Satoshi Furuhashi

Functional role of CD44v‐xCT system in the development of spasmolytic polypeptide‐expressing metaplasia

Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia–carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(–), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v‐xCT system in the development of spasmolytic polypeptide‐expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v+ metaplastic cells manifested upregulation of xCT expression compared with CD44v− cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT‐dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v‐xCT could thus prove effective for prevention or attenuation of the CD44v‐dependent development of preneoplastic lesions and cancer.

Is an estimation of physiologic ability and surgical stress able to predict operative morbidity after pancreaticoduodenectomy

BackgroundMortality rates after pancreaticoduodenectomy (PD) are below 4% in high volume centers, although morbidity rates still remain high. Therefore, it is important to clarify a predictor associated with operative morbidity after PD. The estimation of physiologic ability and surgical stress (E-PASS) score has been developed for comparative audit in general surgical patients.ObjectiveTo evaluate whether E-PASS scoring system could predict the occurrence of complications after PD.MethodsWe performed retrospective analysis of 69 patients (42.0% pancreatic cancer, 31.9% bile duct cancer, and others) who underwent PD using the E-PASS as a predictor of morbidity. Correlations between the incidence rates of postoperative complications and the preoperative risk score (PRS), surgical stress score (SSS) and comprehensive risk score (CRS) of the E-PASS scoring system were evaluated.ResultsOf the 69 patients 30 (43.5%) experienced a total of 54 postoperative complications. All E-PASS scores, especially PRS and CRS were significantly higher in the patients with postoperative complications than in the patients without complication. The complication rate gradually increased as the PRS, SSS and CRS score increased. Under receiver operating characteristic analysis, if a cut-off point of CRS was 0.75, sensitivity and specificity for the prediction of operative morbidity after PD was 80.0 and 79.5%, respectively. Neoadjuvant chemotherapy and intraoperative radiation therapy (IORT) did not influenced on operative morbidity after PD.ConclusionE-PASS scoring system is useful to evaluate for morbidity after PD. Neoadjuvant chemotherapy and IORT could be adapted without significant extra risk for surgical complication.

Nitric Oxide Inhibits the Proliferation and Invasion of Pancreatic Cancer Cells through Degradation of Insulin Receptor Substrate-1 Protein

Nitric oxide (NO), which plays a role in the posttranslational modification of proteins, exhibits tumoricidal activity. However, the mechanism remains largely unclear. We investigated whether the regulation of insulin receptor substrate (IRS)-1 protein expression and insulin/insulin-like growth factor (IGF) signaling by NO is involved in the proliferation and invasion of pancreatic cancer cells. NO donor inhibited insulin/IGF-I–stimulated phosphorylation of insulin receptor/IGF-I receptor, IRS-1, Akt/PKB, and glycogen synthase kinase-3β along with decreased expression of IRS-1 protein in MIAPaCa-2 cells, whereas NO donor enhanced the phosphorylation of extracellular signal-regulated kinase-1/2. In contrast, a selective inducible nitric oxide synthase inhibitor, 1400W, upregulated the expression of IRS-1 protein and the phosphorylation of IRS-1, Akt/PKB, and glycogen synthase kinase-3β, along with enhanced proliferation and invasion of Panc-1 cells expressing inducible nitric oxide synthase protein. NO donor induced IRS-1 protein reduction through increased ubiquitination and degradation. For the detection of the site responsible for NO-induced ubiquitination, IRS-1 deletion mutant genes were transfected and overexpressed in MIAPaCa-2 cells. The results indicate that the COOH terminus of the IRS-1 protein is required for NO donor–induced ubiquitination and protein degradation. Cells stably transfected with COOH-terminal deletion mutants of IRS-1 exhibited reduced IGF signaling and cell proliferation compared with vector alone–transfected cells, with no influence of NO on IGF signaling and invasion, although stable transfectants with full-length IRS-1 protein exhibited remarkable NO-induced reduction in IGF signaling, cell proliferation, and invasion. These findings indicate that NO inhibits the proliferation and invasion of pancreatic cancer cells, at least in part, through upregulation of IRS-1 protein degradation and resultant downregulation of the insulin/IGF-I-Akt pathway. Mol Cancer Res; 8(8); 1152–63. ©2010 AACR.

Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer

BackgroundLittle is known about the clinical significance of TS and DPD in pancreatic cancer. We aimed to evaluate TS and DPD expression levels in not only pancreatic cancer but also surrounding normal pancreatic tissues to assess the clinical implications of the expression of TS and DPD in this study.Patients and methodsPancreatic cancer and normal pancreatic tissues were obtained from 18 patients with pancreatic cancer who underwent pancreatic resection to measure TS and DPD activities. The TS and DPD activities were determined by enzyme-linked immunosorbent assay using non-fixed fresh-frozen specimens.ResultsPancreatic cancer tissues had significantly higher DPD and TS enzyme activities than surrounding normal tissue. Anaplastic ductal carcinoma had higher DPD and TS activities than the other histological types. Patients with high DPD in this study demonstrated poorer prognosis than those with low DPD. On the other hand, there was no statistically significant difference in survival between the high and the low TS groups.ConclusionsThe efficacy of 5-FU may be lower in pancreatic cancer tissue than in normal tissue because DPD activity is upregulated in pancreatic cancer tissue compared to normal pancreatic tissue. It is necessary to develop an effective 5-FU delivery system and/or 5-FU combined with an inhibitor for DPD that can be used when 5-FU must be administered to patients with pancreatic cancer. High DPD activity may be a prognostic factor in patients with pancreatic cancer.

Spleen and gastrosplenic ligament preserving distal pancreatectomy under a minimum incision approach assisted by laparoscopy

BACKGROUND As a modification of hand-assisted laparoscopic pancreatectomy, we devised a method of spleen and gastrosplenic ligament preserving distal pancreatectomy, in which pancreatic resection is performed under direct vision extracorporeally. METHODS The distal pancreas and spleen are pulled out of the peritoneal cavity through the minilaparotomy at the epigastrium following hand-assisted laparoscopic dissection of the distal pancreas. Spleen-preserving pancreatectomy is performed safely under direct vision. The gastrosplenic ligament is also preserved to prevent splenic volvulus after the operation. The transected main pancreatic duct is doubly ligated, and the transected pancreatic stump is sewn manually. The preserved spleen and splenic vessels are placed back in the peritoneal cavity after resection. RESULTS In the current study (n = 3), overall morbidity rate, including splenic volvulus and pancreatic fistula, was 0%. CONCLUSION Preservation of the gastrosplenic ligament and extracorporeal preparation of the transected pancreatic stump under direct vision are useful measures in spleen-preserving distal pancreatectomy under a minimum incision approach assisted by laparoscopy.

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

Nitric oxide (NO) shows tumoricidal activity. We had previously reported that NO downregulates the phosphatidylinositol-3-kinase/Akt pathway, but upregulates the MEK/ERK pathway downstream of growth factor signaling. We hypothesized that NO donor and MEK inhibitor in combination synergistically inhibit the viability of cancer cells compared to either NO donor or MEK inhibitor alone. We determined the effects of S-nitrosoglutathione (GSNO, NO-donor) and U0126 (MEK inhibitor) on insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) signaling, proliferation and invasion in cancer cell lines. GSNO inhibits phosphorylation of IGF-I receptor (IGF-IR), EGF receptor (EGFR) and Akt, but upregulates ERK1/2 phosphorylation in MIAPaCa-2 and HCT-116 cells after stimulation by IGF-I and EGF. On the other hand, U0126 inhibits phosphorylation of ERK1/2, but upregulates phosphorylation of IGF-IR and EGFR in MIAPaCa-2 and HCT-116 cells. The combination of GSNO and U0126 downregulates phosphorylation of IGF-IR, EGFR, Akt and ERK1/2 after stimulation by IGF-I and EGF. GSNO as well as U0126, inhibits the proliferation of MIAPaCa-2, HCT-116, Panc-1, MCF-7, HT-29 and AGS cells in a dose-dependent manner. GSNO and U0126 in combination synergistically inhibit proliferation and invasion of cancer cells. These results indicate that the combined treatment of NO donor and MEK inhibitor may be promising in cancer therapy.

