GSBS Dissertations and Theses

Approval Date

6-25-2012

Document Type

Doctoral Dissertation

Department

Graduate School of Biomedical Sciences, Cancer Biology Program

Subjects

Dissertations, UMMS; Neoplasms; Neoplastic Stem Cells; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Neoplasms, Experimental

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.

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.