Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer.

Japanese mortality due to colorectal cancer is on the rise, surpassing 49,000 in 2015. Many new treatment methods have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2016 for the treatment of colorectal cancer (JSCCR Guidelines 2016) were prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines were prepared by consensus reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches, and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2016.

Preplanned safety analysis of the JFMC37-0801 trial: a randomized phase III study of six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. METHODS: Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1-14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. RESULTS: A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. CONCLUSIONS: Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. TRIAL REGISTRATION: UMIN-CTR, UMIN000001367.

Validation and Modification of the Japanese Classification System for Liver Metastases from Colorectal Cancer: A Multi-institutional Study.

BACKGROUND: A Japanese multicenter study disclosed four prognostic indicators of colorectal cancer liver metastases: ≥5 hepatic tumors (HT), HT size > 5 cm, nodal status (N2) of primary cancer, and the presence of extrahepatic metastases (EM). The Japanese classification was then defined as Stage A, HT1 (≤4 lesions and ≤5 cm) and N0/1; Stage B, HT2 (≥5 lesions or >5 cm) and N0/1, or HT1 and N2; and Stage C, HT2 and N2, HT3 (≥5 lesions and >5 cm) with any N, or EM1 (presence of EM) with any HT/N. This study aimed to validate the prognostic reliability in a recent population and to develop a modified staging system that divided Stage C patients. METHODS: A total of 1185 patients diagnosed with liver metastases between 2007 and 2008 were enrolled in the study. According to the classification, 358, 257, and 570 patients were categorized as Stages A, B, and C, respectively. Stage C was further divided into two groups: Stage C-I, HT3 and N0/1, HT2 and N2, or HT1 and EM1; and Stage C-II, HT3 and N2, or HT2/3 and EM1. RESULTS: Cumulative overall survival curves for Stages A, B, and C were significantly different between each two stages (p < 0.0001, p < 0.0001). The modified system discriminated patients with a relatively better outcome (Stage C-I) from desperate patients (Stage C-II) (p < 0.0001). CONCLUSIONS: The Japanese classification system was adequately validated in a recent population, and the modified system is useful in risk stratification of Stage C cases.

Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms among women and the third largest number among men. Many new methods of treatment have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2014 for treatment of colorectal cancer (JSCCR Guidelines 2014) have been prepared as standard treatment strategies for colorectal cancer, to eliminate treatment disparities among institutions, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding among health-care professionals and patients by making these guidelines available to the general public. These guidelines have been prepared as a result of consensuses reached by the JSCCR Guideline Committee on the basis of careful review of evidence retrieved by literature searches and taking into consideration the medical health insurance system and actual clinical practice in Japan. They can, therefore, be used as a guide for treating colorectal cancer in clinical practice. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions of the Guideline Committee, controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories, on the basis of consensus reached by Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2014.

[Kampo Medicine in Perioperative Care for Cancer Patients].

Operative stress causes various changes in the body, and immunological hypofunction and malnutrition increase complications and adversely affect long-term prognosis. Therefore, reducing operative stress as much as possible, minimizing complications after surgery, and aiming for a satisfactory postoperative course are important. However, difficult and unresolvable situations often arise when only the conventional Western medicine approach is used because the situation and condition varies for each patient. We believe that Kampo medicine is very useful in diverse situations. Particularly, Kampo medicine has been used more frequently in recent years, with the expectation of numerous effects, because the effectiveness of Kampo medicine on various disease states has been proven and the pharmacological ingredients and the mechanisms by which Kampo medicine exerts its effects have been better clarified scientifically. Kampo medicine will have an effect in various situations, and we think that Kampo medicine occupies an important position in team-based medical care with multiple specialists. Kampo medicine compounds have been reported to be useful for the following conditions: Hochuekkito and Juzentaihoto for improving immunocompetence after operative stress, Daikenchuto and Rikkunshito for improving postoperative gastrointestinal motility, Shakuyakukanzoto for postoperative wound pain control, Yokukansan for postoperative delirium, and Inchinkoto for postoperative liver dysfunction. The availability of numerous treatment choices that work well in specific situations would be useful for cancer patients during the perioperative period.