Nitric Oxide Regulates Growth Factor Signaling in Pancreatic Cancer Cells

Growth factor signaling plays a critical role in cancer proliferation and invasion. Therefore, molecules, involved in growth factor signaling have become the targets of cancer therapy, and many drugs targeting growth factor signaling pathways have been developed. Some of these drugs have been used clinically, while many more are being tested in clinical trials. However, to date, molecule-targeted therapies for pancreatic cancer have not been developed.

Solid-pseudopapillary pancreatic tumor, mimicking submucosal tumor of the stomach: A case report

Solid-pseudopapillary tumors of the pancreas (SPTs) are comparatively rare and have low malignancy, with a predilection for young women. Diagnosis is difficult when a SPT develops in a boundary region with other organs. Here, we report a 42-year old woman with a SPT of the pancreas mimicking a submucosal tumor of the stomach on imaging. She was admitted to our hospital complaining of abdominal pain. We suspected a submucosal tumor of the stomach from the findings of endoscopy, endoscopic ultrasonography and abdominal computed tomography. However, angiography showed that some of the tumor vessels arose from the pancreas. Intraoperative findings revealed the tumor originated from the pancreas. Therefore, distal pancreatectomy was performed. The pathological diagnosis was SPT of the pancreas.

Does relative dose intensity of perioperative chemotherapeutic agents correlate survival in patients with pancreatic cancer

e14564 Background: High probability of systemic and/or local relapses occurs even after curative resection of pancreatic cancer (PC). We have introduced a novel multimodality therapy composed of pancreatic resection and intraoperative radiation therapy (IORT) combined with neoadjuvant (NAC) and postoperative adjuvant (AC) combination chemotherapy using gemcitabine (GEM) + 5-FU for patients with PC since 2001 (Ann Surg Oncol in press). The aim of this study was to assess significance of relative dose intensity (RDI) of the perioperative chemotherapeutic agents. METHODS In eligible patients with PC, 5-FU was administered at a dose of 125 mg/m2 on days 1-5 every week as a continuous pancreatic and hepatic arterial infusion, and GEM was infused intravenously at a dose of 800 mg/m2 for 30 min once weekly for 2 weeks for NAC. Pancreatic resection combined with IORT was performed after the completion of NAC. AC was performed in the same regimen as NAC. RESULTS This study enrolled 44 pts (stage Ia; 3pts, stage Ib; 1pt, stage IIa; 10pts, stage IIb; 26pts, stage III; 1pt, stage IV; 3pts). Median follow-up time for survivors was 60.5 months. Actual 1-year and 2-year survival rate was 79.5%, 68.2%, respectively. MST was 33.3 months with a 28.5% of the actuarial 5-year survival. Average RDI of total 5-FU and GEM was 54.8% and 72.0%, respectively. Average RDI of 5-FU and GEM for NAC was 93.2% and 83.0%, respectively. Average RDI of 5-FU and GEM for ACwas 43.5% and 70.5%, respectively. Based on Spearman correlation analyses, RDI of total GEM was statistically correlated with survival (p=0.0005). MST was 38.5 months in those who received >50% of the RDI of GEM, significantly longer than 8.0 months in those who received <50% of the RDI (p<0.0001). RDI of total 5-FU was not statistically correlated with survival (p=0.1364). MST was 38.5 months in those who received >50% of the RDI of 5-FU, not significantly longer than 24.0 months in those who received <50% of the RDI (p=0.0717). CONCLUSIONS RDI of GEM was statistically correlated with survival. It indicated that dose intensity of perioperative GEM injection was an important prognostic factor in patients with PC.