Details of a Researcher - Sakamoto, Michiie

Papers - Sakamoto, Michiie

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Effectiveness of color correction on the quantitative analysis of histopathological images acquired by different whole-slide scanners

Aziz M., Nakamura T., Yamaguchi M., Kiyuna T., Yamashita Y., Abe T., Hashiguchi A., Sakamoto M.

Artificial Life and Robotics (Artificial Life and Robotics) 24 ( 1 ) 28 - 37 2019.03

ISSN 14335298

© 2018, ISAROB. Advances in whole-slide scanning have led to research on digital pathology, including monitor-based diagnosis, feature quantification, and computer-aided diagnosis. The color variations due to the staining process and scanning device are a serious issue that should be solved in whole-slide imaging applications, and methods for color correction have been studied. Nevertheless, the effectiveness of color-correction methods in the quantitative analysis of histopathological images acquired by different whole-slide scanners (WSSs) has not been confirmed. In this work, several liver tissue samples were scanned by different WSSs, and a color-correction method for whole-slide images was applied to the digitized tissue specimens. A set of histological features were extracted from the histopathological images, both without and with color correction, to analyze the effectiveness of the color-correction method in feature quantification and cancer identification.

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Accuracy of non-invasive scoring systems for diagnosing non-alcoholic steatohepatitis-related fibrosis: Multicenter validation study

Itoh Y., Seko Y., Shima T., Nakajima T., Mizuno K., Kawamura Y., Akuta N., Ito K., Kawanaka M., Hiramatsu A., Sakamoto M., Harada K., Goto Y., Nakayama T., Kumada H., Okanoue T.

Hepatology Research (Hepatology Research) 48 ( 13 ) 1099 - 1107 2018.12

ISSN 13866346

© 2018 The Japan Society of Hepatology Aim: Hepatic fibrosis is the most important factor for estimating the prognosis of patients with non-alcoholic fatty liver disease (NAFLD). A novel non-invasive scoring system, the FM-fibro index, showed high accuracy in a pilot study. The purpose of this study was to validate the efficacy of the FM-fibro index in a multicenter cohort. Methods: Among 18 institutions, we analyzed 400 Japanese patients with biopsy-proven NAFLD. We evaluated the accuracies of the FM-fibro index, CA-fibro index, and European Liver Fibrosis (ELF) panel by area under the receiver operator characteristics curves (AUROC). The FM-fibro index includes three formulas for type IV collagen 7S, hyaluronic acid, and vascular cell adhesion molecule-1. Results: Among 400 patients, 205 were women, and the median age was 56 years. The histological distribution of Matteoni types 1, 2, 3, and 4 was 11, 40, 15, and 334, and the distribution of hepatic fibrosis stages 0 to 4 was 67, 183, 55, 63, and 32, respectively. The AUROCs of the FM-fibro index, CA-fibro index, and ELF panel for non-alcoholic steatohepatitis (NASH)-related fibrosis were 0.7178/0.7095/0.7065, 0.7093, and 0.7245, respectively. The sensitivity and specificity of the FM-fibro index for predicting NASH-related fibrosis was 0.5359/0.5210/0.4641 and 0.8333/0.8182/0.8788, respectively. The accuracy of the FM-fibro index was not significantly different from that of the CA-fibro index or the ELF panel. Conclusions: The FM-fibro index can predict NASH-related fibrosis with sufficient accuracy compared with previous scoring systems. Further analyses that verify the accuracy of the FM-fibro index to distinguish significant or advanced fibrosis in patients with NAFLD are awaited. (UMIN-CTR: UMIN000018158).

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CD26 is a potential therapeutic target by humanized monoclonal antibody for the treatment of multiple myeloma

Nishida H., Hayashi M., Morimoto C., Sakamoto M., Yamada T.

