Human mesenchymal stem cells pre-activated with TNF-[alpha] induce apoptosis breast cancer cells by expressing trail : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2013]
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| Subjects: |
| Abstract: | ABSTRACT: Mesenchymal stem/stromal cells (MSCs) can either suppress or promote tumors; data in the literature currently published are conflicting. We observed that incubation of human bone marrow MSCs (hMSCs) with tumor necrosis factor-[alpha] (TNF-[alpha]) up-regulated multiple genes, including TNF-[alpha] related apoptosis inducing ligand (TRAIL). In co-culture, hMSCs activated with TNF-[alpha] (activated hMSCs) induced apoptosis in MDA-MB-231 cancer cells (MDA) in part by expressing TRAIL. hMSCs also expressed TRAIL when exposed to other inflammatory molecules like interferon-gamma (IFN-y) and lipopolysaccharide (LPS) and correspondingly induced MDA apoptosis in co-cultures. Some other cancer cell lines, including additional breast cancer lines, also underwent apoptosis in co-culture with activated hMSCs. Fibroblasts activated with TNF-[alpha] were not able to induce TRAIL-dependent apoptosis in MDA during co-culture. When different preparations of hMSCs from separate donors were used in co-cultures, there was wide variation in their ability to express TRAIL and induce apoptosis in MDA. hMSCs also became less effective at inducing MDA apoptosis after extensive expansion. Doxorubicin, a chemotherapeutic drug, synergistically promoted MDA apoptosis with activated hMSCs. Expression of TRAIL was further up-regulated in hMSCs by RNA and other damage associated molecular pattern molecules (DAMPs) produced by apoptotic MDA in a TLR3-dependent manner; this feed-forward cycle further increased MDA apoptosis. Weekly intravenous infusions of hMSCs pre-activated with TNF-[alpha] into mice with a xenograft metastatic lung tumor model formed by intravenous injection of MDA resulted in hMSC incorporation into tumor nodules. This resulted in decreased lung tumor burden at both early and late time points. These data suggest that culturing hMSCs under appropriate conditions can make them suppress some cancers. |
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| Item Description: | Vita. "Major Subject: Biomedical Sciences". "Submitted to the Office of Research and Graduate Studies of the Texas A&M University System Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2013." Approved as to style and content by: Darwin J. Prockop, Cynthia J. Meininger, Ryang H. Lee, Carl A. Gregory, Alejandro C. Arroliga. |
| Physical Description: | x, 127 leaves : illustrations (mostly color) ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 105-126). |