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Pancreatic Neoplasms: HELP
Articles by Makoto Hashizume
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, M. Hashizume wrote the following 21 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Pancreatic Cancer: Clinical Significance of Biomarkers. 2013

Ohuchida, Kenoki / Ohtsuka, Takao / Mizumoto, Kazuhiro / Hashizume, Makoto / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Gastrointest Tumors · Pubmed #26675163.

ABSTRACT: BACKGROUND: Improvement in the prognosis of patients with pancreatic cancer, novel effective screening and diagnostic strategies and treatments are needed. Recent advances in the understanding of pancreatic carcinogenesis and tumor microenvironment have allowed identification of biomarkers for screening, diagnosis and prediction of cancer treatments, including novel therapies targeting specific cancer or stromal cell subpopulations. Personalized therapy in pancreatic cancer is also promising as several drugs such as S1, capecitabine and gemcitabine reportedly have significant therapeutic effects. Predictive markers are thus needed to select patients most likely to benefit from therapies based on gemcitabine or other drugs. SUMMARY: We review the clinical significance of promising screening, diagnostic, predictive and prognostic biomarkers based on genetic and epigenetic alterations and microRNA abnormalities in pancreatic cancer. We also review new types of biomarkers based on stromal cells, such as pancreatic stellate cells, in the microenvironment of pancreatic cancer.

2 Article Robust 3D image reconstruction of pancreatic cancer tumors from histopathological images with different stains and its quantitative performance evaluation. 2019

Kugler, Mauricio / Goto, Yushi / Tamura, Yuki / Kawamura, Naoki / Kobayashi, Hirokazu / Yokota, Tatsuya / Iwamoto, Chika / Ohuchida, Kenoki / Hashizume, Makoto / Shimizu, Akinobu / Hontani, Hidekata. ·Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya, Japan. mauricio@kugler.com. · Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya, Japan. · Kyushu University, 3-1-1 Maidaishi, Higashi-ku, Fukuoka, Japan. · Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei-shi, Tokyo, Japan. ·Int J Comput Assist Radiol Surg · Pubmed #31267332.

ABSTRACT: PURPOSE: Histopathological imaging is widely used for the analysis and diagnosis of multiple diseases. Several methods have been proposed for the 3D reconstruction of pathological images, captured from thin sections of a given specimen, which get nonlinearly deformed due to the preparation process. The majority of the available methods for registering such images use the degree of matching of adjacent images as the criteria for registration, which can result in unnatural deformations of the anatomical structures. Moreover, most methods assume that the same staining is used for all images, when in fact multiple staining is usually applied in order to enhance different structures in the images. METHODS: This paper proposes a non-rigid 3D reconstruction method based on the assumption that internal structures on the original tissue must be smooth and continuous. Landmarks are detected along anatomical structures using template matching based on normalized cross-correlation (NCC), forming jagged shape trajectories that traverse several slices. The registration process smooths out these trajectories and deforms the images accordingly. Artifacts are automatically handled by using the confidence of the NCC in order to reject unreliable landmarks. RESULTS: The proposed method was applied to a large series of histological sections from the pancreas of a KPC mouse. Some portions were dyed primarily with HE stain, while others were dyed alternately with HE, CK19, MT and Ki67 stains. A new evaluation method is proposed to quantitatively evaluate the smoothness and isotropy of the obtained reconstructions, both for single and multiple staining. CONCLUSIONS: The experimental results show that the proposed method produces smooth and nearly isotropic 3D reconstructions of pathological images with either single or multiple stains. From these reconstructions, microanatomical structures enhanced by different stains can be simultaneously observed.

3 Article Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis. 2019

Yan, Zilong / Ohuchida, Kenoki / Fei, Shuang / Zheng, Biao / Guan, Weiyu / Feng, Haimin / Kibe, Shin / Ando, Yohei / Koikawa, Kazuhiro / Abe, Toshiya / Iwamoto, Chika / Shindo, Koji / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Mizumoto, Kazuhiro / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of General Surgery, Shenzhen University General Hospital, Shenzhen, China. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Cancer Center of Kyushu University Hospital, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. mnaka@surg1.med.kyushu-u.ac.jp. ·J Exp Clin Cancer Res · Pubmed #31133044.

