Browsing by Subject "tumor metastasis"

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    ELEVATED LEVELS OF PLATELETS AND MDM2 EXPRESSION ARE CONTRIB-UTING FACTORS TO FACILITATING THE METASTASIS OF OSTEOSARCOMA
    (Office of the Vice Chancellor for Research, 2012-04-13) Lipking, Kelsey; Kacena, Melissa A.; Konopka, Jeff A.; Mayo, Lindsey D.; Sandusky, George E.
    Osteosarcoma (OS) is the most common form of primary bone cancer and the 6th leading cause of cancer in pediatric patients. A chart review of OS patients treated at this institution suggests that a high platelet count at di-agnosis is significantly (p=0.023) and inversely associated with the first year of survival. As the effects of platelet interaction with OS have been exten-sively researched and suggest that platelets may facilitate tumor metastasis, and the most important prognostic factor for OS patient survival is metasta-sis to the lungs, we hypothesized that platelets increase metastasis to the lungs and reduce survival. Therefore, we sought to determine whether in-creasing platelet numbers in a well characterized OS mouse model would de-crease survival and/or increase metastasis to the lungs. We found that thrombopoietin (TPO) treated mice, had increased platelet numbers, died earlier than placebo treated controls, and that lungs from TPO treated mice contained a small number of large tumor cells (most metastatic lesions were 2-4 cells), whereas lungs from placebo treated controls showed no signs of metastases. Next, an OS tissue microarray (TMA) was built from OS patients seen at our institution over the past 10 years. Mdm2, p53, TPO, and c-mpl expression were evaluated by immunohistochemical (IHC) staining followed by quantitation using the Aperio Imaging system and analysis software. C-mpl (TPO receptor) expression was higher in the metastatic than the primary tumors, suggesting that platelets may contribute to the metastasis of OS. Elevated levels of Mdm2 correlated with metastasis and lower levels of p53, as detected by IHC. In conclusion, both the mouse model and the human OS data were similar, suggesting that both platelets and Mdm2 promote metas-tases in OS.
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    The function of the 130kDa MLCK in regulating in vivo vascular permeability and angiogenesis
    (Office of the Vice Chancellor for Research, 2011-04-08) Chen, Meng; Herring, Paul
    Disruption of endothelial integrity is an essential component of vascular inflammation, angiogenesis, atherosclerosis, and tumor metastasis. Many studies have shown that activation of myosin light chain kinase (MLCK) in endothelial cell is correlated with increase in vascular permeability. Currently, most research in endothelial cells has focused on the 220kDa MLCK isoform which is the predominant isoform present in cultured endothelial cells. However, in freshly isolated uncultured endothelial cells, the 130kDa MLCK predominates. Yet nothing is known about the roles of the 130kDa MLCK isoform in endothelial cells. Therefore, our goal is to determine the role of the 130kDa MLCK in regulating vascular permeability and angiogenesis in vivo. To do this we will generate an endothelial cell-specific 130kDa MLCK knockout mice. As transcripts encoding the 130 and 220kDa MLCK isoforms are produced by independent promoters within the same mylk1 gene, I will selectively knockout the 130kDa MLCK by deleting unique cis-acting gene regulatory elements required for the expression of this transcript. A key element identified within the intron following the first exon of the 130kDa MLCK transcript has been flanked by LoxP sites such that Cre recombinase (Cre) mediated recombination will delete the element and attenuate expression of the 130kDa MLCK. By crossing these floxed mice with Tie2-Cre mice which express Cre specifically in endothelial cells, I will obtain endothelial cellspecific 130kDa MLCK knockout mice. In vivo vascular permeability and angiogenesis assays on these mice will allow me to determine the role played by the 130kDa MLCK in these processes. This study will not only help to identify specific functions of the 130kDa MLCK isoform, but also determine if this is a drug target for developing novel treatments of vascular diseases and cancer.