Blood Cancer Journal (Blood Cancer Journal) 8 ( 11 ) 2018.11

© 2018, The Author(s). CD26, a 110-kDa transmembrane glycoprotein that is expressed on several tumor cells including malignant lymphoma, has been implicated in tumorigenesis: however, little is known regarding its role in multiple myeloma (MM). Recently, we identified CD26 expression on human osteoclasts (OCs) and demonstrated that humanized IgG1 monoclonal antibody targeting CD26, huCD26mAb, inhibits human OC differentiation. Herein, we show that CD26 expression was present on plasma cells in the bone marrow tissues of MM patients. In vitro immunostaining studies revealed that although CD26 expression was low or absent on MM cell lines cultured alone, it was intensely and uniformly expressed on MM cell lines co-cultured with OCs. The augmented CD26 expression in MM cells was exploited to enhance anti-MM efficacy of huCD26mAb via a substantial increase in antibody-dependent cytotoxicity (ADCC) but not complement-dependent cytotoxicity (CDC). Moreover, huCD26mAb in combination with novel agents synergistically enhanced huCD26mAb induced ADCC activity against CD26+ MM cells compared with each agent alone. huCD26mAb additionally reduced the ratio of the side population (SP) fraction in CD26+ MM cells by ADCC. Finally, huCD26mAb significantly reduced the MM tumor burden and OC formation in vivo. These results suggest that CD26 is a potential target molecule in MM and that huCD26mAb could act as a therapeutic agent.

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Evaluation of pancreatic fibrosis with acoustic radiation force impulse imaging and automated quantification of pancreatic tissue components

Fujita Y., Kitago M., Abe T., Itano O., Shinoda M., Abe Y., Yagi H., Hibi T., Ishii M., Nakano Y., Okuma K., Hashimoto M., Takeuchi A., Masugi Y., Jinzaki M., Sakamoto M., Kitagawa Y.

Pancreas (Pancreas) 47 ( 10 ) 1277 - 1282 2018.11

ISSN 08853177

© 2018 Wolters Kluwer Health, Inc. All rights reserved. Objectives The aim of this study was to determine whether computer-assisted digital analysis and acoustic radiation force impulse (ARFI) imaging were useful for assessing pancreatic fibrosis, and if ARFI imaging predicted postoperative pancreatic fistula (POPF). Methods Seventy-eight patients scheduled to undergo pancreatic resection were enrolled. Shear wave velocity (SWV) at the pancreatic neck was measured preoperatively using ARFI imaging. Pancreatic tissue components on a whole slide image were quantified using an automatic image processing software. The relationship between SWV, fibrotic tissue content, and POPF incidence and clinical severity was analyzed. Results The median collagen fiber, fatty tissue, and acinar cell contents were 11.6%, 8.5%, and 61.3%, respectively. Unlike fatty tissue, collagen fiber content and acinar cells were correlated with SWV (ρ = 0.440, P < 0.001 and ρ =-0.428, P < 0.001, respectively). Although collagen fiber content and SWV were associated with the overall incidence of POPF (P = 0.004 and 0.001, respectively), collagen fiber content and SWV had no statistical correlation with clinically relevant POPF (P = 0.268 and 0.052, respectively). Conclusions We objectively quantified the pancreatic tissue components using an automatic image processing software. Shear wave velocity was significantly related to collagen fiber content and suggests that ARFI imaging can be useful for evaluating pancreatic fibrosis.

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Immunohistochemical visualization of the signature of activated Hedgehog signaling pathway in cutaneous epithelial tumors

Tanese K., Emoto K., Kubota N., Fukuma M., Sakamoto M.

Journal of Dermatology (Journal of Dermatology) 45 ( 10 ) 1181 - 1186 2018.10

ISSN 03852407

© 2018 Japanese Dermatological Association Activation of the Hedgehog (HH) signaling pathway plays a critical role in the development of basal cell carcinoma (BCC). HH signaling activity is produced by nuclear translocation of transcription factors, glioma-associated oncogene homolog (GLI). Among three GLI subfamilies, GLI1 is the only full-length transcriptional activator, and its nuclear localization is recognized as a signature event in HH signaling activation. However, limited published work has investigated the nuclear staining of GLI1 protein in human tumor tissue samples by immunohistochemical analysis. In this study, we performed immunohistochemical staining of GLI1 in 382 cases of cutaneous epithelial tumors, including 196 BCC cases, using rabbit monoclonal antihuman GLI1 antibody (C68H3). As a result, 98.2% cases of BCC showed a diffuse and strong nuclear staining pattern regardless of the histological subtype. Positive staining was mainly restricted to the tumor nests, while the overlying epidermis was negative suggesting specificity of the antibody. In further analysis of other cutaneous epithelial tumors, 100% (4/4) cases of trichoblastoma, 15.1% (5/33) Bowen's disease, 3.5% (1/28) actinic keratosis and 12.5% (4/32) squamous cell carcinoma showed the nuclear staining pattern of GLI1. This suggested that HH signaling is also dysregulated in some other cutaneous malignant tumors. In conclusion, the C68H3 antibody is a useful tool for revealing activation of HH signaling in immunohistochemical analysis.