ABSTRACT: BACKGROUND: Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer-stromal interaction. METHODS: Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor. RESULTS: Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer-stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model. CONCLUSIONS: These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis.

4 Article CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis. 2019

Yan, Zilong / Ohuchida, Kenoki / Zheng, Biao / Okumura, Takashi / Takesue, Shin / Nakayama, Hiromichi / Iwamoto, Chika / Shindo, Koji / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of General Surgery, Shenzhen University General Hospital, Shenzhen, China. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Cancer Center, Kyushu University Hospital, Fukuoka, Japan. · Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·J Cancer Res Clin Oncol · Pubmed #30770989.

ABSTRACT: PURPOSE: This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer. METHODS: We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin-CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model. RESULTS: CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK-MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model. CONCLUSIONS: CD110 promotes pancreatic cancer progression and it may serve as a predictive factor for liver metastasis.

5 Article Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix. 2019

Okumura, Takashi / Ohuchida, Kenoki / Kibe, Shin / Iwamoto, Chika / Ando, Yohei / Takesue, Shin / Nakayama, Hiromichi / Abe, Toshiya / Endo, Sho / Koikawa, Kazuhiro / Sada, Masafumi / Horioka, Kohei / Mochidome, Naoki / Arita, Makoto / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Materials Science and Engineering, Faculty of Engineering, Kyushu University, Fukuoka, Japan. ·Int J Cancer · Pubmed #30152542.

ABSTRACT: Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

6 Article Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma. 2018

Koikawa, Kazuhiro / Ohuchida, Kenoki / Ando, Yohei / Kibe, Shin / Nakayama, Hiromichi / Takesue, Shin / Endo, Sho / Abe, Toshiya / Okumura, Takashi / Iwamoto, Chika / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kenoki@surg1.med.kyushu-u.ac.jp. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: mnaka@surg1.med.kyushu-u.ac.jp. ·Cancer Lett · Pubmed #29580808.

ABSTRACT: Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.

7 Article Ultrasensitive MRI detection of spontaneous pancreatic tumors with nanocage-based targeted contrast agent. 2018

Kawano, Takahito / Murata, Masaharu / Kang, Jeong-Hun / Piao, Jing Shu / Narahara, Sayoko / Hyodo, Fuminori / Hamano, Nobuhito / Guo, Jie / Oguri, Susumu / Ohuchida, Kenoki / Hashizume, Makoto. ·Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan. · Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan; Department of Advanced Medical Initiatives, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan; Faculty of Medical Sciences and Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan. Electronic address: m-murata@dem.med.kyuhyu-u.ac.jp. · Division of Biopharmaceutics and Pharmacokinetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. · Faculty of Medical Sciences and Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan. · Department of Advanced Medical Initiatives, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan. · Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan; Department of Advanced Medical Initiatives, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan; Faculty of Medical Sciences and Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, 812-8582, Japan. ·Biomaterials · Pubmed #29107217.

ABSTRACT: Contrast agents with greater specificity and sensitivity are required for the diagnosis of pancreatic cancers by magnetic resonance imaging (MRI). In this study, small heat shock protein 16.5 (Hsp16.5)-based nanocages conjugated to gadolinium(III)-chelated contrast agents and iRGD peptides (which target neuropilin-1 expressed on pancreatic cancer cells) were developed. To investigate whether template size influences relaxivity, nanocages with one to four hydrophobic domains were designed. MRI data showed that larger nanocages had higher T

8 Article Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180. 2018

Koikawa, Kazuhiro / Ohuchida, Kenoki / Takesue, Shin / Ando, Yohei / Kibe, Shin / Nakayama, Hiromichi / Endo, Sho / Abe, Toshiya / Okumura, Takashi / Horioka, Kohei / Sada, Masafumi / Iwamoto, Chika / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohuchida, Riichi / Manabe, Tatsuya / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kenoki@surg1.med.kyushu-u.ac.jp. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Section of Fixed Prosthodontics, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan. ·Cancer Lett · Pubmed #29061505.

