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Resection of the Primary Osteosarcoma Terminates Self-seeding and Facilitates Metastasis

Le Pommellet, Helene Marie

Abstract Details

2017, Master of Science, Ohio State University, Comparative and Veterinary Medicine.
Introduction: Pediatric osteosarcoma is the most common bone cancer in children. Despite aggressive surgical excision and chemotherapy, up to 80% of children die after developing metastasis, despite the absence of metastatic disease at diagnosis. Similar to numerous other cancers, surgical excision of the primary tumor is often followed by development of metastasis. The present study sought to characterize the effect that surgical excision of a primary osteosarcoma has on the subsequent development of lung metastasis. This work hypothesizes a more dynamic model of metastasis development, where circulating tumor cells enter and exit circulation in an equilibrium at both the site of the primary tumor (through the process of self-seeding) and at the metastatic niche (through the process of lung colonization). We specifically sought to identify the contributions of multiple tumor-derived cytokines and chemokines, including IL-6 and IL-8, oncostatin M, and SDF-1, based on our previous work implicating these cytokines in the biology of metastatic colonization of lung. Results: Using a murine model of metastatic osteosarcoma, we determined that surgical removal of a primary tumor caused a significant increase in the number of tumor cells within the lungs. We determined that the presence of a primary tumor could protect lungs from developing metastatic lesions when mice were inoculated with a defined number of osteosarcoma cells intravenously. In the absence of a primary tumor, circulating tumor cells preferentially migrated to the lungs. We identified significant expression of IL-6, IL-8, IL-11, Oncostatin and SDF-1 by osteosarcoma cells in culture. IL-6 and IL- 8 expression was consistently higher than that of other cytokines. All of the cytokines and chemokines tested, including IL-6, IL-8, Oncostatin and SDF-1, induced robust directional migration of osteosarcoma cells using in vitro chemotaxis assays. Conclusion: These results suggest that the presence of a primary tumor influences the migration of circulating tumor cells. Circulating tumor cells preferentially migrate to the primary tumor when present—it is the most favorable environment for growth and survival. After resection of the primary tumor, circulating tumor cells seed to the second most favorable location, the lungs, initiating the development of lung metastasis. Our data suggest that IL-6 and IL-8 likely mediate this process. Both cytokines were highly expressed in osteosarcoma cells and both were capable of inducing migration in vitro. While further work is needed to elucidate this biology in greater detail, this work already suggests that an understanding of these processes could be leveraged to design therapies that manipulate the dynamics of self-seeding and metastatic seeding to prevent and even treat pediatric osteosarcoma.
Ryan Roberts (Advisor)
Cheryl London (Committee Member)
Mary McLoughlin (Committee Member)
54 p.

Recommended Citations

Citations

  • Le Pommellet, H. M. (2017). Resection of the Primary Osteosarcoma Terminates Self-seeding and Facilitates Metastasis [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492703002755525

    APA Style (7th edition)

  • Le Pommellet, Helene. Resection of the Primary Osteosarcoma Terminates Self-seeding and Facilitates Metastasis. 2017. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492703002755525.

    MLA Style (8th edition)

  • Le Pommellet, Helene. "Resection of the Primary Osteosarcoma Terminates Self-seeding and Facilitates Metastasis." Master's thesis, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492703002755525

    Chicago Manual of Style (17th edition)