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Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification

Kurebayashi Y., Ojima H., Tsujikawa H., Kubota N., Maehara J., Abe Y., Kitago M., Shinoda M., Kitagawa Y., Sakamoto M.

Hepatology (Hepatology) 68 ( 3 ) 1025 - 1041 2018.09

ISSN 02709139

© 2018 by the American Association for the Study of Liver Diseases. Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19) + , and/or Sal-like protein 4 (SALL4) + high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC. Conclusion: The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018).

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cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation

Brunt E., Aishima S., Clavien P., Fowler K., Goodman Z., Gores G., Gouw A., Kagen A., Klimstra D., Komuta M., Kondo F., Miksad R., Nakano M., Nakanuma Y., Ng I., Paradis V., Nyun Park Y., Quaglia A., Roncalli M., Roskams T., Sakamoto M., Saxena R., Sempoux C., Sirlin C., Stueck A., Thung S., Tsui W., Wang X., Wee A., Yano H., Yeh M., Zen Y., Zucman-Rossi J., Theise N.

Hepatology (Hepatology) 68 ( 1 ) 113 - 126 2018.07

ISSN 02709139

© 2018 by the American Association for the Study of Liver Diseases. Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as “combined (or mixed) hepatocellular-cholangiocarcinoma.” These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. Conclusion: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).

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Novel method for DNA methylation analysis using high-performance liquid chromatography and its clinical application

Yotani T., Yamada Y., Arai E., Tian Y., Gotoh M., Komiyama M., Fujimoto H., Sakamoto M., Kanai Y.

Cancer Science (Cancer Science) 109 ( 5 ) 1690 - 1700 2018.05

ISSN 13479032

© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The aim of this study was to develop a new methodology that is suitable for DNA methylation diagnostics and to demonstrate its clinical applicability. We developed a new anion-exchange column for high-performance liquid chromatography (HPLC) with electrostatic and hydrophobic properties. Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions. The DNA methylation levels of synthetic DNA were quantified accurately and reproducibly within 10 minutes without time-consuming pretreatment of PCR products, and the measured values were unaffected by the distribution of methylated CpG within the synthetic DNA fragments. When the DNA methylation status of the FAM150A gene, a marker of the CpG island methylator phenotype specific to clear cell renal cell carcinoma (ccRCC), was examined in 98 patients with ccRCC, bulk specimens of tumorous tissue including cancer cells showing DNA methylation of the FAM150A gene were easily identifiable by simply viewing the differentiated chromatograms, even when the cancer cell content was low. Sixteen ccRCC showing DNA methylation more frequently exhibited clinicopathological parameters reflecting tumor aggressiveness (ie, a larger diameter, higher histological grade, vascular involvement, renal vein tumor thrombi, infiltrating growth, tumor necrosis, renal pelvis invasion and higher pathological TNM stage), and had significantly lower recurrence-free and overall survival rates. These data indicate that HPLC analysis using this newly developed anion-exchange column could be a powerful tool for DNA methylation diagnostics, including prognostication of patients with cancers, in a clinical setting.

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Concurrent presentation of an intraductal tubulopapillary neoplasm and intraductal papillary mucinous neoplasm in the branch duct of the pancreas, with a superior mesenteric artery aneurysm: A case report

Inomata K., Kitago M., Obara H., Fujii-Nishimura Y., Shinoda M., Yagi H., Abe Y., Hibi T., Matsubara K., Oshima G., Sekimoto Y., Inoue M., Itano O., Sakamoto M., Kitagawa Y.

