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Papers - KANAI Yae

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Molecular Approach to Uterine Leiomyosarcoma: LMP2-Deficient Mice as an Animal Model of Spontaneous Uterine Leiomyosarcoma.

Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kanai Y, Shiozawa T, Tonegawa S, Konishi I.

Sarcoma (Sarcoma) 2011 476498 2011

Accepted, ISSN 1357714X

Uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion
however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker which distinguishes malignant LMS from benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, in order to establish a treatment method. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40 by 14 months of age. We found LMP2 expression to be absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is a potential diagnostic-biomarker for uterine LMS, and may be targeted-molecule for a new therapeutic approach. Copyright © 2011 Takuma Hayashi et al.

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Use of quantitative shotgun proteomics to identify fibronectin 1 as a potential plasma biomarker for clear cell carcinoma of the kidney

Yokomizo, Akira, Takakura, Michiko, Kanai, Yae, Sakuma, Tomohiro, Matsubara, Junichi, Honda, Kazufumi, Naito, Seiji, Yamada, Tesshi, Ono, Masaya

CANCER BIOMARKERS (IOS PRESS) 10 ( 3-4 ) 175 - 183 2011

Research paper (scientific journal), ISSN 1574-0153

Background: Early detection would be one of the most effective means to improve the outcome of renal cell carcinoma (RCC). We searched for a new plasma marker for RCC using a label-free quantitative shotgun proteomics method.
Methods: Plasma proteins were digested by trypsin, and the resulting peptides were analyzed by 2-Dimensional Image Converted Analysis of Liquid chromatography mass spectrometry (2DICAL). An identified biomarker candidate was subjected to validation using the Amplified Luminescent Proximity Homogeneous Assay (AlphaLISA).
Results: Among a total of 23,407 independent MS peaks, we found that the mean intensity of 59 peaks significantly differed between 20 clear cell RCC patients and 20 healthy controls. MS/MS spectra from 16 of the 59 peaks matched the amino acid sequences of the fibronectin 1 (FN1) gene product. The increased plasma level of FN1 in RCC patients was validated in a cohort of in 77 patients and 130 healthy controls (p < 0.0001).
Conclusions: The FN1 is considered to be a promising biomarker candidate for clear cell RCC. Furthermore, AlphaLISA is an alternate to the conventional enzyme-linked immunosorbent assay and should prove useful for the rapid validation of biomarker candidates.

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ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion.

Yagi R, Tanaka M, Sasaki K, Kamata R, Nakanishi Y, Kanai Y, Sakai R.

Oncogene (NATURE PUBLISHING GROUP) 30 ( 12 ) 1413 - 1421 2011

Accepted, ISSN 09509232

During the analysis of phosphotyrosine-containing proteins in scirrhous gastric carcinoma cell lines, we observed an unusual expression of Arf-GAP with Rho-GAP domain, ankyrin repeat and PH domain 3 (ARAP3), a multimodular signaling protein that is a substrate of Src family kinases. Unlike other phosphotyrosine proteins, such as CUB domain-containing protein 1 (CDCP1) and Homo sapiens chromosome 9 open reading frame 10/oxidative stress-associated Src activator (C9orf10/Ossa), which are overexpressed and hyperphosphorylated in scirrhous gastric carcinoma cell lines, ARAP3 was underexpressed in cancerous human gastric tissues. In this study, we found that overexpression of ARAP3 in the scirrhous gastric carcinoma cell lines significantly reduced peritoneal dissemination. In vitro studies also showed that ARAP3 regulated cell attachment to the extracellular matrix, as well as invasive activities. These effects were suppressed by mutations in the Rho-GTPase-activating protein (GAP) domain or in the C-terminal two tyrosine residues that are phosphorylated by Src. Thus, the expression and phosphorylation state of ARAP3 may affect the invasiveness of cancer by modulating cell adhesion and motility. Our results suggest that ARAP3 is a unique Src substrate that suppresses peritoneal dissemination of scirrhous gastric carcinoma cells. Oncogene (2011) 30, 1413-1421; doi:10.1038/onc.2010.522; published online 15 November 2010

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Genetic and epigenetic alterations during renal carcinogenesis

Arai, Eri, Kanai, Yae

INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY (E-CENTURY PUBLISHING CORP) 4 ( 1 ) 58 - 73 2011

Research paper (scientific journal), ISSN 1936-2625

Renal cell carcinoma (RCC) is not a single entity, but comprises a group of tumors including clear cell RCC, papillary RCC and chromophobe RCC, which arise from the epithelium of renal tubules. The majority of clear cell RCCs, the major histological subtype, have genetic or epigenetic inactivation of the von Hippel-Lindau (VHL) gene. Germline mutations in the MET and fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC. Genome-wide copy number alteration analysis has suggested that loss of chromosome 3p and gain of chromosomes 5q and 7 may be copy number aberrations indispensable for the development of clear cell RCC. When chromosome 1p, 4, 9, 13q or 14q is also lost, more clinicopathologically aggressive clear cell RCC may develop. Since renal carcinogenesis is associated with neither chronic inflammation nor persistent viral infection, and hardly any histological change is evident in corresponding non-tumorous renal tissue from patients with renal tumors, precancerous conditions in the kidney have been rarely described. However, regional DNA hypermethylation on C-type CpG islands has already accumulated in such non-cancerous renal tissues, suggesting that, from the viewpoint of altered DNA methylation, the presence of precancerous conditions can be recognized even in the kidney. Genome-wide DNA methylation profiles in precancerous conditions are basically inherited by the corresponding clear cell RCCs developing in individual patients: DNA methylation alterations at the precancerous stage may further predispose renal tissue to epigenetic and genetic alterations, generate more malignant cancers, and even determine patient outcome. The list of tumor-related genes silenced by DNA hypermethylation has recently been increasing. Genetic and epigenetic profiling provides an optimal means of prognostication for patients with RCCs. Recently developed high-throughput technologies for genetic and epigenetic analyses will further accelerate the identification of key molecules for use in the prevention, diagnosis and therapy of RCCs.