Medication-related factors affecting discharge to home.

To assess the reasons for barriers to home discharge by determining whether they were predicted by medication, clinical variables, and patient characteristics, the retrospective cohort study of 282 patients discharged from Kanazawa Red Cross Hospital in Kanazawa, Japan from January 2011 to December 2012 was performed. The percentage of patients discharged was 67.4%. By multivariate logistic analysis, significant differences in home discharge destination were determined by six factors: the duration of hospitalization before discharge (odds ratio (OR) 0.993; 95% 95% confidence interval (CI) 0.988-0.999), the presence of excretion assistance (OR 0.115; 95% CI 0.043-0.308), individual payment of medical expense (OR 0.344; 95% CI 0.146-0.811), the degree of independent living for the demented elderly (OR4.570; 95% CI 1.969-10.604), presence of the primary caregiver (OR 8.638; 95% CI 3.121-23.906), and admission to a hospital from home (OR 5.483; 95% CI 2.589-11.613). This study suggests that necessity of excretion assistance, long duration of hospitalization, and high individual payment of medical expense were barriers to home discharge. In contrast, three factors i.e., admission to a hospital form home, low degree of independent living for the demented elderly, and presence of the primary caregiver, favored home discharge. The relation between a patient's status (cognitive status and incontinence) and a caregiver has an important effect on the home discharge. However, medication characteristics appeared to have little effect on recuperation destination.

Study protocol of the B-CAST study: a multicenter, prospective cohort study investigating the tumor biomarkers in adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy. Several oral fluorouracil (5-FU) derivatives with different properties are available in Japan, but which drug is the most appropriate for each patient has not been established. Although efficacy prediction of 5-FU derivatives using expression of 5-FU activation/metabolism enzymes in tumors has been studied, it has not been clinically applied. METHODS/DESIGN: The B-CAST study is a multicenter, prospective cohort study aimed to identify the patients who benefit from adjuvant chemotherapy with each 5-FU regimen, through evaluating the relationship between tumor biomarker expression and treatment outcome. The frozen tumor specimens of patients with stage III colon cancer who receives postoperative adjuvant chemotherapy are examined. Protein expression of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) are evaluated using enzyme-linked immunosorbent assay (ELISA). mRNA expression of TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyl transferase (OPRT) are evaluated using reverse transcription polymerase chain reaction (RT-PCR). The patients' clinical data reviewed are as follow: demographic and pathological characteristics, regimen, drug doses and treatment duration of adjuvant therapy, types and severity of adverse events, disease free survival, relapse free survival and overall survival. Then, relationships among the protein/mRNA expression, clinicopathological characteristics and the treatment outcomes are analyzed for each 5-FU derivative. DISCUSSION: A total of 2,128 patients from the 217 institutions were enrolled between April 2009 and March 2012. The B-CAST study demonstrated that large-scale, multicenter translational research using frozen samples was feasible when the sample shipment and Web-based data collection were well organized. The results of the study will identify the predictors of benefit from each 5-FU derivative, and will contribute to establish the "personalized therapy" in adjuvant chemotherapy for colon cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00918827, UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002013.

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

[A case of unresectable HER2-positive advanced gastric cancer successfully treated by combination therapy with trastuzumab and paclitaxel].

