Research Center for Innovative Oncology

Kashiwa, Japan

Research Center for Innovative Oncology

Kashiwa, Japan
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Fujii S.,Research Center for Innovative Oncology | Fukamachi K.,Nagoya City University | Tsuda H.,Nagoya City University | Ito K.,Nagasaki University | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

The neoplastic transformation by mutant RAS is thought to require remodeling of expression of an entire set of genes. However, the underlying mechanism for initiation of gene expression remodeling in tumorigenesis remains elusive. This study was aimed to define the oncogenic role of EZH2, a histone modifier protein that is induced by oncogenic mutant RAS, using pancreatic cancers of transgenic rats exogenously expressing human mutant RAS. Immunohistochemical observation of preneoplastic or cancerous lesions in the animal model suggested that upregulation of Ezh2 protein is an initiating event in pancreatic carcinogenesis. MEK-inhibition or Elk-1-knockdown downregulated EZH2, and MEK-inhibition or EZH2-knockdown restored expression of a tumor suppressor, RUNX3 in human and rat pancreatic cancer cells activated by the oncogenic RAS. Furthermore, Elk-1- or EZH2-knockdown inhibited growth of the cancer cells. These results strongly suggested that the oncogenic RAS upregulates EZH2 through MEK-ERK signaling, resulted in downregulation of tumor suppressors including RUNX3 in pancreatic carcinogenesis. © 2011 Elsevier Inc.


Sasako M.,Hyogo College of Medicine | Inoue M.,Research Center for Cancer Prevention and Screening | Lin J.-T.,National Taiwan University Hospital | Khor C.,National University Hospital Singapore | And 2 more authors.
Japanese Journal of Clinical Oncology | Year: 2010

Epidemiology: Gastric cancer is the second most common cancer in Asia, more than half of the world's gastric cancer cases arise in Eastern Asia, and the majority of Asia's cases still occur in the distal part of the stomach. Etiology and Prevention: The etiology of gastric cancer consists of genetic susceptibility, Helicobacter pylori infection and environmental risk factors. Helicobacter pylori eradication treatment, consumption of fresh vegetables and fruits and use of aspirin and non-steroidal anti-inflammatory drugs seem to reduce the risk of gastric cancer. Endoscopy and Diagnosis: Screening for gastric cancer is cost-effective in countries with high incidence. Risk stratification may increase the cost-effectiveness of screening in populations at moderate risk. Endoscopic resection is curative in a subset of patients with early cancer. Surgery and Adjuvant Treatment: R0 resection with D2 lymph node dissection has produced the best survival data. Some kind of post-operative adjuvant chemotherapy including S-1 is recommended after D2 surgery. Chemotherapy for Advanced Gastric Cancer: As chemotherapy for gastric cancer, fluorouracils plus platinum are the most widely accepted first-line regimens, whereas taxanes or irinotecan are mostly used in second- and third-line settings. Differences in the approval and medical insurance systems may influence the status of these regimens. Trastuzumab in combination with fluorouracils/platinum will be a standard regimen for HER2-positive gastric cancer. Many new targeting agents are currently under investigation, and Asian countries are playing important roles in investigation and development of new and better treatments for this malignancy. © The Author (2010). Published by Oxford University Press. All rights reserved.


Sekine S.,Clinical Pathology Laboratories | Sekine S.,National Cancer Center Research Institute | Yamashita S.,National Cancer Center Research Institute | Tanabe T.,Clinical Pathology Laboratories | And 11 more authors.
Journal of Pathology | Year: 2016

