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dc.contributor.advisorStephen R. Lyle, MD, PhD
dc.contributor.authorMoore, Nathan F.
dc.date2022-08-11T08:08:44.000
dc.date.accessioned2022-08-23T16:05:55Z
dc.date.available2022-08-23T16:05:55Z
dc.date.issued2012-06-25
dc.date.submitted2012-09-27
dc.identifier.doi10.13028/0rvq-7r49
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31969
dc.description.abstractTumor 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.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectNeoplasms
dc.subjectNeoplastic Stem Cells
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectDrug Resistance
dc.subjectNeoplasm
dc.subjectNeoplasms
dc.subjectExperimental
dc.subjectCancer Biology
dc.subjectCells
dc.subjectNeoplasms
dc.subjectPathological Conditions, Signs and Symptoms
dc.subjectPharmaceutical Preparations
dc.subjectTherapeutics
dc.titleSlow-Cycling Cancer Cells: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1622&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/620
dc.legacy.embargo2012-08-01T00:00:00-07:00
dc.identifier.contextkey3354799
refterms.dateFOA2022-08-24T04:00:40Z
html.description.abstract<p>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.</p> <p>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.</p> <p>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.</p>
dc.identifier.submissionpathgsbs_diss/620
dc.contributor.departmentMolecular, Cell and Cancer Biology
dc.description.thesisprogramCancer Biology


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