minute quantities in normal, cirrhotic and non-tumorous tissues. More importantly, CD45ˉCD90+ cells sorted from primary HCC tumor also displayed tumorigenicity, self-renewal and lineage differentiation capacities. CD90+CSCs were found to be more resistant to therapeutic drugs compared to CD90- cells, as reflected by the results of enrichment of the CD90+ CSCs and longer survival rates after chemotherapeutic treatment. The high expression of genes, such as OCT4, MRP3, ABCG2, AKT1, BirC5, BCL2, HA and CD44, in CD90+CSCs may mediate chemoresistance. The majority of CD90+ cells co-expressed CD44, another stem cell marker. Blocking CD44 activities by anti-CD44 antibody increased apoptosis of CD90+ CSCs, sensitized CD90+CSCs to chemotherapeutic drugs in vitro, and decreased tumorigenic and metastatic potentials of CD90+CSCs in vivo, indicating that a therapeutic potential of targeting CD44. However side effects may be problematic due to the endogenous expression of CD44 in healthy tissues and normal lymphocytes. To identify novel gene targets specific to liver CSCs, a sensitive RNA-sequencing (RNA-Seq) technique was used to compare the gene expression profiles between CD90+CSCs sorted from HCC primary tumors and CD90+cells from adjacent non-tumorous tissue (CD90+NTSCs). The up-regulated genes in CD90+CSCs were associated with lipid metabolism, inflammation, and drug resistance. Among the differentially expressed genes, glypican-3 (GPC3) was specifically elevated in CD90+CSCs but not in CD90+NTSCs. Therefore, GPC3 could be a promising gene candidate for HCC therapy as targeting GPC3 should not induce damage to normal liver stem cells. In summary, CD90 is a liver CSCs marker. Identification of CD90+ CSCs in HCC provides new insight into cellular basis of hepatocarcinogenesis, recurrence and metastasis, which opens new avenues for the design of future CSC-targeted therapies. D

Author: Wing-yuen Ho
Publisher:
ISBN:
Category : Cancer cells
Languages : en
Pages : 0

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Author: Kwai-Yee Stephanie Ma
Publisher:
ISBN: 9781374665934
Category :
Languages : en
Pages :

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This dissertation, "Identification and characterization of tumorigenic liver cancer stem/progenitor cells" by Kwai-yee, Stephanie, Ma, 馬桂宜, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Identification and Characterization of Tumorigenic Liver Cancer Stem/Progenitor Cells Submitted by Stephanie Kwai-Yee Ma For the degree of Doctor of Philosophy at The University of Hong Kong July 2007 Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide affecting one million individuals annually. Despite advances in the detection and treatment of the disease, mortality rate remains high because current therapies are limited by the emergence of chemotherapy-resistant cancer cells. Existing chemotherapies against HCC are usually developed against the bulk of the tumor mass, where although they are able to initially shrink the size of the tumor, they fail to eradicate the lesion in full, thus resulting in disease relapse. Recent research efforts in stem cell biology put forth the proposal of a hierarchical "stem cell model of carcinogenesis" which suggests that tumors are organized in a hierarchy of heterogeneous cell populations and that the capability to maintain tumor formation and growth specifically resides in a small population of cells called cancer stem cells (CSCs). The stem cell-like characteristics of these cells and their limited number within the tumor bulk are believed to account for their capability to escape therapies. In this study, we pioneered the identification of an exclusive population of CSCs from human HCC cell lines and xenograft tumors. CD133 expression in cultured cell lines was found to correlate with the ability of the cells to develop tumor in vivo. Functional studies on + - + sorted CD133 and CD133 cells found CD133 cells to be inherently more tumorigenic; showing a greater colony-forming efficiency, higher proliferative output and greater ability to form tumor in vivo. As few as 1000 CD133 cells were sufficient for consistent tumor development in SCID mice while at least 50x as many CD133 cells were necessary to generate a tumor in the same model. Moreover, these cells were found to be endowed with characteristics of stem cells including the preferential expression of "stemness" genes, the ability to self-renew and the ability to differentiate into angiomyogenic-like, non-hepatocyte- like lineages. Further, CD133 was found to be maintained in rare numbers in CD133 induced xenograft tumors and human HCC specimens. In addition, CD133 cells were found to be more resistant to anticancer drugs, doxorubicin and 5-fluorouracil; the molecular mechanism by which was mediated via the PI3K/Akt and Bcl-2 survival pathway. Treatment of CD133 cells with an inhibitor specific to AKT1 particularly reduced the expression of 473 136 survival proteins (P-Akt-Ser, P-Bad-Ser, Bcl-2) normally expressed endogenously. In addition, treatment of unsorted cells with both drugs in culture specifically enriched the CD133 subpopulation. Subsequent investigation by 2D-PAGE technique led to the elucidation of aldehyde dehydrogenase 1A1 (ALDH1A1) as an additional differentially expressed marker useful for HCC CSC identification. ALDH1A1 was exclusively expressed + + + in the CD133 subpopulation. More importantly, CD133 ALDH1A1 cells displayed significant preferential tumorigenic potential in vitro, when compared with their respective + - - - CD133 ALDH1A1 or CD133 ALDH1A1 counterparts. In summary, our findings provide a previously uncharacterized model of liver tumor biology in

Author: Kwai-yee Ma (Stephanie)
Publisher:
ISBN:
Category : Cancer cells
Languages : en
Pages : 386

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Author: Yasunari Kanda
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages :

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Identification and Characterization of Cancer Stem Cells Using Flow Cytometry.

Author: Federica Papaccio
Publisher: Springer Nature
ISBN: 1071637304
Category :
Languages : en
Pages : 263

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Author: Farhadul Islam
Publisher: Springer Nature
ISBN: 9819931851
Category : Medical
Languages : en
Pages : 375

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This book comprehensively reviews the role of cancer stem cells (CSCs) in cancer initiation, progression, and resistance to anticancer therapies. The initial chapters examine the methods and procedure of the detection, isolation, and characterization of CSCs. It also introduces various epigenetic pathways that contribute to cancer initiation and tumorigenesis, particularly regarding the maintenance and survival of CSCs. It also explores the role of CSCs metabolism and the mechanisms of metabolic plasticity of CSCs in cancer biology. Further, it also presents the implications of CSCs on the origin of tumor heterogeneity and on heterogeneity of the therapeutic response. Towards the end, this book highlights the different immunotherapeutic approaches targeting CSCs with the potential of strongly improving cancer outcomes. This book offers a broad framework to scientists and clinicians into the state-of-the-art knowledge on cancer stem cell biology and highlights their therapeutic implications. ​

Author: 蘇珮瑜
Publisher:
ISBN:
Category : Glycoproteins
Languages : en
Pages : 0

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Author: Sharmila A. Bapat
Publisher: Wiley-Interscience
ISBN: 9780470122013
Category : Science
Languages : en
Pages : 0

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Because the concept and discoveries of cancer stem cells are relatively new, scientists and researchers need an introduction to this dynamic area. Cancer Stem Cells presents a consolidated account of the research done to date and recent progresses in the studies of cancer stem cells. Such a presentation facilitates a better understanding of and draws attention to stem cell and cancer biology - two fields that enhance, move, and evolve into each other continuously. It provides an informative study in designing approaches to apply stem cell principles to cancer biology while offering an overview of the challenges in developing combination stem and cancer biology targets for therapeutics. This book serves as a primer for new researchers in the field of cancer biology.