The epithelial-mesenchymal transition (EMT) plays a critical role in embryonic development. EMT is also involved in cancer progression and metastasis and it is probable that a common molecular mechanism is shared by these processes. Cancer cells undergoing EMT can acquire invasive properties and enter the surrounding stroma, resulting in the creation of a favorable microenvironment for cancer progression and metastasis. Furthermore, the acquisition of EMT features has been associated with chemoresistance which could give rise to recurrence and metastasis after standard chemotherapeutic treatment. Thus, EMT could be closely involved in carcinogenesis, invasion, metastasis, recurrence, and chemoresistance. Research into EMT and its role in cancer pathogenesis has progressed rapidly and it is now hypothesized that novel concepts such as cancer stem cells and microRNA could be involved in EMT. However, the involvement of EMT varies greatly among cancer types, and much remains to be learned. In this review, we present recent findings regarding the involvement of EMT in cancer progression and metastasis and provide a perspective from clinical and translational viewpoints. (Cancer Sci 2010; 101: 293-299) D evelopment of distant metastases is the final stage of solid cancer progression and is responsible for the majority of cancer-related deaths.(1) Distant metastasis alone or with concurrent locoregional recurrence accounts for nearly 80% of all first relapses in women with breast cancer.(2) While clinically of great importance, the biology of metastasis remains unsolved. The process of tumor metastasis consists of multiple steps, all of which are required to achieve tumor spreading.(3,4) First, cancer cells escape from the primary tumor site. Next, cancer cells invade the tumor stroma and enter the blood circulation directly or the lymphatic system via intravasation. Most circulating cancer cells undergo apoptosis due to anoikis conditions.(5) If cancer cells survive in circulation they may reach more suitable sites by attaching to endothelial cells and extravasating from the circulation into the surrounding tissues. Finally, distal colonization requires that cancer cells invade and grow in the new environment.Recently, the concept of the epithelial-mesenchymal transition (EMT), as developed in the field of embryology, has been extended to cancer progression and metastasis.(6,7) In vitro and experimental animal model data now support the role of EMT in metastasis, concepts supported by analyses of clinical samples. Indeed, the biology of EMT has been clarified in tumor samples through use of EMT-associated markers, such as mesenchymalspecific markers (i.e. vimentin and fibronectin), (8,9) epithelial specific markers (i.e. E-cadherin and cytokeratin), (10,11) and transcription factors (i.e. SNAIL and SLUG). (12) Most recently, several intriguing studies have described the novel mechanism underlying EMT activation. In the current study, we will discuss the role of small non-coding RNA (micro-RNA) in regulating EMT-r...

Reversible acetylation at the epsilon-amino group of lysines located at the conserved domain of core histones is supposed to play an important role in the regulation of chromatin structure and its transcriptional activity. One promising strategy for analyzing the precise function of histone acetylation is to block the activities of acetylating or deacetylating enzymes by specific inhibitors. Recently, two microbial metabolites, trichostatin A and trapoxin, were found to be potent inhibitors of histone deacetylases. Trichostatin A reversibly inhibits the mammalian histone deacetylase, whereas trapoxin causes inhibition through irreversible binding to the enzyme. The histone deacetylase from a trichostatin A-resistant cell line is resistant to trichostatin A, indicating that the enzyme is the primary target. Both of the agents induce a variety of biological responses of cells such as induction of differentiation and cell cycle arrest. Trichostatin A and trapoxin are useful in analyzing the role of histone acetylation in chromatin structure and function as well as in determining the genes whose activities are regulated by histone acetylation.

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SUMMARY Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, reverse-engineering precision cancer prevention.