ABSTRACT: Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.

9 Article Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells. 2017

Okumura, Takashi / Ohuchida, Kenoki / Sada, Masafumi / Abe, Toshiya / Endo, Sho / Koikawa, Kazuhiro / Iwamoto, Chika / Miura, Daisuke / Mizuuchi, Yusuke / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Manabe, Tatsuya / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. · Kyushu University Hospital Cancer Center, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Oncotarget · Pubmed #28407685.

ABSTRACT: Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.

10 Article Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice. 2017

Endo, Sho / Nakata, Kohei / Ohuchida, Kenoki / Takesue, Shin / Nakayama, Hiromichi / Abe, Toshiya / Koikawa, Kazuhiro / Okumura, Takashi / Sada, Masafumi / Horioka, Kohei / Zheng, Biao / Mizuuchi, Yusuke / Iwamoto, Chika / Murata, Masaharu / Moriyama, Taiki / Miyasaka, Yoshihiro / Ohtsuka, Takao / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: knakata@surg1.med.kyushu-u.ac.jp. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kenoki@surg1.med.kyushu-u.ac.jp. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: mnaka@surg1.med.kyushu-u.ac.jp. ·Gastroenterology · Pubmed #28126348.

ABSTRACT: BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice. METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified. RESULTS: Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category (P = .018), histologic grade (P = .001), lymph node metastases (P < .001), stage (P = .009), perilymphatic invasion (P = .001), and perivascular invasion (P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1.56). Immunoblots showed that PSCs from pancreatic tumor samples expressed higher levels of markers of autophagy than PSCs from chronic pancreatitis samples. Inhibitors of autophagy increased the number of lipid droplets of PSCs, indicating a quiescent state of PSCs, and reduced their production of ECM molecules and interleukin 6, as well as their proliferation and invasiveness in culture. PSCs exposed to autophagy inhibitors formed smaller tumors in nude mice (P = .001) and fewer liver metastases (P = .018) with less peritoneal dissemination (P = .018) compared to PSCs not exposed to autophagy inhibitors. CONCLUSIONS: Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma.

11 Article Cancer-associated peritoneal mesothelial cells lead the formation of pancreatic cancer peritoneal dissemination. 2017

Abe, Toshiya / Ohuchida, Kenoki / Koikawa, Kazuhiro / Endo, Sho / Okumura, Takashi / Sada, Masafumi / Horioka, Kohei / Zheng, Biao / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Manabe, Tatsuya / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·Int J Oncol · Pubmed #28035373.

ABSTRACT: The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.

12 Article CD146 attenuation in cancer-associated fibroblasts promotes pancreatic cancer progression. 2016

Zheng, Biao / Ohuchida, Kenoki / Chijiiwa, Yoshiro / Zhao, Ming / Mizuuchi, Yusuke / Cui, Lin / Horioka, Kohei / Ohtsuka, Takao / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / Nakamura, Masafumi / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. mizumoto@surg1.med.kyushu-u.ac.jp. · Kyushu University Hospital Cancer Center, Fukuoka, Japan. mizumoto@surg1.med.kyushu-u.ac.jp. · Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Mol Carcinog · Pubmed #26373617.

