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This study examined whether mesenchymal stem cells (MSCs), which are stem cells originated from embryonic mesoderm, are able to differentiate into functional hepatocyte-like cells in vitro. MSCs were isolated from human bone marrow and umbilical cord blood, and the surface phenotype and the mesodermal multilineage differentiation potentials of these cells were characterized and tested. To effectively induce hepatic differentiation, we designed a novel 2-step protocol with the use of hepatocyte growth factor and oncostatin M.

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Using high-density oligonucleotide microarrays and functional network analyses, we examined whether MSCs derived from four different origins exhibited unique gene expression profiles individually and then compared the gene expression profiles of all MSCs with those of fetal organs. Our results indicated that within each group of MSCs from the same origin, the variability of the gene expression levels was smaller than that between groups of different origins. Functional genomic studies revealed the specific roles of MSCs from different origins. Our results suggest that amniotic fluid MSCs may initiate interactions with the uterus by upregulating oxytocin and thrombin receptors. Amniotic membrane MSCs may play a role in maintaining homeostasis of fluid and electrolytes by regulating the networks of endothelin, neprilysin, bradykinin receptors, and atrial natriuretic peptide. Cord blood MSCs may be involved in innate immune systems as the neonatal defense system against the earliest encountered pathogens. Adult bone marrow MSCs may be an important source not only of all blood lineages but also of bone formation. However, in spite of the different gene expression profiles seen in MSCs derived from different origins, a set of core gene expression profiles was preserved in these four kinds of MSCs. The core signature transcriptomes of all MSCs, when contrasted against those of fetal organs, included genes involved in the regulation of extracellular matrix and adhesion, transforming growth factor-beta receptor signaling, and the Wnt signaling pathways. Disclosure of potential conflicts of interest is found at the end of this article.

BackgroundThe identification of potential tumor markers can improve therapeutic planning and patient management. The aim of this study was to highlight the significance of IL-6 in esophageal squamous cell carcinoma (SCC).MethodsWe retrospectively analyzed the clinical outcomes of 173 patients with esophageal SCC, and examined the correlation between IL-6 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after manipulation of IL-6 expression.ResultsIn clinical outcome analysis, positive IL-6 staining and poor treatment response was significantly associated with shorter survival. Furthermore, the frequency of IL-6 immunoreactivity was significantly higher in esophageal cancer specimens than in non-malignant epithelium, and this staining was positively linked to the development of distant metastasis (p = 0.0003) and lower treatment response rates (p = 0.0001).By ELISA analysis, IL-6 serum levels were significantly elevated in patients developing disease failure.When IL-6 expression was inhibited, aggressive tumor behavior and radiation resistance could be overcome in vitro and in vivo. The underlying changes included increased cell death, less epithelial-mesenchymal transition and attenuated STAT3 activation. IL-6 inhibition was also associated with attenuated angiogenesis in tumor-bearing mice.ConclusionsIL-6 was significantly associated with poor prognosis in patients with esophageal cancer. Targeting this cytokine could be a promising strategy for treatment of esophageal cancer, as evidenced by inhibition of aggressive tumor behavior and treatment resistance.

The aim of this study was to assess the significance of myeloid-derived suppressor cells (MDSCs) and their association with IL-6 in esophageal squamous cell carcinoma (SCC). We examined the percentage of CD11b+CD14+HLA-DR− myeloid cells and the levels of IL-6 in the peripheral blood of 50 patients with esophageal SCC and 12 healthy controls. Moreover, we evaluated the relationship between MDSC recruitment, IL-6 levels, and tumor progression by adding 4-nitroquinoline 1-oxide (4-NQO) to the drinking water of mice to induce esophageal tumors. Here we demonstrated that circulating CD11b+CD14+HLA-DR− cells were significantly increased in esophageal SCC patients compared with healthy people, and this was associated with the clinical stage, treatment response and circulating IL-6 levels. In a 4-NQO-induced esophageal tumor animal model, MDSC recruitment was associated with invasive esophageal tumors and with increased IL-6 levels. IL-6 stimulated reactive oxygen species, arginase 1 and p-STAT3 in MDSCs. Blockade of IL-6 prevented induction of MDSCs and the incidence of 4-NQO- induced invasive tumors. In conclusion, the levels of MDSCs and IL-6 predicted the prognosis of patients with esophageal SCC. Moreover, we suggest inhibition of IL-6 as a potential strategy for the treatment of esophageal SCC.

The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival. As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.

Studies conducted in Western countries have reported excess risks for second primary malignancies after breast cancer. However, there is little documentation of ethnic differences in these excess risks. Asian women are characterized by younger age at diagnosis of breast cancer, but very few reports are available on the incidences and risks for second primary cancers in this region. Using population-based data from the Taiwan National Cancer Registry (TNCR) for the period 1979 to 2003, we quantified standardized incidence ratios and cumulative incidence of second cancers among 53,783 women with initial diagnoses of breast cancer. Age-specific incidences showed peaks among women in their 40s, and 1,085 cases (2.02%) developed nonbreast second primary cancers. The risk for second cancers differs significantly according to age at diagnosis of breast cancer. In comparison with women diagnosed when z50 years (standardized incidence ratio, 0.96; 95% confidence interval; 0.89-1.04), there were significantly greater risks for bone, corpus uterine, ovarian, thyroid, esophageal, kidney and lung cancers, nonmelanoma skin cancer, and leukemia or lymphoma in women diagnosed when <50 years (standardized incidence ratio, 1.43; 95% confidence interval, 1.29-1.58). The survival probabilities differed between breast cancer patients with and without second cancers (P < 0.001). After diagnosis of the second cancer, the median survival time was only 2.87 years. In conclusion, we confirmed that young age at diagnosis of breast cancer predicted a subsequently increased risk for second malignancies, and the second cancers indeed worsen survivorship in patients who survived breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2647 -55)