MOESM1 of Effects of mesenchymal stem cells on solid tumor metastasis in experimental cancer models: a systematic review and meta-analysis

Additional file 1: Table S1. The detail characteristics of all the publications included

MOESM2 of Effects of mesenchymal stem cells on solid tumor metastasis in experimental cancer models: a systematic review and meta-analysis

Additional file 2: Figure S1. MSCs with promoting effects on tumor metastasis

Goosecoid Promotes the Metastasis of Hepatocellular Carcinoma by Modulating the Epithelial-Mesenchymal Transition

<div><p>The homeobox gene, <i>goosecoid</i> (<i>GSC</i>), is a transcription factor that participates in cell migration during embryonic development. Because cell migration during development has characteristics similar to cell invasion during metastasis, we evaluated the potential role of GSC in the metastasis of hepatocellular carcinoma (HCC). GSC expression in HCC cell lines and tissues was evaluated, and its effects on the migration potential of HCC cells were determined by GSC knock-down and overexpression methods. In addition, the prognostic role of GSC expression in the metastasis of cancer cells in HCC patients was determined. Our data showed that GSC was highly expressed in several HCC cell lines, particularly in a highly metastatic HCC cell line. Overexpression of GSC promoted cell migration and invasion of HCC cells <i>in vitro</i>. Gain-of-function induced the epithelial-mesenchymal transition but not collective cell migration, whereas loss-of-function induced the reverse change. High-level expression of GSC correlated closely with poor survival and lung metastasis in HCC patients; lung metastases showed more upregulated GSC expression than the primary tumor. We conclude that GSC promotes metastasis of HCC potentially through initiating the epithelial-mesenchymal transition. GSC is also a prognostic factor for poor survival and metastasis of HCC, which suggests its potential as a therapeutic target for metastatic HCC.</p></div

Prognostic Significance of the Neutrophil-to-Lymphocyte Ratio in Primary Liver Cancer: A Meta-Analysis

<div><p>The neutrophil-to-lymphocyte ratio (NLR) is a useful biomarker that reflects systemic inflammation responses. However, the prognostic value of the NLR in patients with primary liver cancer (PLC) remains controversial. We performed a meta-analysis of 26 studies (comprising 4,461 patients) to evaluate the association between the pre-treatment NLR and clinical outcomes of overall survival (OS) and disease-free survival (DFS) in patients with PLC. The correlation between NLR and tumor characteristics or other inflammation-related parameters was also assessed. Data were synthesized using the random-effects model of DerSimonian and Laird, and the hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was used to estimate effect size. Our analysis indicated that a high NLR predicted poor OS (HR, 2.102; 95% CI: 1.741–2.538) and DFS (HR, 2.474; 95% CI: 1.855–3.300) for PLC. A high NLR was associated with the presence of tumor vascular invasion (OR: 1.889, 95% CI: 1.487–2.400; <i>p</i><0.001) and an elevated alpha-fetoprotein level (OR: 1.536; 95% CI: 1.152–2.048; <i>p</i> = 0.003). Thus, we conclude that a high NLR indicates a poor prognosis for patients with PLC and may also be predictive for PLC invasion and metastasis. Subgroup analysis suggested that the predictive role of NLR in cholangiocarcinoma is limited, and a further large study to confirm these findings is warranted.</p></div

GSC expression in HCC cell lines.

<p>(A) Western blot indicates that GSC is abnormally expressed in HCC cell lines, whereas it is not detectable in a normal hepatic cell line. (B) Western blot shows that GSC is strongly expressed in the highly metastatic HCC cell line versus the cell line with low metastatic potential. (C) <i>GSC</i> was overexpressed in HCC cells through lentivirus infection. A stable cell line was selected with 3 mg/mL puromycin. Quantitative real-time RT-PCR shows the prominent overexpression of <i>GSC</i> in Hep3B cells, which was confirmed by western blot. The data are presented as the mean ± SD of at least three independent experiments.</p

GSC expression in HCC tumor tissues.

<p>Immunohistochemistry analysis was performed based on tissue microarray. (A) Top-row shows the staining of GSC from strong to low. Bottom-row shows the controls to confirm the specificity of the GSC antibody. Colon tissue staining was used as the positive control. (B) Six tumor tissues in lung metastases from HCC showed the highly expressed GSC. Comparison of two paired tissues (case 5 and case 6) from lung metastatic cancer and primary foci showed the upregulated GSC expression in lung tissues. (200× original magnification, size bar: 100 µm).</p

Forest plots of the association between the NLR and survival of patients with primary liver cancer.

<p>A random-effects model was used. (A) Forest plot of the association between the NLR and OS of 21 studies. (B) Forest plot of the association between the NLR and DFS of 17 studies. Blue represents the HR estimate of each study, whereas red represents the overall pooled effective size. NLR  =  neutrophil-to-lymphocyte ratio; OS  =  overall survival; DFS  =  disease-free survival; *, the different study by Gomez; **, the different study by Wang.</p

Univariate and multivariate analysis of factors associated with survival and lung metastasis in HCC patients.

<p>Univariate and multivariate analysis of factors associated with survival and lung metastasis in HCC patients.</p

Effects of GSC overexpression on migration of HCC.

<p>Hep3B-GSC cells were infected by <i>GSC</i> lentivirus and were selected with puromycin. (A) Wound-healing assay shows that Hep3B-GSC cells migrated faster than normal Hep3B or Hep3B cells without treatment after 24 h and 48 h. The cleared area of Hep3B-GSC was less than the controls. (50× original magnification, size bar: 100 µm) Results were analyzed with the Student <i>t</i> test. (B) Giemsa staining indicated the number of Hep3B-GSC cells that migrated through Matrigel was higher than Hep3B cells without treatment or treated with negative control (100× original magnification, size bar: 100 µm). The data are presented as the mean ± SD of at least three independent experiments. Results were analyzed using Student's <i>t</i> test.</p

GSC expression correlates with poor survival and lung metastasis in HCC.

<p>Immunohistochemistry assay was based on tissue microarray from 112 tumor tissues. (A) Patients with highly expressed GSC had a significantly worse 5-year survival (Kaplan-Meier, log-rank test). (B) Patients with highly expressed GSC had showed early relapse and poor relapse-free survival when compared to other subgroups (Kaplan-Meier, log-rank test). (C) Groups with highly expressed GSC had lower extra-hepatic metastasis-free survival than the group with lower expressed GSC (Kaplan-Meier, log-rank test). (D) Receiver Operating Characteristic (ROC) curve analysis of GSC expression for occurrence of lung metastasis showed areas under the curve (AUC) of >0.5 (<i>P</i><0.05).</p