Gadoxetic acid-enhanced MR imaging is the most useful imaging technique for evaluating small HCC, including early HCC.

Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-β-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-β-induced EMT, and found that TGF-β induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-β-mediated upregulation of δEF1 family proteins, δEF1 and SIP1. δEF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both δEF1 and SIP1, but not either alone, abolished the TGF-β-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of δEF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-β-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, δEF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-β-induced EMT and the progression of breast cancers.

It has been reported that an increased population of regulatory T cells (Tregs) is one of the reasons for impaired anti-tumor immunity. Recently, Foxp3 has been reported as a reliable marker of Tregs. The authors investigated the frequency of Foxp3 1 Tregs within CD4 1 cells in TILs, regional lymph nodes and PBLs of gastric cancer patients (n 5 45). Furthermore, to elucidate the mechanisms behind Treg accumulation within tumors, they evaluated the relationship between CCL17 or CCL22 expression and the frequency of Foxp3 1 Tregs in gastric cancer. CD4 1 CD25 1 Foxp3 1 Tregs as a percentage of CD4 1 cells were counted by flow cytometry and evaluated by immunohistochemistry. Moreover, an in vitro migration assay using Tregs derived from gastric cancers was performed in the presence of CCL17 or CCL22. As a result, the frequency of Foxp3 1 Tregs in TILs was significantly higher than that in normal gastric mucosa (12.4% 6 7.5% vs. 4.1% 6 5.3%, p < 0.01). Importantly, the increase in Tregs in TILs occurred to the same extent in early and advanced disease. Furthermore, the frequency of CCL17 1 or CCL22 1 cells among CD14 1 cells within tumors was significantly higher than that of normal gastric mucosa, and there was a significant correlation between the frequency of CCL17 1 or CCL22 1 cells and Foxp3 1 Tregs in TILs. In addition, the in vitro migration assay indicated that Tregs were significantly induced to migrate by CCL17 or CCL22. In conclusion, CCL17 and CCL22 within the tumor are related to the increased population of Foxp3 1 Tregs, with such an observation occurring in early gastric cancer. ' 2008 Wiley-Liss, Inc.Key words: CCL17; CCL22; Foxp3; regulatory T cells; gastric cancer It has been reported that regulatory T cells (T regs) play important roles in immunological self-tolerance, 1-4 and are functionally immune-suppressive subsets of T cells. T regs are identified as a small population of CD4 1 cells that constitutively express CD25 (IL-2 receptor a chain) on their surface, and several other markers, including CD45RO, glucocorticoid-induced tumor-necrosis factor receptor-related protein (GITR), or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), are also known to be expressed on T regs. [3][4][5] Recently, it has been reported that Foxp3, forkhead/ winged helix transcription factor, is the most reliable marker of T regs 6,7 ; therefore, it is possible to define T regs more strictly as CD4 1 CD25 1 Foxp3 1 cells.In mice, it is known that auto-immune diseases such as ulcerative colitis or Crohn's disease occur due to the depletion of T regs. 6,8 Also in humans, immune dysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is an auto-immune disease developed from a deficiency of T regs. [8][9][10][11] These observations indicate that T regs play important roles in immunological homeostasis. Although the mechanisms of suppression by T regs are still unclear, it has been reported that T regs can inhibit the function of effector T cells directly by cell to cell contact or indirectly via the se...

Carcinomas of the biliary tract have a poor prognosis. It is important to understand the molecular genetic characteristics of these tumours in order to employ newer effective treatments and to improve patient prognosis. There is increasing evidence that overexpression of tyrosine kinase growth factor receptors such as ErbB-2, epidermal growth factor receptor (EGFR), and Met may play important roles in the development of biliary tract carcinomas. The aim of this study was to assess the potential for novel chemotherapies targeting these receptors. Overexpression of the tyrosine kinase receptor proteins was examined by immunohistochemistry in 221 biliary tract carcinomas, of which 28 were from the intrahepatic bile duct, 78 from the extrahepatic bile duct, 89 from the gall bladder, and 26 from the ampulla of Vater. Positively stained tumours were further examined for gene amplification by fluorescence in situ hybridization. Overexpression of ErbB-2 was found in 15.7%, 11.5%, and 5.1% of carcinomas of the gall bladder, ampulla of Vater, and extrahepatic bile duct, respectively, and gene amplification was present in 79% of these. Overexpression of EGFR was found in 8.1% of tumours with no predominant location and was also associated with gene amplification with high frequency (77%). Met overexpression, most frequent in intrahepatic bile duct carcinomas (21.4%), was not associated with gene amplification. It is proposed that the new adjuvant chemotherapies could be directed to carcinomas of the biliary tract in which ErbB-2 and EGFR are overexpressed.

These results strongly suggest that tumor-related factors induce and expand CD4(+)CD25high T regs.