The molecular mechanisms underlying the serrated pathway of colorectal tumourigenesis, particularly those related to traditional serrated adenomas (TSAs), are still poorly understood. In this study, we analysed genetic alterations in 188 colorectal polyps, including hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), TSAs, tubular adenomas, and tubulovillous adenomas by using targeted next-generation sequencing and reverse transcription-PCR. Our analyses showed that most TSAs (71%) contained genetic alterations in WNT pathway components. In particular, PTPRK-RSPO3 fusions (31%) and RNF43 mutations (24%) were frequently and almost exclusively observed in TSAs. Consistent with the WNT pathway activation, immunohistochemical analysis showed diffuse and focal nuclear accumulation of β-catenin in 53% and 30% of TSAs, respectively. APC mutations were observed in tubular and tubulovillous adenomas and in a subset of TSAs. BRAF mutations were exclusively and frequently encountered in serrated lesions. KRAS mutations were observed in all types of polyps, but were most commonly encountered in tubulovillous adenomas and TSAs. This study has demonstrated that TSAs frequently harbour genetic alterations that lead to WNT pathway activation, in addition to BRAF and KRAS mutations. In particular, PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of TSAs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Takeda A.,Ofuna Chuo Hospital | Sanuki N.,Ofuna Chuo Hospital | Fujii H.,Research Center for Innovative Oncology | Yokosuka N.,Yuai Clinic | And 5 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION: The maximum standardized uptake value (SUVmax) on F-fluorodeoxyglucose positron emission tomography is a predictor for overall survival (OS) in non-small-cell lung cancer (NSCLC) after resection. We investigated the association between SUVmax and outcomes in NSCLC after stereotactic body radiotherapy. METHODS: Between 2005 and 2012, 283 patients with early NSCLC (T1a-2N0M0) were treated with stereotactic body radiotherapy; the total doses were 40 to 60 Gy in five fractions. Patients who underwent staging F-fluorodeoxyglucose positron emission tomography scans by a single scanner and were followed up for more than or who died within 6 months were eligible. The optimal threshold SUVmax was calculated for each outcome. Outcomes were analyzed using the Kaplan-Meier method and log-rank test. Prognostic significance was assessed by univariate and multivariate analyses. RESULTS: One hundred fifty-two patients were eligible. Median follow-up was 25.3 (range, 1.3-77.4) months. Local, regional, and distant recurrences, cancer-specific deaths, and deaths from other reasons occurred in 14, 11, 27, 21, and 31 patients, respectively. The optimal threshold SUVmax for local, regional, and distant recurrences, and disease-free survival (DFS), cancer-specific survival, and OS were 2.47 to 3.64. Outcomes of patients with SUVmax lower than each threshold were significantly better than those with higher SUVmax (all p<0.005): 3-year DFS rates were 93.0% versus 58.3% (p<0.001) and 3-year OS rates were 86.5% versus 42.2% (p<0.001), respectively. By multivariate analysis, higher SUVmax was a significantly worse predictor for DFS (p<0.01) and OS (p=0.04). CONCLUSIONS: SUVmax was a predictor for DFS and OS. A high SUVmax may be considered for intensive treatment to improve outcomes. Copyright © 2013 by the International Association for the Study of Lung Cancer.


Fujii S.,Research Center for Innovative Oncology | Yamazaki M.,Research Center for Innovative Oncology | Muto M.,Kyoto University | Ochiai A.,Research Center for Innovative Oncology
Histopathology | Year: 2010

Aims: Superficial squamous epithelial lesions of the pharynx are increasingly recognized by architectural changes in the intraepithelial papillary capillary loop (IPCL) assessed by narrow-band imaging (NBI). The aim was to explore the histology of squamous epithelial precursor lesions and superficial-type pharyngeal squamous cell carcinoma (STPSCC), including squamous cell carcinoma (SCC) in situ and early invasive SCC, by focusing on microvascular irregularities to investigate the composition of those lesions and to explore the pathological characteristics of STPSCCs. Methods and results: Several pathological factors including thickness of intraepithelial squamous cell carcinoma (IESCC) and tumour thickness and microvascular density (MVD) were examined in 104 STPSCCs from 69 patients. The results show that architectural change of IPCL was recognized in precursor lesions in parallel with architectural disturbance and cytological atypia for criteria of diagnosing dysplasia. In 104 STPSCCs, the MVD of IESCC was correlated with the thickness of IESCC (P = 0.0115). Moreover, invasive SCC showed significantly higher MVD of IESCC (P = 0.0078) and there was significant correlation between the thickness of IESCC and subepithelial invasion (P < 0.0001). Conclusions: Microvascular irregularities are an important pathological factor in carcinogenesis and early invasiveness of SCC of the pharynx. © 2010 Blackwell Publishing Limited.


