Human chromosome 13q14 has been identified as one of the hotspots of deletion in prostate cancer, multiple myeloma, and chronic lymphocytic leukemia. Chromosome Condensation 1-like (CHC1L) is an uncharacterized gene in this region. CHC1L is found within the smallest common region of loss of heterozygosity in prostate cancer, and its decreased expression is linked to pathogenesis and progression of both prostate cancer and multiple myeloma. In the present study, we have generated Chc1L gene knockout mice and demonstrated that loss of this gene increases tumorigenesis in two year old mice. Knockout and heterozygous mice are predisposed to development of Histiocytic Sarcoma and Histiocyte-Associated Lymphoma. Bone marrow and splenic cells from 8-12 week old knockout mice have elevated viability ex vivo. These data provide the first direct evidence that CHC1L is a tumor suppressor gene involved in suppression of histiocyte-rich neoplasms.

Human chromosome 13q14 has been identified as one of the hotspots of deletion in prostate cancer, multiple myeloma, and chronic lymphocytic leukemia. Chromosome Condensation 1-like (CHC1L) is an uncharacterized gene in this region. CHC1L is found within the smallest common region of loss of heterozygosity in prostate cancer, and its decreased expression is linked to pathogenesis and progression of both prostate cancer and multiple myeloma. In the present study, we have generated Chc1L gene knockout mice and demonstrated that loss of this gene increases tumorigenesis in two year old mice. Knockout and heterozygous mice are predisposed to development of Histiocytic Sarcoma and Histiocyte-Associated Lymphoma. Bone marrow and splenic cells from 8-12 week old knockout mice have elevated viability ex vivo. These data provide the first direct evidence that CHC1L is a tumor suppressor gene involved in suppression of histiocyte-rich neoplasms.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytic disorder. It is primarily a disease of the long bones. Pulmonary involvement in systemic disease is detected in about half the reported cases. Isolated lung involvement is extremely rare with no clear recommendations for treatment. A 52-year-old caucasian male was evaluated for 1.9 cm × 1.6 cm spiculated nodule in the right upper lobe. Pulmonary function testing and bronchoscopy with endobronchial ultrasound, transbronchial biopsy, and microbiology were inconclusive. Positron emission tomography-computed tomography (PET-CT) was significant for the avidity in same lung nodule along with mediastinal and hilar adenopathy but no bone involvement. Wedge resection with histopathology and immunohistochemistry reported a fibrohistiocytic infiltrate in bronchovascular distribution which was positive for CD68 and negative for CD1A, S100, and BRAF V600E mutation. Magnetic resonance imaging brain ruled out central nervous system involvement. The rarity of the condition along with the complex pathology makes it difficult to diagnose and hence intervene appropriately.

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.

Histiocytic sarcoma (HS) is an exceptionally rare malignant neoplasm derived from dendritic cells and histiocytes, with no available effective treatment options. Akt signaling and proteasome dysfunction have been implicated in the pathogenesis of the disease, both in humans and dogs. Our work aims to investigate the importance of the Akt signaling pathway and evaluate the potential of Akt-targeted therapy in a canine model of histiocytic sarcoma. We demonstrated Akt signaling to be active in 9 out of 10 canine HS tumor samples, regardless the presence of PTEN. Moreover, the Akt signaling pathway appears to be constitutively active in DH82 cells — a cell line model of canine HS, when compared to control canine dendritic cells. Pharmacologic Akt inhibition resulted in significant decrease in Akt S473 phosphorylation, GSK-3β S9 phosphorylation, Akt activity, cell viability, increased apoptosis, and resulted in sensitization to proteasome inhibition-depended cell death in a synergistic manner. Proteasome inhibition using carfilzomib, an irreversible proteasome inhibitor, induced dose-depended/caspase-3 independent cell death, at clinically relevant drug concentrations. The therapeutic effect of Akt inhibition was validated in vivo using a DH82 xenograft murine model. Akt inhibition lead to reduced tumor growth, prolonged overall survival, and ameliorated splenomegaly, but not affected the lung metastasis. Moreover, the therapeutic effect of Akt inhibition was potentiated in combination with carfilzomib. In conclusion, targeting Akt signaling may represent an attractive potential therapeutic target for the HS. Future studies are required to examine the clinical efficacy of Akt-targeted therapy in dogs with HS using novel selective Akt inhibitors. / Ph. D. / Histiocytic sarcoma (HS) is an exceptionally rare cancer of the immune system, with no effective treatment options available. Canine histiocytic sarcoma (cHS) is an aggressive tumor of the same cellular lineage, identified at increased relative frequency in specific dog breeds, with significant translational value. Akt signaling and proteasome dysfunction have been implicated in the pathogenesis of the disease, both in humans and dogs. Our study aims to investigate the importance of the Akt signaling pathway in the dog model of the disease and evaluate the potential of Akt-targeted therapy in a translational of histiocytic sarcoma. The work presented here demonstrates that Akt signaling appears aberrantly and constitutively activated in the canine model of HS. Importantly, Akt inhibition significantly reduced the tumor growth and prolonged the overall survival of the experimental animals. Moreover, Akt inhibition potentiated the anti-cancer activities of other anticancer drugs. Collectively, these findings provide an attractive therapeutic approach for the treatment of HS.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1993. / Vita. Abstract. Includes bibliographical references (leaves 72-74). Also available via the Internet.

Commercial and homemade diets are currently used to treat many canine patients with acquired disorders of the colon. Clinically, the efficacy of diets has been found to be unpredictable. Only one study to date has evaluated the effect of diet on the colonic mucosa. This study showed that diet did not observably alter the colonic mucosa of normal dogs, when biopsy samples were evaluated by light microscopy. The effect of diet on colonic ultrastructure in the dog, using transmission electron microscopy, has not previously been investigated. To determine the effect of diet on colonic ultrastructure, cell height, cell area, microvillus height, number of microvilli/apex width and basement membrane width were measured. Ten cells per animal were evaluated. Six dogs were assigned to the control group and fed the control diet for the duration of the study. Six dogs were fed each of the three test diets at four week intervals. The test diets used included a high fiber diet, a hypoallergenic diet and a highly digestible diet. These diets were selected because they are the diets most often recommended for the canine patient with colonic disorders. The value for cell height for the highly digestible group was significantly greater than the other groups, as measured by ANOV A and Duncan's multiple comparison test. No other significant differences were found. The biological relevance of a significantly different value for cell height alone is difficult to evaluate, as other parameters that would indicate an alteration in maturation or proliferation of the colonic epithelial cells did not change. value for cell height alone is difficult to evaluate, as other parameters that would indicate an alteration in maturation or proliferation of the colonic epithelial cells did not change. Therefore, we conclude that commercial diets do not have an effect on the colonic ultrastructure of normal dogs. Although no effect of diet was found, this study does provide morphologic measurements that can be used as a basis for future ultrastructural studies of the colonic mucosa. / Master of Science