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Nitrite reductase (NIR) from the denitrifying bacterium Alcaligenes faecalis S-6 is a copper-containing enzyme which requires pseudoazurin, a low molecular weight protein containing a single type I copper atom, as a direct electron donor in vivo. Crystallographic analysis shows that NIR is a trimer composed of three identical subunits, each of which contains one atom of type I copper and one atom of type II copper, and that the ligands to the type I and type II copper atoms are the same as those of the Achromobacter cycloclastes NIR. An efficient NIR expression-secretion system in Escherichia coli was constructed and used for site-directed mutagenesis. An NIR mutant with a replacement of the type II copper ligand, His135, by Lys still retained a type II copper site as well as a type I copper atom, but it completely lost nitrite-reducing activity as measured with methyl viologen as an electron donor. On the other hand, another mutant with a replacement of the type I copper ligand, Met150, by Glu contained only a type II copper atom, but it still retained significant nitrite-reducing activity with methyl viologen. When pseudoazurin was used as an electron donor for the reaction, however, Met150Glu failed to catalyze the reduction of nitrite. Kinetic analysis of the electron transfer between NIR and pseudoazurin revealed that the electron-transfer rate between Met150Glu and pseudoazurin was reduced 1000-fold relative to that of wild-type NIR.(ABSTRACT TRUNCATED AT 250 WORDS)

Many studies have shown that tumor‐associated macrophages (TAMs) contribute to tumor development and poor prognosis in various cancers. In this study, we investigated the macrophage populations and phenotypes, and their correlation to angiogenesis, immunosuppression, and clinical prognosis in intrahepatic cholangiocarcinoma (ICC). CD68 (+) and CD163 (+) macrophage infiltration was analyzed in paraffin‐embedded tissue samples from 39 patients. CD163 is used as a marker of M2 macrophages. Neovascularization and infiltration of forkhead box P3 (FOXP3) (+) regulatory T cells were also evaluated. The number of CD68 (+) and CD163 (+) macrophages was positively correlated with the numbers of vessels and regulatory T cells. The number of CD163 (+) cells was more closely associated with them. Intrahepatic cholangiocarcinoma (ICC) patients with high counts of CD163 (+) macrophages showed poor disease‐free survival (P = 0.0426). The macrophage density was not correlated with overall survival. In an in vitro study using ICC cell lines (HuCCT1, RBE, and MEC) and human macrophages, tumor cell supernatant (TCS) from cell lines induced an activation of signal transducers and activators of transcription‐3 (Stat3) and macrophage polarization toward the M2 phenotype. Tumor cell supernatant (TCS) from HuCCT1 most strongly induced Stat3 activation and production of cytokines and other bioactive molecules such as interleukin (IL)‐10, vascular endothelial growth factor (VEGF)‐A, transforming growth factor (TGF)‐β, and matrix metalloproteinase (MMP)‐2. Down‐regulation of Stat3 by siRNA significantly suppressed the production of IL‐10 and VEGF‐A. These results provide suggestive evidence that TAMs contribute to cancer progression via Stat3 activation, and CD163 is useful for evaluating M2 TAMs and predicting the clinical prognosis of ICC patients. (Cancer Sci)

Background/purpose The aim of this study was to create a nomogram to predict the disease-free survival of patients with colorectal liver metastases treated with hepatic resection.Methods Perioperative factors were assessed in 727 hepatectomized patients with colorectal liver metastases between 2000 and 2004 at the 11 institutions of the ''Project Committee of the Liver'' in the Japanese Society of Hepato-Biliary-Pancreatic Surgery. A nomogram was developed as a graphical representation of a stepwise Cox proportional hazards regression model. -011-0460-z Results Perioperative mortality was 0.55%. Disease-free and overall survival rates were 31.2 and 63.8% at 3 years, 27.2 and 47.7% at 5 years, and 24.7 and 38.5% at 10 years, respectively. Six preoperative factors were selected to create the nomogram for disease-free survival: synchronous metastases, 3 points; primary lymph node positive, 3 points; number of tumors 2-4, 4 points and C5, 9 points; largest tumor diameter [5 cm, 2 points; extrahepatic metastasis at hepatectomy, 4 points, and preoperative carbohydrate antigen 19-9 level[100, 4 points. The estimated median disease-free survival time was easily calculated by the nomogram: [8.4 years for patients with 0 points, 1.9 years for 5 points, 1.0 years for 10 points, and the rates were lower than 0.6 years for patients with more than 10 points. Conclusions This nomogram can easily calculate the median and yearly disease-free survival rates from only 6 preoperative variables. This is a very useful tool to determine the likelihood of early recurrence and the necessity for perioperative chemotherapy in patients with colorectal liver metastases after hepatic resection.123 J Hepatobiliary Pancreat Sci (2012) 19:72-84 DOI 10.1007/s00534