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Preclinical Modeling of Musculoskeletal Cancer

Chaffee, Beth K

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Preclinical animal models serve as invaluable tools in the investigation of disease and the development of novel therapeutic strategies to prevent and treat disease. Osteosarcoma is the most common primary bone tumor in humans and dogs, and is associated with a high rate of lung metastasis. In order to successfully develop new strategies to improve outcomes for OSA patients, we sought to develop a clinically relevant mouse model with spontaneous metastasis. We successfully developed a model that mimicked the biologic behavior seen in dogs and in people with osteosarcoma. This included development of a primary bone tumor that was surgically amputated followed by development of lung metastasis. Lung metastases were quantified using stereological principles with an average of 33% of lung affected by metastasis in the model. We then used this model to investigate changes in gene expression that occur between primary and metastatic OSA that might be critical to the metastatic cascade and therefore be viable targets for therapy. Eighty genes were identified as differentially expressed between primary and metastatic tumors. Identified genes ranged from well-known genes involved in cancer to others that are yet unnamed. The model was also used with primary canine- derived patient OSA tissue. These tissues will be used to further investigate selected genes identified by microarray. Radiation therapy is an important modality in the treatment of many types of cancer; however there are important adverse effects to bone that must be considered. Following exposure to external beam radiation, there is loss of trabecular bone with an associated decrease in bone strength and increase in brittleness. This leads to a markedly increased rate of fracture in irradiated bones. We utilized a previously developed mouse model of radiation induced bone damage and examined changes in mechanical properties as well as changes in osteoclasts. Changes in mechanical properties mirrored those previously reported for the model. We also discovered that osteoclasts increase initially, followed by a decrease at 12 weeks post irradiation. To further investigate the effects of radiation on osteoclasts, we exposed osteoclast precursors and mature cells to radiation and quantified cell viability. As expected, mature osteoclasts were more radioresistant than osteoclast precursors. Multiple factors are likely involved in radiation-induced changes in bone, including changes in osteoclast number and function.
Matthew Allen (Advisor)
Krista La Perle (Committee Member)
Thomas Rosol (Committee Member)
Thomas Scharschmidt (Committee Member)
145 p.

Recommended Citations

Citations

  • Chaffee, B. K. (2013). Preclinical Modeling of Musculoskeletal Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376844544

    APA Style (7th edition)

  • Chaffee, Beth. Preclinical Modeling of Musculoskeletal Cancer. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1376844544.

    MLA Style (8th edition)

  • Chaffee, Beth. "Preclinical Modeling of Musculoskeletal Cancer." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376844544

    Chicago Manual of Style (17th edition)