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PTEN DELETION INDUCED TUMOR INITIATING CELLS:
STRATEGIES TO ACCELERATE THE DISEASE PROGRESSION OF
LIVER CANCER
by
Vivian Galicia Medina
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
(SYSTEMS BIOLOGY AND DISEASE)
May 2011
Copyright 2011 Vivian Galicia Medina
Object Description
| Title | PTEN deletion induced tumor initiating cells: Strategies to accelerate the disease progression of liver cancer |
| Author | Galicia Medina, Vivian A. |
| Author email | vgalicia@usc.edu; vivgalici@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Systems Biology & Disease |
| School | Keck School of Medicine |
| Date defended/completed | 2011-03-18 |
| Date submitted | 2011 |
| Restricted until | Unrestricted |
| Date published | 2011-05-07 |
| Advisor (committee chair) | Stiles, Bangyan |
| Advisor (committee member) |
Roy-Burman, Pradip Ou, James |
| Abstract | Progenitor or tumor initiating cells (TICs) are “altered” stem cells with the capacity to form solid tumors. Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome ten) and its downstream target Protein Kinase B (AKT2) are aberrantly expressed in liver cancers. The focus of my doctoral studies is to use liver specific Pten (Pm) and Pten/Akt2 deletion (Dm) murine models to investigate the role of hepatic TICs in vivo. Proliferation of hepatic progenitor cells in has been reported in various murine models of hepatotoxin induced liver injury. Pm mice develop liver cancer following an extensive phase of chronic lipid accumulation and demonstrate escalating levels of hepatic injury markers from 6-12M, prior to TIC proliferation. In addition, TUNEL analysis revealed that hepatocytes from Pm mice undergo extensive apoptosis relative to control mice. We hypothesize that hepatocyte cell death induced by hepatic injury presents an opportunity for TICs to proliferate and consequently form mixed lineage tumors. Based on these findings, I sought to investigate different strategies employed by TICs for liver tumor development. The first is taking advantage of an injured niche which is addressed in chapter two. Attenuation of hepatic injury by Akt2 deletion reduces progenitor cell proliferation and delays tumor development. Treatment of double mutant mice with 3,5-dietoxycarbonyl-1,4 dihydrocollidine (DDC) shows that the primary effect of AKT2 loss is attenuation of hepatic injury and not inhibition of progenitor cell proliferation in response to injury. My primary study also revealed that the Wnt/β-Catenin signaling pathway is the likely molecular mediator of cancer stem cell proliferation in our Pm model. In chapter three we explore inhibition of the Wnt/β-Catenin signaling pathway as a means to inhibit TIC proliferation. We demonstate that Wnt/β-Catenin inhibitor ICG-001 attenuates proliferation of hepatic tumor initiating cell line P0.; Lastly, we explore evasion of cell cycle regulation by cancer stem cells using hepatic LKB1/Pten deletion (DM). This study revealed that monoallelic deletion of LKB1 in Pm mice causes an earlier onset of bilineage liver cancer development. This acceleration of tumor formation is associated with disregulation of cell cycle inhibitor p21. The findings from these studies are not only relevant to liver cancer research, but to multiple organ cancer stem cell systems which may employ similar tactics for malignant transformation. |
| Keyword | Pten; tumor initiating cells; liver cancer |
| 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-m3926 |
| Rights | Galicia Medina, Vivian A. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Galicia-4520 |
| Archival file | uscthesesreloadpub_Volume44/etd-Galicia-4520.pdf |
Description
| Title | Page 1 |
| Full text | PTEN DELETION INDUCED TUMOR INITIATING CELLS: STRATEGIES TO ACCELERATE THE DISEASE PROGRESSION OF LIVER CANCER by Vivian Galicia Medina 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 (SYSTEMS BIOLOGY AND DISEASE) May 2011 Copyright 2011 Vivian Galicia Medina |
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