Document Type

Dissertation

Date of Degree

Fall 2009

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Marcelo B. Soares

Abstract

Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. To achieve a greater understanding of chondrosarcoma tumorigenesis, a model for human chondrosarcoma has been established in a rat system. The model, known as the Swarm rat chondrosarcoma (SRC), resembles human chondrosarcoma and provides a system to study tumor growth and progression. Here we examined the influence of the tumor microenvironment and the impact of genome-wide hypomethylation on the behavior of SRC tumors, two factors known to contribute fundamentally to the development and progression of solid tumors.

Previous studies with SRC revealed that tumor microenvironment can significantly influence chondrosarcoma malignancy, but the underlying biologic mechanisms have not been defined. To address this issue we carried out epigenetic and gene expression studies on the SRC tumors that were initiated at different transplantation sites. The epigenetic analysis revealed that microenvironmental changes could promote global DNA hypomethylation in SRC cells. Subsequent gene expression analyses revealed that the transplantation site had a significant impact on the gene expression profiles of SRC tumors. These SRC tumors had unique gene expression profiles, and we were able to identify genes that were differentially expressed between SRC tumors originating from different transplantation sites. Functional analyses of two differentially expressed genes, thymosin-beta-4 and c-fos, provided insight into the role that these genes may play in the development and progression of chondrosarcoma.

Keywords

cancer, Chondrosarcoma, gene expression, methylation, microenvironment, tumor

Pages

xviii, 115 pages

Bibliography

Includes bibliographical references (pages 102-115).

Comments

This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: http://www.lib.uiowa.edu/sc/contact/.

Copyright

Copyright 2009 Christopher Allan Hamm

Additional Files

Appendix_A.xls (7778 kB)
Appendix A

Appendix_B.xls (143 kB)
Appendix B

Appendix_C.xls (161 kB)
Appendix C

Appendix_D.xls (9268 kB)
Appendix D

Appendix_E.xls (189 kB)
Appendix E

Included in

Genetics Commons

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