ABSTRACT: Cancer-associated fibroblasts (CAFs) are heterogeneous cell populations that influence tumor initiation and progression. CD146 is a cell membrane protein whose expression has been implicated in multiple human cancers. CD146 expression is also detected in pancreatic cancer stroma; however, the role it plays in this context remains unclear. This study aimed to clarify the function and significance of CD146 expression in pancreatic cancer. We performed immunohistochemical staining to investigate the prevalence of CD146 expression in stromal fibroblasts in pancreatic cancer. We also examined the influence of CD146 on CAF-mediated tumor invasion and migration and CAF activation using CD146 small interfering RNA or overexpression plasmids in primary cultures of CAFs derived from pancreatic cancer tissues. CD146 expression in CAFs was associated with high-grade pancreatic intraepithelial neoplasia and low histological grade invasive ductal carcinoma of the pancreas, while patients with low CD146 expression had a poorer prognosis. Blocking CD146 expression in CAFs significantly enhanced tumor cell migration and invasion in a co-culture system. CD146 knockdown also promoted CAF activation, possibly by inducing the production of pro-tumorigenic factors through modulation of NF-κB activity. Consistently, overexpression of CD146 in CAFs inhibited migration and invasion of co-cultured cancer cells. Finally, CD146 expression in CAFs was reduced by interaction with cancer cells. Our findings suggest that decreased CD146 expression in CAFs promotes pancreatic cancer progression. © 2015 Wiley Periodicals, Inc.

13 Article Design and Function of Engineered Protein Nanocages as a Drug Delivery System for Targeting Pancreatic Cancer Cells via Neuropilin-1. 2015

Murata, Masaharu / Narahara, Sayoko / Kawano, Takahito / Hamano, Nobuhito / Piao, Jing Shu / Kang, Jeong-Hun / Ohuchida, Kenoki / Murakami, Takashi / Hashizume, Makoto. ·§Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan. · ⊥Laboratory of Tumor Biology, Takasaki University of Health and Welfare, Takasaki, Gunma 370-0033, Japan. ·Mol Pharm · Pubmed #25811429.

ABSTRACT: We describe the development of neuropilin 1-binding peptide (iRGD)-nanocages that specifically target human pancreatic cancer cells in which an iRGD is joined to the surface of naturally occurring heat shock protein (HSP) cages. Using a genetic engineering approach, the iRGD domain was joined to the C-terminal region of the HSP cage using flexible linker moieties. The characteristics of the interdomain linkages between the nanocage and the iRGD domain play an important role in the specificity and affinity of the iRGD-nanocages for their target cells. An engineered L30-iRGD-nanocage with 30 amino acid linkers, (GGS)10, showed greater binding affinity for pancreatic cancer cells relative to that of other linkers. Furthermore, a moderately hydrophobic anticancer drug, OSU03012, was successfully incorporated into the L30-iRGD-nanocage by heating the mixture. The OSU03012-loaded L30-iRGD-nanocage induced cell death of pancreatic cancer cells by activating the caspase cascade more effectively than the same concentrations of free OSU03012. The iRGD-nanocages show great potential as a novel nanocarrier for pancreatic cancer-targeted drug delivery.

14 Article Minimally invasive image analysis of biliary-pancreatic structure for preoperative simulation. 2014

Maeda, Takashi / Konishi, Kozo / Tanouez, Kazuo / Taketomi, Akinobu / Shirabe, Ken / Maehara, Yoshihiko / Hashizume, Makoto. · ·Hepatogastroenterology · Pubmed #25436373.

ABSTRACT: For preoperative assessment of the pancreatic tumors, we developed minimally invasive method to extract the pancreatic duct from multidetector row computed tomography (MD-CT) images and to visualize the biliarypancreatic structures, tumor and adjacent organs simultaneously using an image workstation.

15 Article Mass spectrometry-based metabolic profiling of gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. 2014

Fujimura, Yoshinori / Ikenaga, Naoki / Ohuchida, Kenoki / Setoyama, Daiki / Irie, Miho / Miura, Daisuke / Wariishi, Hiroyuki / Murata, Masaharu / Mizumoto, Kazuhiro / Hashizume, Makoto / Tanaka, Masao. ·From the *Innovation Center for Medical Redox Navigation; †Departments of Surgery and Oncology, Graduate School of Medical Sciences; ‡Department of Advanced Medical Initiatives, Graduate School of Medical Sciences; §Faculty of Agriculture; ∥Bio-Architecture Center, Kyushu University, Fukuoka, Japan; and ¶Kyushu University Hospital Cancer Center, Fukuoka, Japan. ·Pancreas · Pubmed #24518513.

