| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2006: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2005: ¥9,200,000 (Direct Cost: ¥9,200,000)
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| Research Abstract |
Glioblastoma multiforme (GBM) is the most malignant glioma because of its high infiltration into the normal brain parenchyma. Factors that influence the motility of GBM cells are of particular interest because GBM cells are highly invasive. We recently showed that autotaxin (ATX), a potent cell motility-stimulating factor that was originally isolated from melanoma cells, has lysophospholipase D activity. Lysophospholipase D produces a bioactive phospholipid, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC), and regulates cell motility through G protein-coupled receptors for LPA. In this study we found that ATX is highly expressed in GBM tissues but not in tissues from other brain tumors. In addition, LPA_1, an LPA receptor responsible for LPA-driven cell motility, is predominantly expressed in GBM. Among 50 tumor cell lines derived from various tissues, several cell lines, especially glioblastoma, express a significant amount of ATX at both the mRNA and protein levels. These cells were also found to express LPA_1 mRNA predominantly and showed LPA_1-dependent cell migration in response to LPA and ATX in the Boyden-chamber assay. The glioblastoma that showed the highest ATX expression (SNB-78), as well as ATX-stable transfectants showed LPA_1-dependent cell migration in response to both LPA and LPC in both the Boyden-chamber and a wound healing assays. The LPA_1-dependent cell migration was completely abolished by an LPA_1-antagonist, Ki16425. Our results suggest that the autocrine production of LPA by cancer cell-derived ATX and exogenous LPC contribute to the invasiveness of GBM cells and that LPA_1, ATX and LPC-producing enzymes are potential targets for GBM therapy.
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