Kinoshita T.,Research Center for Innovative Oncology | Kinoshita T.,National Cancer Center Hospital East | Ishii G.,Research Center for Innovative Oncology | Hiraoka N.,National Cancer Center Research Institute | And 8 more authors.
Cancer Science | Year: 2013

Recently, an association between tumor infiltrating Forkhead box P3 regulatory T cells (Treg) and an unfavorable prognosis has been clinically shown in some cancers, but the mechanism of Treg induction in the tumor microenvironment remains uncertain. The aims of the present study were to examine the relationship between Treg and patient outcome and to investigate whether Treg induction is influenced by the characteristics of cancer-associated fibroblasts (CAF) in lung adenocarcinoma. The numbers of Treg in both the tumor stroma and the tumor nest were counted in 200 consecutive pathological stage I lung invasive adenocarcinoma specimens. To examine whether the characteristics of CAF influence Treg induction, we selected and cultured CAF from low Treg and high Treg adenocarcinoma. The number of Treg was much higher in the stroma than in the nest (P < 0.01). Patients with high Treg had a significantly poorer prognosis than those with low Treg (overall survival: P = 0.03; recurrence-free survival: P = 0.02; 5-year overall survival: 85.4% vs 93.0%). Compared with the CAF from low Treg adenocarcinoma, culture supernatant of the CAF from high Treg adenocarcinoma induced more Treg (P = 0.01). Also, CAF from high Treg adenocarcinoma expressed significantly higher mRNA levels of transforming growth factor-β (P = 0.01) and vascular endothelial growth factor (P = 0.01), both of which are involved in Treg induction. Our studies suggest the possibility that CAF expressing immunoregulatory cytokines may induce Treg in the stroma, creating a tumor-promoting microenvironment in lung adenocarcinoma that leads to a poor outcome. © 2013 Japanese Cancer Association.


Hoshino A.,University of Tokyo | Hoshino A.,Research Center for Innovative Oncology | Ishii G.,Research Center for Innovative Oncology | Ito T.,University of Tokyo | And 7 more authors.
Cancer Research | Year: 2011

During the metastatic process, cancer cells interact with vascular adventitial fibroblasts (VAF), which are the main components of the outermost connective tissue layer of blood vessels. This activity suggests the presence of a specific tumor microenvironment in the perivascular area. The s.c. coinjection of human lung adenocarcinoma cell lines (A549, PC-14, and CRL-5807) and human VAF (hVAF) resulted in a high rate of tumor formation, compared with the coinjection of these cell lines and human lung tissue-derived fibroblasts (hLF). A cDNA microarray analysis revealed a higher expression level of podoplanin in hVAFs than in hLFs (4.7-fold). Flow cytometry analysis also showed a higher expression level of podoplanin in hVAFs (43% ± 17.5%) than in hLFs (16% ± 10.3%). Sorted podoplanin-positive hVAFs displayed enhanced tumor formation, lymph node metastasis, and lung metastasis of A549 compared to sorted podoplanin-negative hVAFs. Knockdown of podoplanin in hVAFs decreased the augmenting effect of tumor formation and in vitro colony formation. The overexpression of podoplanin in hVAFs hastened the tumor formation of A549, compared with control hVAFs. Furthermore, the analysis of small-sized human lung adenocarcinoma (n = 112) revealed that patients with podoplanin-positive cancer-associated fibroblasts had a significantly higher rate of lymph node metastasis and a high risk of recurrence. These results indicate a promotive effect of hVAFs mediated by podoplanin on cancer progression and suggest that the perivascular environment may constitute a specific niche for tumor progression. ©2011 AACR.


