[in Japanese]

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Epithelial to mesenchymal transition (EMT) is characterized by the disassembly of cell-cell contacts, reorganization of the actin cytoskleleton, and cell-cell separation. This transition is considered to be an important event during malignant tumor progression and metastasis. Since transforming growth factor (TGF) β has been shown to induce EMT in pancreatic carcinoma cells, we examined whether bone morphogenetic protein (BMP) , which is a member of the TGF family, could induce EMT in pancreatic carcinoma cells. We revealed that BMP4 induces EMT in pancreatic carcinoma cells and that its target gene MSX2 is indispensable to this process. In addition, we demonstrated that evaluation of the MSX2 mRNA level in ERCP brushing samples would be useful to distinguish pancreatic cancer from chronic pancreatitis. These findings suggest that EMT plays a pivotal role in pancreatic carcinoma development and that validation of EMT-related gene expression would be a useful clinical application for the diagnosis of pancreatic cancer.

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To improve the prognosis of patients with pancreatic cancer, it is necessary to establish diagnostic methods for the detection of early pancreatic cancer. Also, it is often difficult to distinguish pancreatic cancer from mass-forming pancreatitis or other pancreatic diseases. We have been investigating the changes in mRNA expression of pancreatic cancer-related molecules during pancreatic carcinogenesis to improve the diagnostic ability for pancreatic cancer. First, we performed laser-microdissection to isolate the PanIN and IPMN cells as well as the invasive ductal carcinoma cells and normal ductal cells and measured the expression of S100 and MUC family genes using quantitative real-time RT-PCR. Furthermore, we analyzed the expression of these genes in pancreatic juice and examined its clinical implication. Here, we summarize our results and discuss about the future of pancreatic cancer diagnosis.

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Recently, by using pancreas-specific conditional activation or knockout of clinically relevant pancreatic cancer-related genes and signaling pathways, genetically engineered murine models(GEMs) of pancreatic ductal adenocarcinoma have been developed. Pancreas-specific Kras activation results in mouse PanIN(pancreatic intraepithelial neoplasia) lesions. Further, simultaneous inactivation of either tumor suppressor pathway (p16, p53, or TGF-β signal) dramatically accelerates the tumor progression into invasive cancer. The tumor demonstrates ductal adenocarcinoma with abundant stromal expansion including marked fibrosis, desmoplasia, which recapitulates the human disease very well.
These genetically-engineered models have an advantage over xenograft models in that they recapitulate multi-step carcinogenesis and the tumor microenvironment of human disease.
Detailed analysis of current and future GEMs will provide better understanding of pancreatic carcinogenesis and progression as well as of the origin of pancreatic cancer, leading to refined methods for its diagnosis, therapy and prevention.

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The ineffectiveness of curative resection and conventional chemotherapy and radiation therapy in most pancreatic cancer patients indicates how challenging the development of novel therapeutics for pancreatic cancer is. In this respect, molecular target-directed therapy holds great promise. Here we review the molecular pathways deregulated in pancreatic cancer cells and a number of phase III clinical trials of molecular targeting therapies in combination with gemcitabine for pancreatic cancer patients. Unlike non-small cell lung and colorectal cancers, the effects of these therapies on pancreatic cancer patients are far from our expectation, and there is a need for more promising therapeutic targets. To address this point, we outline the molecular basis of our proposal that glycogen synthase kinase (GSK) 3β is an emerging therapeutic target for gastrointestinal cancers including pancreatic cancer.

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Despite advances in surgical procedures and the development of new therapeutics, pancreatic cancer remains one of the most difficult diseases to cure. There are very few effective chemotherapy drugs without adverse effects. Therefore, many patients and clinicians want new effective anti-cancer drugs that have no adverse effects. Oncolytic viruses can replicate inside tumors and produce viral proteins within and on the surface of tumor cells. Viral infection stimulates the host immune response, including anti-cancer immunity, which can inhibit local tumor growth and suppress metastatic tumors. Clinical trials have examined the efficacy and safety of oncolytic viruses in over 1,000 cases worldwide. We here review the feasibility of oncolytic virus therapy, including basic research and clinical trials, employed in our facility for pancreatic cancer.