World Journal of Surgical Oncology (World Journal of Surgical Oncology) 16 ( 1 ) 2018.04

© 2018 The Author(s). Background: Since the concept of intraductal tubulopapillary neoplasm (ITPN) was introduced in the current World Health Organization classification of tumors, the number of reports of ITPN occurrence has increased gradually. However, ITPN is usually located in the main pancreatic duct, with few reports of a branch duct ITPN. As a result, imaging protocols for the diagnosis of a branch duct ITPN have not been established. Case presentation: We report a case of a concurrent presentation of a branch duct ITPN and intraductal papillary mucinous neoplasm (IPMN) in the head of the pancreas, with a superior mesenteric artery (SMA) aneurysm. Initially, the cystic masses in the pancreatic head were diagnosed as branch duct IPMNs, with treatment consisting of a pylorus-preserving pancreaticoduodenectomy, in combination with an aneurysmectomy performed for treatment of the SMA aneurysm. Pathological examination confirmed these cysts were a combination of branch-type ITPN and IPMN. The patient recovered from the treatment without complication, with no evidence of recurrence over a period of 34 months post-surgery. Conclusion: This case report of a synchronous presentation of an ITPN and IPMN indicates the difficulty in differentiating these two types of neoplasms in the branch duct of the pancreatic head.

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Mesenchymal–epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells

Fujii-Nishimura Y., Yamazaki K., Masugi Y., Douguchi J., Kurebayashi Y., Kubota N., Ojima H., Kitago M., Shinoda M., Hashiguchi A., Sakamoto M.

Pathology International (Pathology International) 68 ( 4 ) 214 - 223 2018.04

ISSN 13205463

© 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd Epithelial–mesenchymal transition (EMT) promotes invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the importance of its reverse process, mesenchymal–epithelial transition (MET), for PDAC remains unclear. We aimed to characterize the histological finding “focal differentiation” in PDAC at perineural invasion sites in the context of MET and to investigate the role of Schwann cells in inducing tumor MET. Tumor differentiation and immunohistochemical expressions of E-cadherin, SMAD3, and vimentin at perineural invasion sites were examined in 168 PDAC tissues. Four PDAC cell lines were co-cultured with Schwann cells to investigate cell morphology, motility, or EMT-related markers using immunocytochemistry and quantitative PCR. Of 168 tumors, 124 (74%) showed focal differentiation with enhanced E-cadherin membrane expression (P < 0.001) and decreased nuclear accumulation of SMAD3 (P < 0.001). Among 115 PDACs harboring grade 1/2 tumor, tumors with focal differentiation showed worse survival compared to those without focal differentiation (P = 0.019). PDAC cells co-cultured with Schwann cells demonstrated a sheet-like appearance, increased E-cadherin expression, decreased expressions of SMAD3 and vimentin, and reduced cell motility. In conclusion, MET-like change is induced by Schwann cells, suggesting that Schwann cells contribute to PDAC colonization in pancreatic nerves through activating the MET machinery inside tumor cells in the pancreatic tumor microenvironment.

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Impact of resection and ablation for single hypovascular hepatocellular carcinoma ≤2 cm analysed with propensity score weighting

Takayasu K., Arii S., Sakamoto M., Matsuyama Y., Kudo M., Kaneko S., Nakashima O., Kadoya M., Izumi N., Takayama T., Ku Y., Kumada T., Kubo S., Kokudo T., Hagiwara Y., Kokudo N.

Liver International (Liver International) 38 ( 3 ) 484 - 493 2018.03

ISSN 14783223

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Background and Aims: Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated. Methods: The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child-Pugh A/B, single hypovascular HCC ≤2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence-free survivals were compared in original and a propensity score weighted pseudo-population with 732 patients. Results: The median follow-up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo-population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36-0.86) and RFA (HR, 0.75; 95% CI, 0.57-1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence-free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non-SR. No treatment-related death occurred. Conclusions: For patients with single hypovascular HCC ≤2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA.

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Overexpression of adenylate cyclase-associated protein 2 is a novel prognostic marker in malignant melanoma

Masugi, Y., Tanese, K., Emoto, K., Yamazaki, K., Effendi, K., Funakoshi, T., Mori, M. and Sakamoto, M.