A 54-year-old man was referred to our hospital for close examination and treatment of an advanced gastric cancer. Gastrointestinal endoscopic examination showed a type 3 tumor, which was diagnosed as well-differentiated adenocarcinoma, and computed tomography showed multiple enlarged liver metastases in both the lobes. He underwent gastrojejunostomy and was treated with S-1 and cisplatin combination chemotherapy. However, after 4 courses of chemotherapy, progression of disease occurred. Because the human epidermal growth factor receptor type 2(HER2) test was positive, we started trastuzumab and paclitaxel combination chemotherapy as a second-line treatment. After administration of 7 courses of trastuzumab and 5 courses of paclitaxel, the primary lesion and multiple liver metastases were greatly reduced. Trastuzumab and paclitaxel combination chemotherapy appears to be an effective treatment for HER2-positive advanced gastric cancer.

Selective lymphadenectomy of para-aortic lymph nodes for advanced gastric cancer.

The Japanese randomized trial comparing standard D2 with D2 plus additional para-aortic lymph node (PAN) dissection for advanced gastric cancer (JCOG study 9501) did not demonstrate any difference in survival between the two groups. It is unknown whether there is any prognostic benefit in dissection for subgroups of PAN. Non-inferiority in survival of the patients with PAN metastasis to the patients having n2 metastasis was examined according to the subgroup of PANs and the tumor location. The survival curve of n2 patients (n=131) were retrospectively compared with that of patients with PAN metastasis (n=55) and also compared with that of patients with metastasis to subgroup of PANs by the location of primary tumor (regions U, M and L). Expectedly, the prognosis of the n2 patients is significantly better than that of the patients with PAN metastasis, but there was no difference in the survival times between the n2 (+) group and the a2-lat (+) or the b1-int (+) group, suggesting that the a2-lat or the b1-int dissection matched the D2 dissection. Furthermore, the importance in dissection of the a2-lat and the b1-int was investigated according to the primary tumor location. The patients with metastasis to a2-lat in the region U, a2-lat and b1-int in the region M and b1-int in the region L demonstrated prognostic non-inferiority to the patients having n2 metastasis. Selective lymphadenectomy of subgroups of PANs in which metastases are highly suspected according to the tumor location is one of treatment strategies to advanced gastric cancer.

Dual anti-cancer effects of weekly intraperitoneal docetaxel in treatment of advanced gastric cancer patients with peritoneal carcinomatosis: a feasibility and pharmacokinetic study.

This study evaluated the feasibility and pharmacology of intraperitoneal docetaxel (IP docetaxel) when administered weekly for 3 consecutive weeks, followed by 1 week without treatment. A total of 24 patients with peritoneal carcinomatosis of gastric cancer (10 preoperative, 7 postoperative and 7 recurrent) were enrolled in this study. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and was administered in a 1 h dosage of 25, 35, 45 and 60 mg/m(2) to determine the maximum tolerated dose (MTD). To measure the docetaxel concentration, blood and peritoneal fluid samples were collected 0.5, 1, 2, 3, 6 and 24 h after administering the drug to 15 patients. A total of 109 chemotherapy cycles were administered, with a median of four cycles per patient (range 2-9). The MTD of the weekly IP docetaxel was defined at 60 mg/m(2). At a docetaxel dosage of 60 mg/m(2) per week, the dose-limiting events of grade 3 abdominal pain and grade 3 diarrhea, which may be associated with local toxicity, occurred. Peak concentrations of peritoneal fluid ranged from 24.5 to 68.7 microg/ml. The mean ratio of the area under concentration (AUC) in the peritoneal fluid to the plasma concentration was 515. Furthermore, the mean of plasma AUC by IP docetaxel was 5.63 microg h/ml versus that of IV docetaxel at a dose of 60 mg/m(2). The response rate of the preoperative IP docetaxel was 80% (4 CR, 4 PR, 1 NC and 1 PD), which was judged with laparoscopy and peritoneal lavage cytology. Gastrectomy, with D2 lymph node dissection, was performed on all of the patients evaluated as CR. The weekly IP docetaxel demonstrated a low toxicity and high efficacy for peritoneal carcinomatosis with dual anti-cancer effects via the peritoneal surface and capillary blood supply due to its unique pharmacokinetic property.

Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (Translated Version).

