Pancreatic cancer (PaCa) tends to be resistant to chemotherapy and is associated with a very poor prognosis. It has been previously reported by the authors that integrin-linked kinase (ILK) is a prognostic factor in PaCa. ILK expression was examined in a newly established gemcitabine (Gem)-resistant (Gem-R) PaCa cell line and it was demonstrated that ILK expression was upregulated compared with that in Gem-sensitive (Gem-S) cells. In the present study, the effects of increased ILK expression in Gem-R PaCa cells were evaluated and it was examined whether compound 22 (Cpd22), an ILK inhibitor, exerted antitumor effects not only in Gem-S cells but also in Gem-R cells. Reverse transcription-quantitative polymerase chain reaction and western blotting revealed that ILK expression was higher in Gem-R PaCa cells than in Gem-S PaCa cells. Cpd22 inhibited the growth of PaCa cells in a concentration-dependent manner. Cpd22 also inhibited the growth of Gem-R PaCa cells. The invasive and angiogenic potential of Gem-R PaCa cells was enhanced compared with that in Gem-S cells; however, ILK small interfering RNA and Cpd22 treatment suppressed this enhancement of invasive potential compared with that in Gem-S cells. The addition of Cpd22 to Gem also improved the sensitivity of Gem-R cell lines to Gem. Furthermore, enhanced Akt signaling was associated with increased malignancy in Gem-R cell lines. In conclusion, ILK was upregulated with resistance and may be involved in tumor angiogenesis, invasive potential, and chemotherapy resistance, which were all suppressed by Cpd22 treatment. Thus, Cpd22 may be a novel therapeutic agent for the treatment of PaCa.

Girdin, an actin-binding protein, is reportedly involved in the invasion and angiogenesis of various cancers. It has been suggested that the flavonoid Scutellarin (SCU) inhibits Girdin signaling. In the present study, the function and therapeutic applications of Girdin in pancreatic cancer (PaCa) were investigated. Immunohistochemical staining of Girdin in resected PaCa specimens from the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science showed that high Girdin expression was associated with poor overall survival and relapse-free survival, as well as with T factor, indicating invasion into the surrounding tissues. On the other hand, Girdin was highly expressed in almost all PaCa cell lines, and the migration ability of Girdin-knockdown cell lines was decreased even under epidermal growth factor (EGF) stimulation. In addition, SCU suppressed PaCa cell migration by inhibiting the phosphorylation of Girdin. The expression and production of vascular endothelial growth factor A (VEGF-A) was significantly decreased in Girdin-knockdown cell lines. Furthermore, in Matrigel tube formation assays performed using culture supernatant, the lumen-forming ability of vascular endothelial cells was also decreased in Girdin-knockdown cell lines. However, SCU treatment did not significantly alter the expression or production of VEGF-A. These results suggested that Girdin is involved in EGF signaling-mediated migration of PaCa cells, that SCU inhibits PaCa invasion by suppressing Girdin activity, and that Girdin is also involved in angiogenesis via an activation pathway different from the action site of SCU. Girdin may be a prognostic biomarker, and the development of a novel molecular-targeted drugs for Girdin may improve the prognosis of PaCa in the future.

BackgroundNeuroendocrine tumors of the minor papilla are very rare, and only 20 cases have been reported in the literature. Neuroendocrine carcinoma of the minor papilla with pancreas divisum has not been reported; thus, this report describes the first case. Neuroendocrine tumors of the minor papilla have been reported in association with pancreas divisum in about 50% of cases reported in the literature. We herein present our case of neuroendocrine carcinoma of the minor papilla with pancreas divisum in a 75-year-old male with a systematic literature review of the previous 20 reports of neuroendocrine tumors of the minor papilla.Case presentationA 75-year-old man was referred to our hospital for evaluation of dilation of the main pancreatic duct noted on abdominal ultrasonography. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed a dilated dorsal pancreatic duct, which was not connected to the ventral pancreatic duct; however, it opened to the minor papilla, indicating pancreas divisum. The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater. A contrast-enhanced computed tomography scan showed a 12-mm hypervascular mass near the ampulla of Vater. Endoscopic ultrasonography showed a defined hypoechoic mass in the minor papilla with no invasion. The biopsies performed at the previous hospital found adenocarcinoma. The patient underwent a subtotal stomach-preserving pancreaticoduodenectomy. The pathological diagnosis was neuroendocrine carcinoma. At the 15-year follow-up visit, the patient was doing well with no evidence of tumor recurrence.ConclusionIn our case, because the tumor was discovered during a medical check-up relatively early in the course of disease, the patient was doing well at the 15-year follow-up visit with no evidence of tumor recurrence. Diagnosing a tumor of the minor papilla is very difficult because of the relatively small size and submucosal location. Carcinoids and endocrine cell micronests in the minor papilla occur more frequently than generally thought. It is very important to include neuroendocrine tumors of the minor papilla in the differential diagnosis of patients with recurrent pancreatitis or pancreatitis of unknown cause, especially for patients with pancreas divisum.