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BONE MARROW DERIVED MESENCHYMAL STEM CELLS PROMOTE
SURVIVAL AND DRUG RESISTANCE IN TUMOR CELLS
by
Scott Anthony Bergfeld
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
(PATHOBIOLOGY)
December 2013
Copyright 2013 Scott Anthony Bergfeld
Object Description
| Title | Bone marrow derived mesenchymal stem cells promote survival and drug resistance in tumor cells |
| Author | Bergfeld, Scott Anthony |
| Author email | bergfeld@usc.edu;sbergfeld@chla.usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2013-06-18 |
| Date submitted | 2013-10-04 |
| Date approved | 2013-10-04 |
| Restricted until | 2013-10-04 |
| Date published | 2013-10-04 |
| Advisor (committee chair) | DeClerck, Yves A. |
| Advisor (committee member) |
Hofman, Florence M. Asgharzadeh, Shahab Adams, Gregor B. |
| Abstract | Bone marrow mesenchymal stem cells (BMMSC) are recruited to primary tumors and have been reported to display pro-tumorigenic as well as anti-tumorigenic activities. We hypothesize that circulating BMMSC are incorporated into tumor sites and protect tumor cells from therapy-induced apoptosis. Adherent stromal cells isolated from murine bone marrow that expressed phenotypic and functional characteristics of BMMSC were tested for their effect on 4T1 murine mammary adenocarcinoma and LL/2 Lewis lung carcinoma cells. Primary BMMSC stimulated the expansion of 4T1 cells in 3D co-cultures and conditioned medium from these cells increased the viability of 4T1 and LL/2 cells in 2D cultures. Analysis of apoptosis in 4T1 cells exposed to BMMSC conditioned medium under low serum concentrations (0.5 to 1%) revealed a 2-fold reduction in apoptosis as determined by Annexin V expression and caspase-3 and caspase-9 activity. Furthermore, exposure of 4T1 and LL/2 cells to BMMSC conditioned medium increased the viability of 4T1 and LL/2 cells when treated with paclitaxel or doxorubicin at therapeutic concentrations. This protective effect was accompanied by significant reductions in caspase-3 activity and Annexin V expression. We then demonstrated that BMMSC are attracted specifically by 4T1 and LL/2 cells in vitro, and in vivo migrate into the invasive front of 4T1 tumors implanted in mice. When co-injected with 4T1 cells in the mammary fat pad of mice subsequently treated with doxorubicin, they inhibit drug-induced apoptosis by 42 percent. Overall, our data identify BMMSC as an important mediator of tumor cell survival and treatment resistance in primary tumors. |
| Keyword | mesenchymal stem cells; tumor microenvironment; drug resistance; apoptosis |
| Language | English |
| Format (imt) | application/pdf |
| 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 | Bergfeld, Scott Anthony |
| Access conditions | 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@usc.edu |
| Filename | etd-BergfeldSc-2080.pdf |
| Archival file | uscthesesreloadpub_Volume8/etd-BergfeldSc-2080.pdf |
Description
| Title | Page 1 |
| Full text | BONE MARROW DERIVED MESENCHYMAL STEM CELLS PROMOTE SURVIVAL AND DRUG RESISTANCE IN TUMOR CELLS by Scott Anthony Bergfeld 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 (PATHOBIOLOGY) December 2013 Copyright 2013 Scott Anthony Bergfeld |
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