Hereditary colorectal cancer accounts for less than 5% of all colorectal cancer cases. Some of the unique characteristics that are commonly encountered in cases of hereditary colorectal cancer include early age at onset, synchronous/metachronous occurrence of the cancer, and association with multiple cancers in other organs, necessitating different management from sporadic colorectal cancer. While the diagnosis of familial adenomatous polyposis might be easy because usually 100 or more adenomas that develop in the colonic mucosa are in this condition, Lynch syndrome, which is the most commonly associated disease with hereditary colorectal cancer, is often missed in daily medical practice because of its relatively poorly defined clinical characteristics. In addition, the disease concept and diagnostic criteria for Lynch syndrome, which was once called hereditary non-polyposis colorectal cancer, have changed over time with continual research, thereby possibly creating confusion in clinical practice. Under these circumstances, the JSCCR Guideline Committee has developed the "JSCCR Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (HCRC)," to allow delivery of appropriate medical care in daily practice to patients with familial adenomatous polyposis, Lynch syndrome, or other related diseases. The JSCCR Guidelines 2016 for HCRC were prepared by consensus reached among members of the JSCCR Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR Guidelines 2016 for HCRC.

[Consideration of preventive free-flowing IV infusion method for vinorelbine].

Vinorelbine is administered to treat solid tumors such as non-small cell lung cancer and breast cancer, and good treatment results have been reported. Although this agent is known to cause phlebitis, some studies indicated that its administration over 5 minutes or less decreased the incidence of this adverse effect to approximately 5%. However,most studies employed bolus injection, and no study has reported completing drip infusion within 5 minutes. In the present study,we investigated the preventive effects on phlebitis of administering this agent over 5 minutes or less by drip infusion,which is simpler and more useful than intravenous injection. We administered vinorelbine 35 times to 6 patients with breast cancer or non-small cell lung cancer. The mean administration period was 3 minutes and 59 seconds +/-22 seconds, and the incidence of phlebitis was 5.7%. Our administration method involving drip infusion prevented phlebitis as markedly as by intravenous injection. In addition,there were no marked differences in the incidences of adverse effects other than phlebitis. The administration method employed in this study (drip infusion within five minutes) prevented vinorelbine-induced phlebitis, and was simpler than intravenous injection.

Multicenter phase II study of infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first-line treatment in patients with metastatic colorectal cancer (CELINE trial).

The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX-6)] in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Sixty patients with a median age of 64 years (range, 38-82 syears) received a biweekly intravenous infusion of cetuximab (500 mg/m2 on day 1) followed by FOLFOX-6 (2-hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2, and 5-FU as a 400 mg/m2 bolus followed by a 46-hour 2,400 mg/m2 infusion on days 1-3). Patient response rate was 70%, with 95% disease control rates. The median progression-free survival was 13.8 months. Thirteen patients (21.7%) were able to undergo resection of previously unresectable metastases, with the aim of curing them. The median follow-up was 22.7 months, and median overall survival was 31.0 months. Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated. The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX-6 was well tolerated and had a manageable safety profile for the first-line treatment of KRAS wild-type metastatic colorectal cancer. Efficacy was comparable to other treatment regimens. The results support the administration of biweekly cetuximab in combination with FOLFOX-6, which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers.

[A case of monolobar Caroli's disease].

The patient was a 45-year-old man, with no complaints. It was pointed out that he had a cystic lesion in the liver by abdominal ultrasonography at routine medical check-up. With close examinations, the tumor was multilocular cystic lesion in the right lobe of the liver, whose size was 35mm in diameter. We supposed it was a biliary cystadenoma (adenocarcinoma), echinococcosis, or degenerated hemangioma. And we performed partial hepatectomy. Finally, it was diagnosed as pure type monolobar Caroli's disease by pathological examination. This was a rare case of Caroli's disease which arose limitedly in monolobe. And we could curatively resect it by hepatectomy.