ABSTRACT: OBJECTIVES: Gemcitabine resistance (GR) is one of the critical issues for therapy for pancreatic cancer, but the mechanism still remains unclear. Our aim was to increase the understanding of GR by metabolic profiling approach. METHODS: To establish GR cells, 2 human pancreatic cancer cell lines, SUIT-2 and CAPAN-1, were exposed to increasing concentration of gemcitabine. Both parental and chemoresistant cells obtained by this treatment were subjected to metabolic profiling based on liquid chromatography-mass spectrometry. RESULTS: Multivariate statistical analyses, both principal component analysis and orthogonal partial least squares discriminant analysis, distinguished metabolic signature of responsiveness and resistance to gemcitabine in both SUIT-2 and CAPAN-1 cells. Among significantly different (P < 0.005) metabolite peaks between parental and GR cells, we identified metabolites related to several metabolic pathways such as amino acid, nucleotide, energy, cofactor, and vitamin pathways. Decreases in glutamine and proline levels as well as increases in aspartate, hydroxyproline, creatine, and creatinine levels were observed in chemoresistant cells from both cell lines. CONCLUSIONS: These results suggest that metabolic profiling can isolate distinct features of pancreatic cancer in the metabolome of gemcitabine-sensitive and GR cells. These findings may contribute to the biomarker discovery and an enhanced understanding of GR in pancreatic cancer.

16 Article MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene. 2012

Ohuchida, Kenoki / Mizumoto, Kazuhiro / Lin, Cui / Yamaguchi, Hiroshi / Ohtsuka, Takao / Sato, Norihiro / Toma, Hiroki / Nakamura, Masafumi / Nagai, Eishi / Hashizume, Makoto / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@med.kyushu-u.ac.jp ·Ann Surg Oncol · Pubmed #22407312.

ABSTRACT: BACKGROUND: There is increasing evidence that microRNAs are differentially expressed in many types of cancers. Despite progress in analyses of microRNAs in several types of cancers, the functional contributions of microRNAs to pancreatic cancer remain unclear. METHODS: In the present study, the expression levels of specific microRNAs identified by microarray analyses were examined in a panel of 15 pancreatic cancer cell lines. We then investigated the functional roles of these microRNAs in the proliferation and invasion of pancreatic cancer cells. RESULTS: Based on the microarray data, we found frequent and marked overexpression of miR-10a, miR-92, and miR-17-5p in pancreatic cancer cell lines. Microdissection analyses revealed that miR-10a was overexpressed in pancreatic cancer cells isolated from a subset of primary tumors (12 of 20, 60%) compared with precursor lesions and normal ducts (P<.01). In vitro experiments revealed that miR-10a inhibitors decreased the invasiveness of pancreatic cancer cells (P<.01), but had no effect on their proliferation. Inhibition of HOXA1, a target of miR-10a, promoted the invasiveness of pancreatic cancer cells (P<.01). CONCLUSIONS: The present data suggest that miR-10a is overexpressed in a subset of pancreatic cancers and is involved in the invasive potential of pancreatic cancer cells partially via suppression of HOXA1.

17 Article Ultra-minimally invasive local immune cell therapy and regenerative therapy by multi-piercing surgery for abdominal solid tumor: therapeutic simulation by natural orifice translumenal endoscopic surgery-assisted needlescopic surgery using 3-mm diameter robots. 2011

Ohdaira, Takeshi / Tsutsumi, Norifumi / Xu, Hao / Mori, Megumu / Uemura, Munenori / Ieiri, Satoshi / Hashizume, Makoto. ·Department of Advanced Medicine and Innovative Technology, Kyshu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka, 812-8582, Japan. takeshiws.ohdaira@nifty.com ·J Hepatobiliary Pancreat Sci · Pubmed #21487759.