Pathol Int 2015.09

ISSN 1440-1827

Malignant melanoma is one of the lethal malignant tumors worldwide. Previously we reported that adenylate cyclase-associated protein 2 (CAP2), which is a well-conserved actin regulator, was overexpressed in hepatocellular carcinoma; however, CAP2 expression in other clinical cancers remains unclear. The aim of the current study was to clarify the clinicopathological significance of CAP2 overexpression in malignant melanoma. Immunohistochemical analyses revealed that many melanoma cells exhibited diffuse cytoplasmic expression of CAP2, whereas no normal melanocytes showed detectable immunostaining for CAP2. A high level of CAP2 expression was seen in 14 of 50 melanomas and was significantly correlated with greater tumor thickness and nodular melanoma subtypes. In addition, a high level of CAP2 expression was associated with poor overall survival in univariate and multivariate analyses. For 13 patients, samples of primary and metastatic melanoma tissue were available: four patients exhibited higher levels of CAP2 expression in metastatic tumor compared to the primary site, whereas no patient showed lower levels of CAP2 expression in metastatic melanomas. Our findings show that CAP2 overexpression is a novel prognostic marker in malignant melanoma and that CAP2 expression seems to increase stepwise during tumor progression, suggesting the involvement of CAP2 in the aggressive behavior of malignant melanoma.

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Classification of three-generation models on magnetized orbifolds

Abe, T., Fujimoto, Y., Kobayashi, T., Miura, T., Nishiwaki, K., Sakamoto, M. and Tatsuta, Y.

Nuclear Physics B 894 374 - 406 2015.05

ISSN 0550-3213

We classify the combinations of parameters which lead three generations of quarks and leptons in the framework of magnetized twisted orbifolds on T-2/Z(2), T-2/Z(3), T-2/Z(4) and T-2/Z(6) with allowing nonzero discretized Wilson line phases and Scherk-Schwarz phases. We also analyze two actual examples with nonzero phases leading to one-pair Higgs and five-pair Higgses and discuss the difference from the results without nonzero phases studied previously. (Note: this article is registered under preprint number: arXiv:1501.02787 [hep-ph].) (C) 2015 The Authors. Published by Elsevier B.V.

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Upregulation of integrin beta 4 promotes epithelial-mesenchymal transition and is a novel prognostic marker in pancreatic ductal adenocarcinoma

Masugi, Y., Yamazaki, K., Emoto, K., Effendi, K., Tsujikawa, H., Kitago, M., Itano, O., Kitagawa, Y. and Sakamoto, M.

Laboratory Investigation 95 ( 3 ) 308 - 319 2015.03

ISSN 0023-6837

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and often lethal malignant tumor. Several studies have shown that epithelial-mesenchymal transition (EMT) is frequently observed in clinical samples of PDA and is related to high metastatic rates and poor outcomes. To identify candidate molecules regulating EMT in PDA, we previously used cDNA microarray analysis and identified integrin beta 4 (ITGB4) as one of the genes upregulated in high-EMT xenografts derived from PDA patients. The aim of the current study was to clarify the clinicopathological and functional significance of ITGB4 overexpression in PDA. ITGB4 upregulation in high-EMT xenografts was confirmed by immunohistochemistry. Immunohistochemical analyses of 134 surgically resected PDA cases revealed intratumoral heterogeneity with respect to ITGB4 expression and showed that cancer cells undergoing EMT often display strong diffuse ITGB4 expression. High levels of ITGB4 expression were significantly correlated with the hallmarks of EMT (solitary cell infiltration, reduced E-cadherin expression, and increased vimentin expression), with high tumor grade, and with the presence of lymph node metastasis, and showed an independent prognostic effect. Immunocytochemical analyses of PDA cell lines revealed that localization of ITGB4 changed from regions of cell-cell contact to diffuse cytoplasm and cell edges with occasional localization in filopodia during EMT. Knockdown of ITGB4 reduced the migratory and invasive ability of PDA cells. Overexpression of ITGB4 promoted cell scattering and cell motility in combination with downregulation of E-cadherin and upregulation of vimentin expression. In conclusion, we elucidated the prognostic and clinicopathological significance of ITGB4 overexpression in PDA and also the potential role for ITGB4 in the regulation of cancer invasion and EMT.

