21 research outputs found
Matrix Metalloproteinase-10 Is Required for Lung Cancer Stem Cell Maintenance, Tumor Initiation and Metastatic Potential
Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10β/β mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells
Atypical Protein Kinase CΞΉ Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells
Atypical Protein Kinase CΞΉ Is Required for Bronchioalveolar Stem Cell Expansion and Lung Tumorigenesis
Matrix Metalloproteinase-10 Promotes Kras-Mediated Bronchio-Alveolar Stem Cell Expansion and Lung Cancer Formation
Mmp10 is required for <i>Kras</i>-induced expansion and transformation of BASCs <i>in vitro.</i>
<p>BASCs isolated from Ntg, <i>Mmp10<sup>β/β</sup></i>, <i>LSL-Kras</i>, and <i>LSL-Kras/Mmp10<sup>β/β</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>β/β</sup></i> mice. Fold of Ntg +/<i>β</i>SEM. nβ=β3, *p<0.000008. <b>C</b>) Morphology of BASC colonies from Ntg, <i>Mmp10<sup>β/β</sup></i>,<i>LSL-Kras</i>, and <i>LSL-Kras/Mmp10<sup>β/β</sup></i> mice. <b>D</b>) Analysis of BASC colony size. %Ntg +/βSEM. nβ=β85 Ntg, 56 <i>Mmp10<sup>β/β</sup></i>,30 (<i>LSL-Kras</i>) and 80 (<i>LSL-Kras/Mmp10<sup>β/β</sup></i>). *p<0.00001 Ntg vs, <i>LSL-Kras;</i> **p<0.00001 <i>LSL-Kras</i> vs. <i>LSL-Kras/Mmp10<sup>β/β</sup></i>.</p
The 10 most highly correlated signatures associated with high Mmp10 in lung cancer.
<p>Gene sets marked in bold text contain Mmp10 as part of the gene signature.</p
Validation of the association between high Mmp10 in lung tumors and cancer stem cell signatures.
<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.
<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 expression correlates with cancer stem cell genotypes and metastasis in human lung tumors.
<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=β30; * pβ=β2.8Γ10<sup>β33</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=β3, normals, nβ=β9, No Mets, nβ=β7, Met.; NSβ=β not significant, *pβ=β0.008; **pβ=β0.04. <b>C</b>) Mmp10 mRNA expression in human tumors. Data are expressed as fold-change from matched normal.</p