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THE CANCER STEM-LIKE PHENOTYPE:
THERAPEUTICS, PHENOTYPIC PLASTICITY AND
MECHANISTIC STUDIES
by
Kaijie He
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
August 2012
Copyright 2012 Kaijie He
Object Description
| Title | The cancer stem-like phenotype: therapeutics, phenotypic plasticity and mechanistic studies |
| Author | He, Kaijie |
| Author email | hekaijie@gmail.com;khe@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular and Cellular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-05-17 |
| Date submitted | 2012-07-24 |
| Date approved | 2012-07-24 |
| Restricted until | 2012-07-24 |
| Date published | 2012-07-24 |
| Advisor (committee chair) | Pinski, Jacek K. |
| Advisor (committee member) |
Goldkorn, Amir Adams, Gregor B. Kobielak, Agnieszka Kahn, Michael |
| Abstract | Cancer claims over 500,000 lives in the U.S. annually, a mortality rate that is largely attributable to solid tumors that have metastasized and become resistant to available treatments. This type of disease progression may be mediated by cancer stem cells (CSC), rare and unique cancer cells recently identified in many types of malignancies, and these CSC are thought to play a central role in tumor formation, therapy-resistance, and ultimately cancer progression and metastasis. ❧ Unfortunately, however, to date there are very few effective CSC-targeting therapies. To address this question, we isolated a putative CSC population from human prostate tumors and cell lines, and we showed for the first time that these cells possess extremely high telomerase activity relative to the bulk, unselected cancer cells. Strikingly, telomerase interference – reprogramming telomerase to add incorrect “toxic” telomeres – could induce rapid apoptosis and marked growth inhibition in prostate CSC and abrogated their ability to form new tumors in SCID mice, which offers the first tumor-derived and in vivo evidence that telomerase may ultimately form the basis for more effective new CSC-targeting therapies. ❧ The drug resistant and brisk tumor initiation abilities have been viewed as pre-existing phenotypes only present in the small subpopulation of cancer stem cells, and they have been intuitively conceptualized as self-renewing founder cells from which more differentiated cancer cells derive. However, recent work in cancer cell lines has demonstrated that drug-resistant tumor initiating features can emerge de novo within fractionated subpopulations of cells initially lacking these phenotypes. In our study, we used a “side population” cancer stem cell model with GFP-labeling technique, and demonstrated for the first time that adaptive, cancer-promoting traits like drug-resistance and brisk tumor initiation arise not only as solitary events under selective pressures, but also as highly orchestrated transitions occurring concurrently in large numbers of cells even without specifically-induced drug selection, ectopic gene expression, or fractionation into subpopulations. In addition, our follow-up mechanistic studies have identified the PI3K/Akt/b-catenin/CBP pathway to play a critical role in regulating this dynamic equilibrium and regeneration of CSC. We hope our findings would contribute to a better understanding of CSC, and can potentially offer new strategies for targeting these drug-resistant, tumor-forming cells, ultimately leading to more effective treatments for patients. |
| Keyword | cancer stem cell; telomerase; side population; plasticity; signaling pathway |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | He, Kaijie |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@dots.usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-HeKaijie-973.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | THE CANCER STEM-LIKE PHENOTYPE: THERAPEUTICS, PHENOTYPIC PLASTICITY AND MECHANISTIC STUDIES by Kaijie He A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (GENETIC, MOLECULAR AND CELLULAR BIOLOGY) August 2012 Copyright 2012 Kaijie He |
