Browsing by Subject "Lymphoma"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Comparative and molecular approaches to improve identification, classification, and therapeutic approaches to cancer(2013-01) Frantz, Aric M.A major area of contemporary research in cancer is focused on improving tumor classification into clinically relevant subgroups of disease. To achieve this, it is important to understand the molecular events that driver tumor heterogeneity both at the cellular level and at the tissue level. I initially tested the hypothesis that canine lymphoma is composed of a group of molecularly distinct entities with prognostic significance. The results show that canine lymphoma can be stratified into molecular subgroups that have prognostic value and can assist to guide therapy. Next, I tested the hypothesis that canine hemangiosarcoma (HSA) is organized hierarchically with a cancer stem cell (CSC)-like population of cells at the apex. The data show that variable numbers of CSC-like cells are invariably present in HSA. These CSC-like cells retain the capacity to differentiate into vascular, inflammatory, or adipogenic tissue, suggesting that their multipotency is a contributing factor to the observed heterogeneity in this disease. Finally, I tested the hypothesis that CSCs, or CSC-like cells from three histologically distinct types of canine cancer (HSA, osteosarcoma, and glioblastoma) share molecular and functional properties. Using a system that allowed me to eliminate tumor-specific culture conditions, I showed that despite extensive heterogeneity in CSC-like cells from these tumors, they all showed reduced activity of pathways associated with proliferation and development. In summary, my results confirm that cellular heterogeneity exists both within and among tumors. A better understanding of the mechanisms that drive this will improve patient stratification and guide efforts to develop rational, more effective therapies.Item The functional role of the activating receptors Tim-3 and CD16 in human natural killer (NK) cell biology(2012-09) Gleason, Michelle KathleenHuman natural killer (NK) cells are lymphocytes that develop in the bone marrow from hematopoietic progenitor cells (HPCs) and are also found in the lymph nodes, spleen and peripheral blood (PB), where they comprise 10-15% of the mononuclear cell fraction. PB NK cells are phenotypically defined as expressing the surface receptor CD56 (NCAM, neural cell adhesion molecule) and lacking expression of CD3. They mediate their function through the exocytosis of granules that contain lytic enzymes such as perforin and granzymes, the expression of death receptor ligands, the expression of FcRgammaIIIA (CD16, a mediator of antibody-dependent cell-mediated cytotoxicity or ADCC), and the secretion of cytokines and chemokines. As a result, NK cells take part in both the innate and adaptive immune responses and have critical roles in the control of early viral infection, hematopoietic cell transplantation (HCT) and tumor immunosurveillance. The ability of NK cells to differentiate normal healthy cells (self) from infected or transformed (non-self) cells is regulated by a sophisticated repertoire of cell surface receptors that control their activation, proliferation and effector functions. The net balance of inhibitory and activating signals transmitted by these receptors determines whether an NK cell will eliminate its target. The work presented in this manuscript focuses on the modulation of NK cell effector function by two receptors found in their activating repertoire, namely Tim-3 and CD16, and their potential for enhancing the therapeutic effects of NK cells for the treatment of human hematopoietic malignancies.