Investigations into the role of inflammation in tumorigenesis

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Virginia Tech


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.



inflammation, tumorigenesis, histiocytic sarcoma, signaling pathways, breast cancer