Radiotherapy represents a major treatment option for patients with pancreatic cancer, but recent evidence suggests that radiation can promote invasion and metastasis of cancer cells. Interactions between cancer cells and surrounding stromal cells may play an important role in aggressive tumor progression. In the present study, we investigated the invasive phenotype of pancreatic cancer cells in response to coculture with irradiated fibroblasts. Using in vitro invasion assay, we demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of pancreatic cancer cells and, surprisingly, the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. The hepatocyte growth factor (HGF) secretion from fibroblasts remained unchanged after irradiation, whereas exposure of pancreatic cancer cells to supernatant from irradiated fibroblasts resulted in increased phosphorylation of c-Met (HGF receptor) and mitogen-activated protein kinase activity, possibly or partially via increased expression of c-Met. We also demonstrated that scattering of pancreatic cancer cells was accelerated by the supernatant from irradiated fibroblasts. The enhanced invasiveness of pancreatic cancer cells induced by coculture with irradiated fibroblasts was completely blocked by NK4, a specific antagonist of HGF. These data suggest that invasive potential of certain pancreatic cancer cells is enhanced by soluble mediator(s) released from irradiated fibroblasts possibly through up-regulation of c-Met expression/phosphorylation and mitogen-activated protein kinase activity in pancreatic cancer cells. Our present findings further support the potential use of NK4 during radiotherapy for patients with pancreatic cancer.

Due to the poor prognosis of pancreatic cancer, novel diagnostic modalities for early diagnosis and new therapeutic strategy are urgently needed. Recently, microRNA-21 (miR-21) was reported to be strongly overexpressed in pancreatic cancer as well as in other solid cancers. We investigated the functional roles of miR-21, which have not been fully elucidated in pancreatic cancer. miR-21 expression was assessed in pancreatic cancer cell lines (14 cancer cell lines, primary cultures of normal pancreatic epithelial cells and fibroblasts, and a human normal pancreatic ductal epithelial cell line) and pancreatic tissue samples (25 cancer tissues and 25 normal tissues) by quantitative real-time reverse transcription-PCR amplification. Moreover, we investigated the proliferation, invasion, and chemoresistance of pancreatic cancer cells transfected with miR-21 precursor or inhibitor. miR-21 was markedly overexpressed in pancreatic cancer cells compared with nonmalignant cells, and miR-21 in cancer tissues was much higher than in nonmalignant tissues. The cancer cells transfected with the miR-21 precursor showed significantly increased proliferation, Matrigel invasion, and chemoresistance for gemcitabine compared with the control cells. In contrast, inhibition of miR-21 decreased proliferation, Matrigel invasion, and chemoresistance for gemcitabine. Moreover, miR-21 positively correlated with the mRNA expression of invasion-related genes, matrix metalloproteinase-2 and -9, and vascular endothelial growth factor. These data suggest that miR-21 expression is increased in pancreatic cancer cells and that miR-21 contributes to the cell proliferation, invasion, and chemoresistance of pancreatic cancer.

Background. The clinicopathologic and immunohistochemical features of the primary gastric hepatoid adenocarcinomas still remain unclear. Methods. The authors evaluated 28 hepatoid adenocarcinomas (HC) of the stomach on the basis of characteristic histologic features resembling hepatocellular carcinoma, which were selected from the 7200 cases of primary gastric carcinoma in their files. Additionally, 22 alpha‐fetoprotein (AFP)‐positive adenocarcinomas without hepatoid features (APC) were also selected. Results. The HC cases fell into the following two groups: HC with AFP‐positive tumor cells (Group 1; 15 cases) and HC without AFP‐positive cells (Group 2; 13 cases). Histologically, the glycogen granules and hyaline globules were common features in HC. The incidence of a venous invasion of HC (Groups 1 and 2) was higher than that of APC (Group 3). There were no significant differences among the three groups regarding clinical features, macroscopic features, and the incidence of lymphatic permeation. An immunohistochemical study showed that HC had differentiation into various directions. As for the advanced carcinomas, the 5‐year survival rates of patients with HC (Groups 1 and 2) and those with APC (Group 3) were 11.9% (21.4%, 8.3%) and 38.2%, respectively. The prognosis of Group 1 was similar to that of Group 2, but was poorer than that of Group 3. Conclusions. The findings suggested that HC, as shown by its characteristic histologic features, had a poor prognosis whether producing AFP or not, and that HC should therefore be distinguished from AFP‐positive carcinoma without hepatoid features.

Recent microarray analyses showed that the S100 family contains members that are candidate diagnostic markers or therapeutic targets. In the present study, to evaluate the involvement of S100A6 in pancreatic cancer and its clinical usefulness for diagnosis, we examined S100A6 mRNA expression in pancreatic tissues and pancreatic juice from patients with different pancreatic diseases. To investigate the role of S100A6 in carcinogenesis of pancreatic cancer and the potential of S100A6 as a diagnostic marker for early detection of pancreatic cancer, we did immunohistochemistry and microdissection-based mRNA analysis of pancreatic normal ducts, pancreatic intraepithelial neoplasias, and invasive ductal carcinomas. We also used in vitro experiments and microarray analysis with RNA interference to evaluate the functional role of S100A6 and its potential as a therapeutic target for pancreatic cancer. S100A6 mRNA levels were significantly higher in carcinoma specimens than in nonneoplastic tissues. In pancreatic juice, there was a significant difference in S100A6 expression between patients with carcinoma and those with nonneoplastic disease. Receiver operating characteristic curves revealed that S100A6 might be a useful marker for diagnosis of pancreatic cancer. Immunohistochemistry and microdissection-based analysis showed differential expression of S100A6 among normal ducts, pancreatic intraepithelial neoplasias, andinvasive ductal carcinomas. In vitro data showed that inhibition of S100A6 decreased proliferation and invasiveness of cancer cells, and these findings were supported by microarray data. Our present results suggest that quantitation of S100A6 mRNA is a promising tool for diagnosis of pancreatic cancer, and that S100A6 may be a promising therapeutic target for pancreatic cancer.Pancreatic cancer is the fifth most common cause of tumor-related deaths in the industrialized world (1, 2). Fewer than 10% to 20% of patients are candidates for surgery at the time of presentation, and <20% of patients who undergo curative resection are alive after 5 years (3, 4). Despite recent progress, there is no modality for early detection of pancreatic cancer. With the exception of a recent report describing successful use of adjuvant chemotherapy in the ESPAC-1 trial (5), there has been no report of effective treatment of advanced pancreatic cancer, including local and metastatic disease. To improve the prognosis of patients with pancreatic cancer, we need effective screening strategies and effective treatments for the disease once it has been detected.Microarray analysis allows simultaneous monitoring of the expression of thousands of genes and is a powerful tool for identifying genes associated with pancreatic carcinoma. Microarray analyses recently showed expression of S100A2 and S100A6 to be up-regulated in pancreatic cancer (6 -8). S100 family proteins are small Ca 2+ , Zn 2+ , and Cu 2+ binding proteins of the EF-hand type and have been implicated in regulation of a variety of intracellular and extracellular p...

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