The objective of this research is to define the role of glycosphingolipids in brain tumor growth and vascularity (i.e., angiogenesis). Gangliosides are sialic acid-containing glycolipids that are enriched in plasma membranes and are shed from tumor cells into the extracellular matrix. Gangliosides may influence brain tumor angiogenesis through multiple effects on the tumor cells and tumor associated host cells, e.g., endothelial cells and macrophages. Preliminary findings from this laboratory suggest that the simple monosialoganglioside GM3 is antiangiogenic and that more complex gangliosides (GM2, GM1, GDla and GTlb) are proangiogenic in experimental mouse brain tumors. We propose that altering tumor ganglioside composition will influence tumor growth and vascularity. We will test this hypothesis by manipulating the genes for GalNAc transferase (GalNac-T) and sialyltransferase 2 (SAT-2), two essential enzymes required for the synthesis of complex gangliosides. These genes will be up-regulated or down-regulated in stable transfectants of three well-established experimental brain tumors, i.e., the mouse EPEN and CT-2A tumors and the human glioma U87. These tumors are good models for the proposed studies because they differ in ganglioside composition, vascularity, and growth rate. Control untransfected or vector transfected tumors will be compared with their stable transfectants and will be studied as solid tumors grown in vivo and as cell lines grown in vitro. The degree of tumor angiogenesis in vivo will be assessed from analysis of microvessel density, tumor growth rate, vascular endothelial growth factor (VEGF) expression, and macrophage infiltration. The mechanisms by which gangliosides influence angiogenesis will be examined using cultured endothelial cells and the Matrigel plug model of angiogenesis. The proposed research will better define the relationship between gangliosides and tumor angiogenesis and can lead to new experimental strategies for managing brain tumors.
| Seyfried, Thomas N; Flores, Roberto; Poff, Angela M et al. (2015) Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett 356:289-300 |
| Seyfried, Thomas N; Flores, Roberto E; Poff, Angela M et al. (2014) Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 35:515-27 |
| Seyfried, Thomas N; Huysentruyt, Leanne C (2013) On the origin of cancer metastasis. Crit Rev Oncog 18:43-73 |
| Seyfried, Thomas N; Marsh, Jeremy; Shelton, Laura M et al. (2012) Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res 100:310-26 |
| Huysentruyt, Leanne C; Akgoc, Zeynep; Seyfried, Thomas N (2011) Hypothesis: are neoplastic macrophages/microglia present in glioblastoma multiforme? ASN Neuro 3: |
| Mulrooney, Tiernan J; Marsh, Jeremy; Urits, Ivan et al. (2011) Influence of caloric restriction on constitutive expression of NF-?B in an experimental mouse astrocytoma. PLoS One 6:e18085 |
| Seyfried, Thomas N; Kiebish, Michael A; Marsh, Jeremy et al. (2011) Metabolic management of brain cancer. Biochim Biophys Acta 1807:577-94 |
| Shelton, Laura M; Huysentruyt, Leanne C; Mukherjee, Purna et al. (2010) Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro 2:e00038 |
| Shelton, Laura M; Huysentruyt, Leanne C; Seyfried, Thomas N (2010) Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model. Int J Cancer 127:2478-85 |
| Huysentruyt, Leanne C; Seyfried, Thomas N (2010) Perspectives on the mesenchymal origin of metastatic cancer. Cancer Metastasis Rev 29:695-707 |
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