ABSTRACT: BACKGROUND/PURPOSE: We have invented multi-piercing surgery (MPS) which could potentially solve the triangular formation loss and device clashing which occur in single-port surgery (SPS), as well as restricted visual field, organ damage by needle-type instruments, and impaired removal of a resected organ from the body which occur in needlescopic surgery (NS). MPS is natural orifice translumenal endoscopic surgery (NOTES)-assisted NS. We used 3-mm diameter robots as needle-type instruments for MPS to examine the possibility of local immune cell therapy and regenerative therapy using stem cells for pancreatic cancer. METHODS: In MPS using two robots, the therapeutic cell suspension was injected into a target region of pancreas in two pigs. Both retention of a capsule of liquid cell suspension and invasive level were evaluated. RESULTS: Triangular formation could be ensured. The use of small-diameter robots allowed (1) the surgical separation of the pancreas and the retroperitoneum, and (2) the formation of the capsule containing the immune cell and stem cell suspension. The endoscope for NOTES provided a clear visual field and also assisted the removal of a resected organ from the body. The visual field of the endoscope could be oriented well by using an electromagnetic navigation system. CONCLUSIONS: MPS using small-diameter robots could potentially solve the issues inherent in SPS and NS and could allow minimally invasive local immune cell and stem cell therapy.

18 Article MicroRNA expression as a predictive marker for gemcitabine response after surgical resection of pancreatic cancer. 2011

Ohuchida, Kenoki / Mizumoto, Kazuhiro / Kayashima, Tadashi / Fujita, Hayato / Moriyama, Taiki / Ohtsuka, Takao / Ueda, Junji / Nagai, Eishi / Hashizume, Makoto / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@surg1.med.kyushu-u.ac.jp ·Ann Surg Oncol · Pubmed #21347785.

ABSTRACT: BACKGROUND: To improve the prognosis of patients after resection of pancreatic cancer, the most appropriate and efficient treatment should be provided to specific subsets of patients. Our aim was to identify promising microRNAs as markers to predict responses to gemcitabine in patients with resected pancreatic cancer. METHODS: Two gemcitabine-resistant pancreatic cancer cell lines were established, and global microRNA expression analyses was performed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Eleven miRNAs were selected as putative predictive markers and analyzed by means of macrodissected formalin-fixed, paraffin-embedded samples obtained from 90 patients with or without gemcitabine treatment after resection of pancreatic cancer. RESULTS: We identified 24 microRNAs whose expression was altered in gemcitabine-resistant cells. qRT-PCR analyses showed that patients with high miR-142-5p and miR-204 expression had significantly longer survival times than those with low miR-142-5p (P = 0.0077) and miR-204 (P = 0.0054) expression in the gemcitabine-treated group. This was not seen in the nontreated group. Multivariate analyses showed that miR-142-5p expression was an independent prognostic marker only in patients treated with gemcitabine (P = 0.034). CONCLUSIONS: miR-142-5p is a promising predictive marker for gemcitabine response in patients with resected pancreatic cancer.

19 Article Gemcitabine synergistically enhances the effect of adenovirus gene therapy through activation of the CMV promoter in pancreatic cancer cells. 2010

Onimaru, M / Ohuchida, K / Egami, T / Mizumoto, K / Nagai, E / Cui, L / Toma, H / Matsumoto, K / Hashizume, M / Tanaka, M. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan. ·Cancer Gene Ther · Pubmed #20395979.

ABSTRACT: Adenovirus-mediated gene therapy shows remarkable promise as a new strategy for advanced pancreatic cancer, but satisfactory clinical results have not yet been obtained. To improve this gene therapy, we investigated the effects of gemcitabine (GEM) on transgene expression by adenoviral vectors and their biological effects. We used Ad-lacZ and adenoviral vector-expressing NK4 (Ad-NK4) as representative adenoviral vectors. These vectors express beta-galactosidase (beta-gal) and NK4 (which inhibits the invasion of cancer cells), respectively, under the control of the CMV promoter. Cells were infected with the individual adenoviruses and then treated with GEM. GEM increased beta-gal mRNA expression and beta-gal activity, and increased NK4 expression in both culture media and within infected cells, in dose-dependent manners. The increased expression of NK4 delivered by Ad-NK4 had biological effects by inhibiting the invasion of cancer cells. GEM also enhanced NK4 expression in SUIT-2 cells transfected with an NK4-expressing plasmid, suggesting that GEM enhanced CMV promoter activity. In in vivo experiments, NK4 expression within subcutaneously implanted tumors was increased in GEM-treated mice compared with control mice. These results suggest that adenovirus-mediated gene therapy with GEM may be a promising approach for treating pancreatic cancer, and that this combination therapy may decrease the risks of side effects.

