Inflammation has been found to play a role in the development of many different tumors. However, a tumor's ability to evade immune cell recognition can be integral to its progression as well. The following works explore this complicated role with a focus on histiocytic sarcoma (HS) and breast cancer. Chapter 1 opens with a broad overview of inflammation in tumorigenesis while Chapter 2 focuses on a review and discussion of current HS literature. Our investigations into the role of inflammation specifically in HS are initiated in Chapter 3 where we explore the role of the regulatory NLR, NLRX1, in the development of HS in mice. NLRX1 is an intracellular patter recognition receptor that functions to regulate pro-inflammatory cell pathways. Our studies reveal that in carcinogen-induced HS in mice, NLRX1 acts as a tumor suppressor. Moreover, when NLRX1 is lost, tumors that develop are associated with increases in expression of genes in NF-κB and AKT pathways. Though uncommon, HS is a clinically relevant tumor in dogs. In Chapter 4, we further investigate the role of the pathways identified in Chapter 3 in canine patients. Not only were these pathways increased, but our results also revealed previously unreported differences in tumors diagnosed as HS versus those diagnosed as hemophagocytic HS. To improve the use of canine HS both as an experimental and translational model, we sought to create a murine xenograft model. In Chapter 5, we discuss the development of our model and the results of pilot studies using targeted drug therapy. The focus of Chapters 3-5 is to further explore the role of inflammation in the development of HS. However, as aforementioned, the role of inflammation in tumorigenesis is quite complicated. In Chapter 6, we aim to address the concept that the lack of inflammation through immune evasion, can also be important in tumors. Breast cancer in humans is traditionally recognized as being highly immunosuppressive. In this final chapter, we investigate the use of an attenuated strain of bacteria to treat these tumors by way of shifting the immunosuppressive tumor microenvironment to a more pro-inflammatory state. / Ph. D. / The role of inflammation in the development and progression of cancer has been studied for many years. It is well-accepted that chronic inflammation can lead to an environment that is favorable for tumor development. However, more recently it has been shown that being able to escape the immune system and avoid inflammation can also be important in tumor development. The aim of this work was to further investigate these dichotomous roles. In Chapters 1-5 we review and further explore the role of inflammation in a poorly studied tumor called histiocytic sarcoma (HS). Through our studies we have found that a receptor protein present in many cells, NLRX1, is important in the development of chemically-induced HS in mice. Moreover, the development of these tumors is associated with increases in pro-inflammatory and cell growth pathways. Further studies reveal that these pathways are also important to the development of the tumor in dogs. Because HS is rare and poorly studied in humans, we describe the development of an additional mouse model to study HS. This model will help reveal important information about the disease in dogs that can help us study it in humans. Finally, in Chapter 6, we sought to investigate the other potential role of inflammation in decreasing tumorigenesis. In these studies, we used a mouse model of breast cancer to investigate whether or not we could decrease tumorigenesis by increasing the immune system’s ability to recognize the tumor.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/90788 |
| Date | 05 January 2018 |
| Creators | Coutermarsh-Ott, Sheryl |
| Contributors | Biomedical and Veterinary Sciences, Allen, Irving C., Huckle, William R., LeRoith, Tanya, Dervisis, Nikolaos G., Meng, Xiang-Jin |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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