[Effectiveness of intraperitoneal chemotherapy using new-aged drugs for the peritoneal dissemination of gastric cancer].

We evaluated the effectiveness of intraperitoneal chemotherapy for peritoneal dissemination of gastric cancer. A total of 104 patients with primary gastric cancer with peritoneal dissemination were enrolled in this study. In 72 of the 104 patients with gastrectomy performed, 5 patients underwent CDDP-ip (50-100 mg/100-200 ml), 16 patients underwent CHPP (CDDP 300 mg, MMC 30 mg, ETP 150 mg/8 l/42-43 degrees C/60 min), and 17 patients underwent CMV-ip (CDDP 150 mg, MMC 20 mg, ETP 100 mg/1 l/60 min). The prognosis of patients who underwent CMV-ip was significantly better than those who received other therapies. In 26 patients with severe peritoneal dissemination who were treated with TS-1 (60 mg/m2) and taxane-ip (docetaxel 40-60 mg/body or paclitaxel 120-180 mg/body), 9 of 18 responders performed complete cytoreduction. The median survival time (MST) in these 9 patients was 944 days and a 2-year survival rate was 63%. A multimodal therapy consisting of systemic chemotherapy, intraperitoneal chemotherapy and complete cytoreductive surgery may provide good prognosis to the gastric cancer patients with peritoneal dissemination.

Treatment Rationale and Study Design for Clinical Trial on the Efficacy of UFT/LV for Stage II Colorectal Cancer With Risk Factors for Recurrence (JFMC46-1201).

BACKGROUND: The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. PATIENTS AND METHODS: This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m(2)/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.

Angiotensin II activates MAP kinase and NF-kappaB through angiotensin II type I receptor in human pancreatic cancer cells.

Pancreatic ductal cancer has higher angiotensin II concentrations compared with normal pancreas or other solid tumors. This study examined angiotensin II type 1 (AT1) receptor expression and the role of angiotensin II in proliferation and survival of human pancreatic cancer cells. All three pancreatic cancer cell lines studied, from well to poorly-differentiated types, HPAF-II, AsPC-1, and Panc-1, showed strong expression of AT1 receptor. In contrast, HT-29 human colon cancer cells showed extremely weak expression. Angiotensin II stimulated the growth of pancreatic cancer cells through MAP kinase activation but had no significant effect on proliferation of HT-29 colon cancer cells. In addition, angiotensin II significantly prevented cisplatin (CDDP)-induced apoptosis through NF-kappaB activation and the subsequent production of anti-apoptotic molecules, including survivin and Bcl-XL, in pancreatic cancer cells. These findings suggest that angiotensin II plays a role in the growth and chemoresistance of AT1-positive pancreatic cancer cells through its action as a potent mitogen and anti-apoptotic molecule.

Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, modulates the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3.

Activation of peroxisome proliferator-activated receptor (PPAR)-gamma induces terminal differentiation and growth inhibition associated with G1 cell cycle arrest in some cancer cells. The multifunctional molecule beta-catenin performs important roles in intercellular adhesion and signal transduction. However, no report has focused on actions of PPAR-gamma in regulating the E-cadherin/beta-catenin system. We examined whether thiazolidinedione (TZD), a potent PPAR-gamma ligand, could modulate the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3, that has been found to express PPAR-gamma. According to Western blotting, TZD markedly increased differentiation markers including E-cadherin and carcinoembryonic antigen, while beta-catenin did not change significantly. In untreated cells, fluorescence immunostaining demonstrated beta-catenin predominantly in the cytoplasm and/or nucleus; in TZD-treated cells, beta-catenin localization had dramatically shifted to the plasma membrane, in association with increased E-cadherin at this site. Thus, a PPAR-gamma ligand appears to participate not only in induction of differentiation in pancreatic cancer cells, but also in the regulation of the E-cadherin/beta-catenin system. Such ligands may prove clinically useful as cytostatic anticancer agents.