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OATP1B3 expression is strongly associated with Wnt/beta-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma

Ueno, A., Masugi, Y., Yamazaki, K., Komuta, M., Effendi, K., Tanami, Y., Tsujikawa, H., Tanimoto, A., Okuda, S., Itano, O., Kitagawa, Y., Kuribayashi, S. and Sakamoto, M.

Journal of Hepatology 61 ( 5 ) 1080 - 1087 2014.11

ISSN 0168-8278

Background & Aims: In the current era of emerging molecular targeted drugs, it is necessary to identify before treatment the specific subclass to which a tumour belongs. Gadoxetic acid is a liver-specific contrast agent that is preferentially taken up by hepatocytes. Therefore, gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) should provide precise molecular information about hepatocellular carcinomas (HCCs). The aim of this study was to investigate the transporters of gadoxetic acid in HCC comprehensively and to analyse the molecular regulatory mechanism of such transporters.

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Quantification of collagen and elastic fibers using whole-slide images of liver biopsy specimens

Abe, T., Hashiguchi, A., Yamazaki, K., Ebinuma, H., Saito, H., Kumada, H., Izumi, N., Masaki, N. and Sakamoto, M.

Pathology International 63 ( 6 ) 305 - 310 2013.06

ISSN 1320-5463

Histological evaluation of fibrosis after a liver biopsy is crucial for evaluating the pathology of patients with chronic liver disease. Previous studies have reported quantitative analyses of fibrosis using images of collagen-stained sections. However, analysis of these studies requires manual selection of the region of interest. In addition, the quantification of elastic fibers is not considered. The present study was conducted in order to measure both the collagen and elastic fiber area ratios using Elastica van Gieson-stained whole-slide images (WSIs) of liver biopsy specimens. High-resolution WSIs provide precise color classification, enabling accurate detection of even fine collagen and elastic fibers. To minimize the influence of pre-existing fibrous tissue, median area ratios of the collagen and elastic fibers were independently calculated from the image tiles of the WSIs. These median area ratios were highly concordant with area ratios after the pre-existing fibrous tissues were manually trimmed from the WSI. Further, these median area ratios were correlated with liver stiffness as measured by transient elastography (collagen: r=0.73 [P<0.01], elastic: r=0.53 [P<0.01]). Our approach to quantifying liver fibrosis will serve as an effective tool to evaluate liver diseases in routine practice.

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Leucine-rich repeat-containing G protein-coupled receptor 5 regulates epithelial cell phenotype and survival of hepatocellular carcinoma cells

Fukuma, M., Tanese, K., Effendi, K., Yamazaki, K., Masugi, Y., Suda, M. and Sakamoto, M.

Experimental Cell Research 319 ( 3 ) 113 - 121 2013.02

ISSN 0014-4827

The leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), also known as GPR49, is a seven-transmembrane receptor that is expressed in stem cells of the intestinal crypts and hair follicles of mice. LGR5 is overexpressed in some types of human cancer, and is one of the target genes of the Wnt signaling pathway. To explore the function of LGR5 in cancer cells, stable hepatocellular carcinoma (HCC) cell lines expressing FLAG-tagged LGR5 were established. Overexpression of LGR5 resulted in changes in cell shape from an extended flat (mesenchymal) phenotype to a round aggregated (stem cell-like) phenotype. Cells transfected with LGR5 showed higher colony forming activity, and were more resistant to a cytotoxic drug than cells transfected with empty vector. Overexpression of LGR5 inhibited cell motility. LGR5-transfected cells formed nodule type tumors in the livers of immunodeficient mice, whereas empty vector-transfected cells formed more invasive tumors. Down-regulation of LGR5 changed the morphology of HCC cells from the aggregated phenotype to an extended spindle phenotype, and cell motility was increased. This is the first study reporting the functional role of LGR5 in the biology of HCC cells, and the results suggest that aberrant expression of LGR5 regulates epithelial cell phenotype and survival. (c) 2012 Elsevier Inc. All rights reserved.

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A serum "sweet-doughnut" protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis

Kuno, A., Ikehara, Y., Tanaka, Y., Ito, K., Matsuda, A., Sekiya, S., Hige, S., Sakamoto, M., Kage, M., Mizokami, M. and Narimatsu, H.

