CCL2-CCR2 axis promotes metastasis of nasopharyngeal carcinoma by activating ERK1/2-MMP2/9 pathway

Distant metastasis remains the major failure of nasopharyngeal carcinoma (NPC). In this study, the roles of chemokine C-C motif ligand 2 (CCL2), and its receptor chemokine C-C motif receptor type 2 (CCR2) on NPC metastasis were investigated. Serum CCL2 and CCL2/CCR2 expression level were remarkably increased in NPC patients compared to non-tumor patients by ELISA and IHC analyses. High expressions of CCL2/CCR2 were significantly associated with NPC metastasis and poor overall survival (OS). High expression of CCR2 is an independent adverse prognostic factor of OS and distant metastasis free survival (DMFS). Overexpressions of CCL2 and CCR2 were detected in high-metastatic NPC cell lines. Upregulating CCL2 and CCR2 respectively in low-metastatic NPC cell lines could promote cell migration and invasion, and exogenous CCL2 enhanced the motility in CCR2-overexpressing cells. On the other hand, downregulating CCL2 and CCR2 respectively in high-metastatic NPC cell lines by shRNA could decrease cell migration and invasion. However, exogenous CCL2 could not rescue the weaken ability of motility of CCR2-silencing cells. In nude mouse model, distant metastasis was significantly facilitated in either CCL2-overexpressing or CCR2-overexpressing groups, which was more obvious in CCR2-overexpressing group. Also, distant metastasis was considerably inhibited in either CCL2-silencing or CCR2-silencing groups. Dual overexpression of CCL2/CCR2 could activate extracellular signal-regulated kinase (ERK1/2) signaling pathway, which sequentially induced matrix metalloproteinase (MMP) 2 and 9 upregulations in the downstream. In conclusion, CCL2-CCR2 axis could promote NPC metastasis by activating ERK1/2-MMP2/9 pathway. This study helps to develop novel therapeutic targets for distant metastasis in NPC

Effectiveness of regional innovation actions: cases from small, low-innovative regions

This paper attempts to identify the suitability of centrally designed innovation-related regional actions, examining the case of regions that started innovative activities from a low development level. Using the case of two Greek regions, the paper analyses the legacy left to the regional systems by a series of regional innovation programmes implemented during the 1990s and 2000s, whose main priorities were designed centrally without any regional consultation. The findings suggest that these programmes often provide the means for generating the first steps towards the creation of a Regional Innovation System; however often they create a dependency on publicly funded programmes

Cancer cell redirection biomarker discovery using a mutual information approach

<div><p>Introducing tumor-derived cells into normal mammary stem cell niches at a sufficiently high ratio of normal to tumorous cells causes those tumor cells to undergo a change to normal mammary phenotype and yield normal mammary progeny. This phenomenon has been termed cancer cell redirection. We have developed an <i>in vitro</i> model that mimics <i>in vivo</i> redirection of cancer cells by the normal mammary microenvironment. Using the RNA profiling data from this cellular model, we examined high-level characteristics of the normal, redirected, and tumor transcriptomes and found the global expression profiles clearly distinguish the three expression states. To identify potential redirection biomarkers that cause the redirected state to shift toward the normal expression pattern, we used mutual information relationships between normal, redirected, and tumor cell groups. Mutual information relationship analysis reduced a dataset of over 35,000 gene expression measurements spread over 13,000 curated gene sets to a set of 20 significant molecular signatures totaling 906 unique loci. Several of these molecular signatures are hallmark drivers of the tumor state. Using differential expression as a guide, we further refined the gene set to 120 core redirection biomarker genes. The expression levels of these core biomarkers are sufficient to make the normal and redirected gene expression states indistinguishable from each other but radically different from the tumor state.</p></div

Molecular signatures that demonstrate the greatest MI ratio.

<p>Molecular signatures that demonstrate the greatest MI ratio.</p

The experimental system and global gene expression pattern.

<p><b>A</b>: The experimental system consists of six cell groups; normal (A) and tumor (B) cells were mixed in either a 1:1 or 50:1 (normal:tumor) ratio and cultured for 4 days, then magnetically sorted based on expression of erbB2 into four resultant groups: normal (D) or tumor (F) from the 1:1 mixing and normal (C) and redirected tumor (E) from the 50:1 mixing; <b>B</b>: Heatmap of all transcripts present in the microarray, log₂ expression values normalized by column; columns are identified at the bottom of the figure with their cell group classification and replicate number.</p

Molecular signature mutual information distinguishes cell groups.

<p>The MI(A,E)/MI(E,B) distribution in the center is for all molecular signatures. The lower ratios to the left of the distribution represent molecular signatures where the redirected state (E) is closer to the tumor state (B); The higher ratios to the right of the distribution represent molecular signatures where the redirected state (E) is closer to the normal state (A). Sample molecular signatures in the 3D insets show cell group replicate differences at percentiles 1, 2, 5 (left column, bottom to top) and 95, 98, 99 (right column, top to bottom) of the MI ratio distribution. Molecular signature markers: red markers at the base of the distribution indicate the position of the significant molecular signatures along the distribution; blue markers and arrows indicate the position of the most adversely affected molecular signature after the addition of the extended genes (left marker, PID_CERAMIDE_PATHWAY) and the molecular signature with the most improved ratio after extension (right marker, REACTOME_SOS_MEDIATED_SIGNALLING).</p

Representative cancer redirection molecular signatures.

<p>Markers indicate genes with at least one transcript identified as significantly differentially expressed. Gene names in gray are those added by interaction with the original molecular signatures members. Heatmaps for all groups are available in Supplemental Dataset 1. (A) Molecular signature of the SOS mediated signaling pathway. (B) Molecular signature of the Notch HLH pathway. (C) Immunoflourescent staining of cells for P-erbB2 (green) and Mapk1 (red). Nuclei counterstained with DAPI. Scale bars = 40 <b><i>μ</i></b>m. Lower right image is DIC image with Xgal stained lacZ⁺ cells evident. (D) Western blots probed for Notch2. <b><i>β</i></b>-actin used as loading control. A-Normal cell lysates, B-Cancer cell lysates, E-Lysates from 1:50 cultures.</p