20 Article Combination with low-dose gemcitabine and hTERT-promoter-dependent conditionally replicative adenovirus enhances cytotoxicity through their crosstalk mechanisms in pancreatic cancer. 2010

Onimaru, Manabu / Ohuchida, Kenoki / Nagai, Eishi / Mizumoto, Kazuhiro / Egami, Takuya / Cui, Lin / Sato, Norihiro / Uchino, Junji / Takayama, Koichi / Hashizume, Makoto / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan. ·Cancer Lett · Pubmed #20163915.

ABSTRACT: To overcome the limited clinical efficacy of conditionally replicative adenoviruses (CRAds), we investigated the effects of combination therapy with gemcitabine (GEM) and the hTERT-promoter-dependent CRAd (hTERT-CRAd), Ad5/3hTERTE1. This combination therapy exhibited enhanced cytotoxic effects on pancreatic cancer both in vitro and in vivo. Furthermore, we revealed that this enhancement effect was due to the multiple bidirectional interactions between hTERT-CRAd and GEM. The GEM-sensitizing effect of E1 expression derived from hTERT-CRAd, and the enhancement effect by GEM on hTERT promoter activity which led to the increase of adenovirus E1 and viral infectivity. This combination therapy may be a promising therapeutic approach for pancreatic cancer.

21 Article hTERT-promoter-dependent oncolytic adenovirus enhances the transduction and therapeutic efficacy of replication-defective adenovirus vectors in pancreatic cancer cells. 2010

Onimaru, Manabu / Ohuchida, Kenoki / Mizumoto, Kazuhiro / Nagai, Eishi / Cui, Lin / Toma, Hiroki / Takayama, Koichi / Matsumoto, Kunio / Hashizume, Makoto / Tanaka, Masao. ·Department of Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Cancer Sci · Pubmed #20059477.

ABSTRACT: Adenovirus-mediated gene therapy shows promise for cancer therapy, but transgene expression of replication-defective adenovirus may be low and transient in clinical settings. Recent reports have shown that the use of a conditionally replication-competent adenovirus (CRAd) enhanced the gene transduction of a replication-defective adenovirus vector. The control of tumor-stromal interactions has also been determined to be important in cancer therapy. In this study, we investigated the effect of the human telomerase reverse transcriptase (hTERT)-CRAd, Ad5/3hTERTE1, which possesses the tumor-specific hTERT promoter with the chimeric fiber 5/3, on the transgene expression and therapeutic efficacy of a replication-defective adenovirus vector expressing NK4 under the control of the CMV promoter, Ad-NK4. In addition, we established a new strategy to target both cancer cells and cancer-stromal interactions. Human pancreatic cancer cells were infected with Ad-NK4 and either Ad5/3hTERTE1 (CRAd-combination group) or Ad5/3hTERTLuc (control-combination group). In the CRAd-combination group, Ad-NK4-delivered transgene expression was increased, leading to an enhanced inhibitory effect on the invasion of cancer cells. In in vivo experiments, NK4 expression within tumors and its inhibitory effect on tumor growth, angiogenesis, and metastasis were enhanced in the CRAd-combination group. These results suggest that hTERT-CRAd enhances the transgene expression and therapeutic efficacies of Ad-NK4, possibly through the in-trans replication of Ad-NK4 induced by adenovirus E1 derived from co-infected hTERT-CRAd. This approach may be a promising combination therapy against advanced pancreatic cancer.