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Vascular endothelial growth factor receptor 2 (VEGFR2) is an essential factor in the tumor angiogenesis and growth of pancreatic cancer. Immunotherapy using epitope peptide for VEGFR2 (VEGFR2-169) that successfully induced specific cytotoxic T lymphocytes (CTLs) to the peptides in cancer patients is expected to improve the clinical outcome. Therefore, a phase I clinical trial using a combination of VEGFR2-169 with gemcitabine was conducted for patients with advanced pancreatic cancer. VEGFR2-169 peptide was subcutaneously injected weekly in a dose-escalation manner (doses of 0.5, 1.0, 2.0mg/body, 6 patients/1 cohort) . No dose limiting toxicity was observed. Specific CTLs reacting to VEGFR2-169 peptide were induced in 11 (61%) of the 18 patients. From an immunological point of view, the optimal dose might be 2.0mg/body. A randomized Phase II/III clinical trial started in January 2009 to demonstrate the clinical benefits of VEGFR2-169 for advanced pancreatic cancer patients treated with gemcitabine.

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The concept of autoimmune pancreatitis (AIP) has recently been proposed to denote chronic pancreatitis caused by an autoimmune abnormality. AIP sometimes shows extra-pancreatic lesions that are recognized as one manifestation of IgG4-related systemic diseases. We present three patients with extra-pancreatic lesions associated with AIP. All cases were middle-aged to elderly men with high serum IgG4 concentrations. Two cases had both cholangitis and nephritis, and one case had retroperitoneal fibrosis with AIP. All cases were consistent with the AIP diagnostic criteria of 2006 and were treated with steroid therapy. One patient was found to have lung cancer during follow-up.

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A 58 year-old man with right renal cell carcinoma (RCC) and a tumor in the pancreas head underwent right nephrectomy and pylorus preserving pancreaticoduodenectomy simultaneously. The tumor in the pancreas head showed marked enhancement in dynamic CT and dynamic MRI studies. The tumor did not show FDG accumulation on PET at all, whereas a slight accumulation of FDG was observed on RCC. Therefore, the tumor in the pancreas head was diagnosed as a non-functional endocrine tumor. Pathohistological findings revealed that the tumor was a solitary metastasis from RCC. It has been difficult to distinguish a hypervascular tumor in the pancreas from a metastatic tumor from RCC. Since even FDG-PET, an extremely useful imaging modality for metastasis examinations, could not identify as metastasis from RCC, we should be careful about the differential diagnosis in cases with advanced RCC.

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A 49-year-old woman was admitted to our hospital with a cystic mass of 17mm in diameter at the head of the pancreas that had been noted on abdominal ultrasonography in her regular medical check-up. Contrast-enhanced computed tomography showed a low density mass with blood supply in the peripheral wall, and magnetic resonance imaging revealed that the mass was clearly cystic. Endoscopic retrograde cholangio-pancreatography showed no communication between the cystic mass and pancreatic ducts. After obtaining informed consent, a pylorus-preserving pancreaticoduodenectomy was performed. The resected specimen showed a cystic tumor with bloody content smaller than 2.0cm with a thick fibrous capsule. The histological diagnosis was a non-functioning well-differentiated endocrine tumor (benign behaviour) . Although pancreatic cystic mass smaller than 2.0cm in diameter is often taken a wait-and-see approach closely without treatment, the treatment strategy has to be decided in a cautious manner because it might be potentially-malignant as our case.

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We herein report a case of traumatic pancreas injury (type IIIb) treated by middle pancreatectomy. A 27-year-old woman was admitted to our hospital due to abdominal pain after blunt trauma on her epigastrium. Abdominal CT scan showed hematoma and main pancreatic duct disruption at the pancreas body. Emergency operation was performed 12 hours after the abdominal trauma. Intraoperative findings revealed a hematoma in the mesocolon and lesser omentum, and the pancreatic parenchyma and the main pancreatic duct were disrupted. Middle pancreatectomy was employed and the proximal stump of the main pancreatic duct was ligated and the pancreatic parenchyma was closed. The distal side of the pancreas was anastomosed to the stomach. After surgery, both endocrine and exocrine pancreatic functions were well preserved.

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