Sato M.,Research Center for Innovative Oncology | Kojima M.,Research Center for Innovative Oncology | Nagatsuma A.K.,Research Center for Innovative Oncology | Nakamura Y.,Research Center for Innovative Oncology | And 2 more authors.
Pathology International | Year: 2014

The purpose of this study was to set the optimal preanalytical fixation protocol to enhance analytical and postanalytical phase accuracy and consistency. Twenty-five normal colorectal tissues were fixed using various formalin concentrations, pHs, and fixation periods. All specimens were embedded in paraffin and 4μm sections were used for immunohistochemistry of Ki-67, and extraction and amplification of DNA and RNA. The Ki-67 labeling index and the successful gene amplification rate for DNA and mRNA were evaluated and compared among variously fixed tissue samples. Ki-67 positivity was enhanced by low pH and short fixation time, and was influenced by the type of antibody, but not by the staining (with or without using an autostainer) method. DNA amplification by PCR was strongly influenced by pH of formalin. cDNA amplification could be accomplished only with the shortest PCR fragment of 142 bp, and longer fixation times impaired the amplification. These data suggest that multiple different factors influence immunohistochemical results and gene amplification using DNA and mRNA. We recommend, based on data from this comprehensive analysis, a 10% neutral buffered formalin and fixation times of no longer than 1 week to produce consistent immunohistochemical slides and DNA amplification within 500 bp in pathology laboratories. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.


Fujii S.,Research Center for Innovative Oncology | Tokita K.,Research Center for Innovative Oncology | Wada N.,National Cancer Center Hospital East | Ito K.,Nagasaki University | And 3 more authors.
Oncogene | Year: 2011

EZH2 overexpression occurs in various malignancies and is associated with a poor outcome. We have so far demonstrated that EZH2 downregulates the important genes such as E-cadherin and RUNX3 by increasing histone H3K27 trimethylation. However, the mechanism of EZH2 overexpression in various cancer cells remains unclear. In this study we carried out a promoter analysis of the EZH2 gene and investigated whether a survival signal that is upregulated in cancer cells is related to overexpression at the transcription level. We also explored the clinical relevance of the signaling pathway that leads to EZH2 overexpression in breast cancer and demonstrated that MEK-ERK1/2-Elk-1 pathway leads to EZH2 overexpression. The triple-negative and ERBB2-overexpressing subtypes of breast cancer are known to contain more rapidly proliferating breast cancer cells. The signaling pathway connected to EZH2 overexpression was associated with both aggressive subtypes of breast cancer. We show the significance that overexpression of histone modifier protein EZH2 in cancer cells and our study could pave the way for EZH2 inhibition to become an efficient treatment for more aggressive breast cancers.Oncogene advance online publication, 18 April 2011; doi:10.1038/onc.2011.118.


Kojima M.,Research Center for Innovative Oncology | Ishii G.,Research Center for Innovative Oncology | Atsumi N.,Research Center for Innovative Oncology | Nishizawa Y.,National Cancer Center Hospital East | And 2 more authors.
Cancer Science | Year: 2010

CD133-positive cells have been reported to possess a cancer-initiating-cell phenotype and the property of resistance to chemoradiation therapy in colorectal cancer. The aim of the present study was to evaluate quantitative and locational changes in CD133-positive cells in rectal cancer patients who received preoperative chemoradiation therapy. The prognostic significance of CD133 expression in patients with preoperative chemoradiation therapy was also analyzed. Immunohistochemical staining for CD133 and cancer-initiating-cell marker CD44 were performed in 92 surgically resected rectal cancers. Of the 92 cases, 43 patients received preoperative chemoradiation therapy and 49 patients underwent surgery alone. Forty pretherapic biopsy specimens from 43 patients in preoperative chemoradiation therapy group were also analyzed. CD133-positive cases were more common in the preoperative chemoradiation therapy group than in the surgery-alone group (P=0.03). Further, CD133-positive cases were more common in the preoperative chemoradiation therapy group than in pretherapic biopsy specimens (P=0.02). In the preoperative chemoradiation therapy group, the CD133-positive cases showed poorer prognosis than the CD133-negative cases. On the other hand, the frequency of CD44-positive case within cancer tissue was similar between the preoperative chemoradiation therapy group and the surgery-alone group. CD44 expression in the preoperative chemoradiation therapy group was not associated with prognosis. CD44- and CD133-positive cells were distributed evenly within the tumor both in the preoperative chemoradiation therapy group and surgery-alone group, and locational alteration was not observed. The therapy-resistant ability of CD133-positive cells can be associated with poor outcome in the patients with preoperative chemoradiation therapy. © 2010 Japanese Cancer Association.

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