Scientific Reports 3 2013.01

ISSN 2045-2322

Although liver fibrosis reflects disease severity in chronic hepatitis patients, there has been no simple and accurate system to evaluate the therapeutic effect based on fibrosis. We developed a glycan-based immunoassay, FastLec-Hepa, to fill this unmet need. FastLec-Hepa automatically detects unique fibrosis-related glyco-alteration in serum hyperglycosylated Mac-2 binding protein within 20 min. The serum FastLec-Hepa counts increased with advancing fibrosis and illustrated significant differences in medians between all fibrosis stages. FastLec-Hepa is sufficiently sensitive and quantitative to evaluate the effects of PEG-interferon-alpha/ribavirin therapy in a short post-therapeutic interval. The obtained fibrosis progression is equivalent to -0.30 stages/year in patients with sustained virological response, and 0.01 stages/year in relapse/nonresponders. Furthermore, long-term follow-up of the severely affected patients found hepatocellular carcinoma developed in patients after therapy whose FastLec-Hepa counts remained above a designated cutoff value. FastLec-Hepa is the only assay currently available for clinically beneficial therapy evaluation through quantitation of disease severity.

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Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression

Effendi, K., Yamazaki, K., Mori, T., Masugi, Y., Makino, S. and Sakamoto, M.

Experimental Cell Research 319 ( 1 ) 35 - 44 2013.01

ISSN 0014-4827

Cyclase-associated protein 2 (CAP2) is a conserved protein that is found up-regulated in hepatocellular carcinoma (HCC). By using zebrafish, combined with HCC cell lines, we further investigated the role of CAP2. The zebrafish CAP2 sequence was 60% identical to human CAP2 with 77% homology in the C-terminal actin-binding domain, and 58% in the N-terminal cyclase-binding domain. CAP2 expression was observed during zebrafish development and was preferentially expressed in the skeletal muscle and heart. Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema. CAP2 was observed co-localized with actin in zebrafish skeletal muscle, and in the leading edge of lamellipodium in HCC cell lines. CAP2 silencing resulted in a defect in lamellipodium formation and decreased cell motility in HCC cell lines. Strongly positive expression of CAP2 was observed in 10 of 16 (63%) poorly, 30 of 68 (44%) moderately, and 2 of 21 (10%) well differentiated HCC. CAP2 expression was significantly associated with tumor size, poor differentiation, portal vein invasion, and intrahepatic metastasis. Our results indicate that an important conserved function of CAP2 in higher vertebrates may be associated with the process of skeletal muscle development. CAP2 also played an important role in enhancing cell motility, which may promote a more invasive behavior in the progression of HCC. These findings highlight the link between development and cancer. (C) 2012 Elsevier Inc. All rights reserved.

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Investigation of proNT/NMN secretion from small cell lung carcinoma cells using a mouse xenograft model

K. Wakabayashi-Nakao, K. Maruyama, H. Ishii, K. Muramatsu, K. Hatakeyama, K. Ohshima, S. Ogura, T. Nakajima, K. Yamaguchi and T. Mochizuki

Oncol Rep 28 ( 4 ) 1181 - 6 2012.10

ISSN 1791-2431

Proneurotensin/neuromedin N (proNT/NMN), the precursor of neurotensin (NT) and neuromedin N (NMN), is produced by cancer tissues derived from the pancreas and colon. NT stimulates tumor growth and proliferation through its receptors; however, little is known about the precursor molecule in cancer tissues. We previously demonstrated that proNT/NMN is secreted from small cell lung carcinoma (SCLC) cell lines in serum-free conditioned medium, but not from non-small cell lung carcinoma (NSCLC) cell lines. It was suggested that this precursor may serve as a tumor marker for SCLC. In this study, we established in vivo xenograft models to evaluate the possibility of proNT/NMN as a specific tumor marker. SBC3 cells, derived from human SCLC, were inoculated into mice, and the proNT/NMN levels in plasma and tumor tissues were detected using specific antibodies. In contrast to control mouse plasma, the proNT/NMN levels in tumor-bearing mice increased as the tumors grew, and the elevated plasma proNT/NMN levels were decreased by tumor resection. Moreover, proNT/NMN was expressed in SBC3 tumors, suggesting that proNT/NMN was secreted into blood from the tumor, and this secretion may be specific to SCLC.

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