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    Slow-Cycling Cancer Cells: A Dissertation

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    Authors
    Moore, Nathan F.
    Faculty Advisor
    Stephen R. Lyle, MD, PhD
    Academic Program
    Cancer Biology
    UMass Chan Affiliations
    Molecular, Cell and Cancer Biology
    Document Type
    Doctoral Dissertation
    Publication Date
    2012-06-25
    Keywords
    Neoplasms
    Neoplastic Stem Cells
    Antineoplastic Combined Chemotherapy Protocols
    Drug Resistance
    Neoplasm
    Neoplasms
    Experimental
    Cancer Biology
    Cells
    Neoplasms
    Pathological Conditions, Signs and Symptoms
    Pharmaceutical Preparations
    Therapeutics
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    Abstract
    Tumor recurrence after chemotherapy is a major cause of patient morbidity and mortality. Recurrences are thought to be due to small subsets of stem-like cancer cells that are able to survive chemotherapy and drive tumor re-growth. A more complete understanding of stem-like cancer cell regulation is required to develop therapies to better target and eliminate these cells. Slow-cycling stem cells are integral components of adult epithelial tissues and may give rise to cancer stem cell populations that share similar characteristics. These slow-cycling adult stem cells are inherently resistant to traditional forms of chemotherapy and transference of this characteristic may help to explain therapy resistance in cancer stem cell populations. Using a novel application for the proliferation marker CFSE, we have identified populations of slow-cycling cancer cells with tumor initiating capabilities. As predicted, slow-cycling cancer cells exhibit a multi-fold increase in chemotherapy resistance and retain the ability to re-enter the cell cycle. Furthermore, we observed consistent over-expression of the CDK5 activator, p35, in slow-cycling cancer cells. Manipulation of p35 expression in cancer cells affects cell cycle distribution and survival when these cells are treated with traditional forms of chemotherapy. Additionally, we demonstrate that alterations in p35 expression affect BCL2 levels, suggesting a mechanism for the survival phenotype. Combined, our data suggest a model whereby slow-cycling stem-like cancer cells utilize the p35/CDK5 complex to slow cell cycling speed and promote resistance to chemotherapy. Future p35 targeting, in combination with traditional forms of chemotherapy, may help eliminate these cells and reduce tumor recurrence rates, increasing long-term patient survival.
    DOI
    10.13028/0rvq-7r49
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31969
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/0rvq-7r49
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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