Hemangiomas represent the most common soft tissue tumor in children and hemangioendothelioma (HE) are a clinical subtype. Proliferating HE are associated with macrophage infiltration and MCP-1 expression. Macrophages seen in proliferating neoplasms, such as those seen in HE are referred to as tumor associated macrophages (TAM) and their biological role has not been defined. It is hypothesized that TAM facilitate angiogenesis to support HE development. Macrophages possess NADPH oxidase that generates substantial amounts of inducible reactive oxygen species (ROS), which are now recognized as key signaling mediators. Specifically, ROS have been described to be a key player in facilitating the expression of angiogenic factor and neovascularization as well. Therefore, it is possible that macrophage-derived ROS may drive hemangioendothelioma development. In the proposed study, the candidate will test the hypothesis that MCP-1 recruited TAM and its ROS derivative play a critical role in promoting angiogenesis and hemangioendothelioma (HE) development. In vivo and in vitro experiments will be conducted using a murine model of HE and culture EOMA cells, respectively. The proposal rests on a striking finding that MCP-1 and NADPH oxidase are key contributors to HE development. These results were derived from the use of appropriate knock-out animal models. To test the stated hypothesis, the following three specific aims will be addressed:
Aim #1 : Determine the significance of macrophages in HE development.
Aim #2 : Characterize in vitro whether macrophage-derived ROS influences the angiogenic characteristics behavior of EOMA cells and whether H202 is the primary signaling molecule mediating the effect of ROS;
and Aim #3 : Test in vivo the significance of macrophage-derived ROS on HE development. The long-term goal is to develop a research career in the field of clinically relevant angiogenesis and underlying mechanisms. The current proposal includes didactic and research training elements towards the development of a surgical scientist career of a hispanic woman plastic surgeon.
| Gordillo, Gayle; Fang, Huiqing; Park, Hana et al. (2010) Nox-4-dependent nuclear H2O2 drives DNA oxidation resulting in 8-OHdG as urinary biomarker and hemangioendothelioma formation. Antioxid Redox Signal 12:933-43 |
| Gordillo, Gayle; Fang, Huiqing; Khanna, Savita et al. (2009) Oral administration of blueberry inhibits angiogenic tumor growth and enhances survival of mice with endothelial cell neoplasm. Antioxid Redox Signal 11:47-58 |
