Authors
Moore, Nathan F.Faculty Advisor
Stephen R. Lyle, MD, PhDAcademic Program
Cancer BiologyUMass Chan Affiliations
Molecular, Cell and Cancer BiologyDocument Type
Doctoral DissertationPublication Date
2012-06-25Keywords
NeoplasmsNeoplastic Stem Cells
Antineoplastic Combined Chemotherapy Protocols
Drug Resistance
Neoplasm
Neoplasms
Experimental
Cancer Biology
Cells
Neoplasms
Pathological Conditions, Signs and Symptoms
Pharmaceutical Preparations
Therapeutics
Metadata
Show full item recordAbstract
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-7r49Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31969Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/0rvq-7r49