16 research outputs found

    Mmp10 plays a promotive role in urethane-induced lung tumorigenesis.

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    <p><i>Mmp10<sup>βˆ’/βˆ’</sup></i> mice and Ntg littermates were injected with urethane and analyzed as described in <i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026439#s4" target="_blank">Materials and Methods</a></i>. <b>A</b>) H & E and immunohistochemical staining for Mmp10 in urethane-induced lung tumors. Higher magnification image of Mmp10 immunostaining is shown in the inset. Quantitative analysis of tumor number <b>B</b>), tumor size <b>C</b>) and tumor burden <b>D</b>) in urethane-treated Ntg (nβ€Š=β€Š7) and <i>Mmp10<sup>βˆ’/βˆ’</sup></i> (nβ€Š=β€Š12) mice. Mean +/βˆ’SEM; p<. 0.012 tumor number; p<0.019 tumor burden; pβ€Š=β€Š0.034 tumor size). <b>E</b>) Urethane-induced tumors from Ntg and Mmp10<i><sup>βˆ’</sup></i><sup>/<i>βˆ’</i></sup> mice were graded as hyperplasia, adenoma or adenocarcinoma using published criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026439#pone.0026439-KellySpratt1" target="_blank">[26]</a>. Results are presented as the percentage of total tumors of each grade. Statistical analysis using Mann-Whitney U test revealed no statistically significant difference in tumor grade between urethane-induced tumors in Ntg and Mmp10<i><sup>βˆ’</sup></i><sup>/<i>βˆ’</i></sup> mice (pβ€Š=β€Š0.39).</p

    Mmp10 expression correlates with cancer stem cell genotypes and metastasis in human lung tumors.

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    <p><b>A</b>) Gene expression data from primary human lung adenocarcinomas were divided into two groups of 30 samples consisting of lowest (Low) and highest (High) Mmp10 expressing lung tumors. nβ€Š=β€Š30; * pβ€Š=β€Š2.8Γ—10<sup>βˆ’33</sup>. <b>B</b>) Mmp10 in normal lung versus lung tumors with (<b><i>Met.</i></b>) and without (<b><i>No Met.</i></b>) bone metastases. nβ€Š=β€Š3, normals, nβ€Š=β€Š9, No Mets, nβ€Š=β€Š7, Met.; NSβ€Š=β€Š not significant, *pβ€Š=β€Š0.008; **pβ€Š=β€Š0.04. <b>C</b>) Mmp10 mRNA expression in human tumors. Data are expressed as fold-change from matched normal.</p

    Mmp10 is required for <i>Kras</i>-induced expansion and transformation of BASCs <i>in vitro.</i>

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    <p>BASCs isolated from Ntg, <i>Mmp10<sup>βˆ’/βˆ’</sup></i>, <i>LSL-Kras</i>, and <i>LSL-Kras/Mmp10<sup>βˆ’/βˆ’</sup></i> mice were treated with AdCre and plated in three-dimensional Matrigel culture as described in <i>Experimental Procedures</i>. <b>A</b>) Flow cytometry of isolated BASCs for SPC and CCSP <b>B</b>) QPCR for Mmp10 in BASCs from Ntg, <i>LSL-Kras,</i> and <i>LSL-Kras/Mmp10<sup>βˆ’/βˆ’</sup></i> mice. Fold of Ntg +/<i>βˆ’</i>SEM. nβ€Š=β€Š3, *p<0.000008. <b>C</b>) Morphology of BASC colonies from Ntg, <i>Mmp10<sup>βˆ’/βˆ’</sup></i>,<i>LSL-Kras</i>, and <i>LSL-Kras/Mmp10<sup>βˆ’/βˆ’</sup></i> mice. <b>D</b>) Analysis of BASC colony size. %Ntg +/βˆ’SEM. nβ€Š=β€Š85 Ntg, 56 <i>Mmp10<sup>βˆ’/βˆ’</sup></i>,30 (<i>LSL-Kras</i>) and 80 (<i>LSL-Kras/Mmp10<sup>βˆ’/βˆ’</sup></i>). *p<0.00001 Ntg vs, <i>LSL-Kras;</i> **p<0.00001 <i>LSL-Kras</i> vs. <i>LSL-Kras/Mmp10<sup>βˆ’/βˆ’</sup></i>.</p

    Validation of the association between high Mmp10 in lung tumors and cancer stem cell signatures.

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    <p>Gene sets marked in bold text were also significantly enriched in the high Mmp10 lung tumor gene set analysis outlined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026439#pone-0026439-g005" target="_blank">Figure 5</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026439#pone-0026439-t001" target="_blank">Table 1</a>.</p

    Association of metastatic lung cancer genes with cancer stem cell signatures.

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    <p>Gene sets marked in bold text are cancer stem cell signatures also identified as highly correlated with lung tumors expressing high Mmp10.</p

    Mmp10 is necessary for <i>Kras<sup>LA2</sup></i>-induced lung tumorigenesis <i>in vivo.</i>

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    <p><b>A</b>) Immunohistochemical staining of <i>Kras<sup>LA2</sup></i> lung tumor for mouse MMP10. Higher magnification image of Mmp10 immunostaining is shown in the inset. Quantitative analysis of <b>B</b>) tumor number, <b>C</b>) tumor size and <b>D)</b> tumor burden in <i>Kras<sup>LA2</sup></i> and <i>Kras<sup>LA2</sup>/Mmp10<sup>βˆ’/βˆ’</sup></i> mice. Columns, mean; bars, SEM, nβ€Š=β€Š13, (*) denotes pβ€Š=β€Š0.04. E) Tumors from <i>Kras<sup>LA2</sup></i> and <i>Kras<sup>LA2</sup>/Mmp10<sup>βˆ’/βˆ’</sup></i> mice were categorized as advanced adenomatous hyperplasia (AAH), or grade 1,2 or 3 adenomas using the published scoring criteria described by Jackson et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026439#pone.0026439-Jackson1" target="_blank">[28]</a>. Results are presented as the percentage of total tumors of each grade. Statistical analysis using Mann-Whitney U test revealed a significant decrease in higher grade tumors in <i>Kras<sup>LA2</sup>/Mmp10<sup>βˆ’/βˆ’</sup></i> mice; *p<0.002.</p
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