Research for molecular mechanisms of lymphangiogenesis and lymph node metastasis

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1.The expression of lymphatic marker, podoplanin by cancer were associated with the frequency of lymph node metastasis.We established novel anti-human podoplanin antibodies, and found the expression by several cancer cells using tissue microarrays. We also found that podoplanin was the specific marker for mesothelioma.2.Homeobox gene, prox1 as a novel tumor suppressor gene.We found that there was a significant correlation between prox1 expression and the differentiation scores of the tumors. Subsequently, we also showed that low expression of prox1 in tumors was closely associated with a poor prognosis. The specific knockdown of prox1 by RNA interference strongly accelerated in vitro cell growth, while the over-expression of prox1 greatly suppressed the growth.3.Two populations of Thy1-positive mesenchymal cells regulate the in vitro maturation of hepatic progenitor cellsWe determined that the mucin-type transmembrane glycoprotein gp38 could distinguish the cuboidal cells from the spin … More dle cells by immunocytochemistry. In vitro maturation of hepatic progenitor cells promoted by gp38-positive cells may be opposed by an inhibitory effect of gp38-negative cells, which likely maintain the immature, proliferative state of CD49f-positive cells.4.Differentiation of lymphatic endothelial cells from Embryonic Stem cells on OP9 stromal cellsVEGFR-2^+ cells derived from ES cells differentiated into LECs at day3 on OP9 stromal cells defined by the expression of prox1, VEGFR-3 and another lymphatic marker podoplanin. VEGFR-2^+ cells gave rise to LYVE-1^+ embryonic ECs, which were negative for prox1 on day1 but turned to prox1^+ LECs by day3. VEGFR3-Fc or Tie2-Fc, sequestering VEGF-C or angiopoietin 1 (Ang1), suppressed colony formation of LECs on OP9 cells. However, addition of VEGF-C and Ang1 in combination with VEGF to the culture of VEGFR-2^+ cells on collagen-coated dishes failed to induce LECs. LEC inducing activity of OP9 cells was fully reproduced on PFA-fixed OP9 cells with the conditioned medium. Less