Diagnosis and Prognostication of Ductal Adenocarcinomas of the Pancreas Based on Genome-Wide DNA Methylation Profiling by Bacterial Artificial Chromosome Array-Based Methylated CpG Island Amplification

Gotoh, Masahiro, Arai, Eri, Wakai-Ushijima, Saori, Hiraoka, Nobuyoshi, Kosuge, Tomoo, Hosoda, Fumie, Shibata, Tatsuhiro, Kondo, Tadashi, Yokoi, Sana, Imoto, Issei, Inazawa, Johji, Kanai, Yae

JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY (HINDAWI PUBLISHING CORPORATION) 2011 780836 2011

Research paper (scientific journal), ISSN 1110-7243

To establish diagnostic criteria for ductal adenocarcinomas of the pancreas (PCs), bacterial artificial chromosome (BAC) array-based methylated CpG island amplification was performed using 139 tissue samples. Twelve BAC clones, for which DNA methylation status was able to discriminate cancerous tissue (T) from noncancerous pancreatic tissue in the learning cohort with a specificity of 100%, were identified. Using criteria that combined the 12 BAC clones, T-samples were diagnosed as cancers with 100% sensitivity and specificity in both the learning and validation cohorts. DNA methylation status on 11 of the BAC clones, which was able to discriminate patients showing early relapse from those with no relapse in the learning cohort with 100% specificity, was correlated with the recurrence-free and overall survival rates in the validation cohort and was an independent prognostic factor by multivariate analysis. Genome-wide DNA methylation profiling may provide optimal diagnostic markers and prognostic indicators for patients with PCs.

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Serous cystic neoplasm in an intrapancreatic accessory spleen (vol 60, 681, 2010)

Hori, Shutaro, Nara, Satoshi, Shimada, Kazuaki, Ojima, Hidenori, Kanai, Yae, Hiraoka, Nobuyoshi

PATHOLOGY INTERNATIONAL (WILEY-BLACKWELL PUBLISHING, INC) 60 ( 12 ) 798 - 798 2010.12

Research paper (scientific journal), ISSN 1320-5463

Association of CYP19A1 polymorphisms with risks for atypical adenomatous hyperplasia and bronchioloalveolar carcinoma in the lungs

Kohno, Takashi, Kakinuma, Ryutaro, Iwasaki, Motoki, Yamaji, Taiki, Kunitoh, Hideo, Suzuki, Kenji, Shimada, Yoko, Shiraishi, Kouya, Kasuga, Yoshio, Hamada, Gerson Shigeaki, Furuta, Koh, Tsuta, Koji, Sakamoto, Hiromi, Kuchiba, Aya, Yamamoto, Seiichiro, Kanai, Yae, Tsugane, Shoichiro, Yokota, Jun

CARCINOGENESIS (OXFORD UNIV PRESS) 31 ( 10 ) 1794 - 1799 2010.10

Research paper (scientific journal), ISSN 0143-3334

Estrogen has been indicated to play an etiological role in the development of lung adenocarcinoma (ADC), particularly bronchioloalveolar carcinoma (BAC), a type of ADC that develops from a benign adenomatous lesion, atypical adenomatous hyperplasia (AAH). Polymorphisms in the CYP19A1 gene cause interindividual differences in estrogen levels. Here, 13 CYP19A1 single-nucleotide polymorphisms (SNPs) were examined for associations with lung AAH risk. AAH is detected as ground-glass opacity (GGO) by computed tomography (CT) examination, and this study consisted of 100 individuals diagnosed with GGO in their lungs among 3088 CT-based cancer screening examinees and 424 without. Minor allele carriers for the rs3764221 SNP showed an elevated risk for GGO [odds ratio (OR) = 1.72, P = 0.017]. Associations of this SNP with risks for lung AAH and BAC in the lungs were next examined using 359 ADC cases whose resected lung lobes were subjected to a histological examination for AAH accompaniment and the presence of BAC components and 330 controls without cancer. The ORs were also increased for lung ADC accompanied by AAH (OR = 1.74, P = 0.029) as well as lung ADC with BAC components (OR = 1.41, P = 0.091). The minor allele was associated with an increased circulating estradiol level (P = 0.079) in a population of 363 postmenopausal women without cancer. These results indicate that CYP19A1 polymorphisms are involved in the risk for lung AAH and BAC in the lungs by causing differences in estrogen levels.

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Serous cystic neoplasm in an intrapancreatic accessory spleen

Shutaro Hori, Satoshi Nara, Kazuaki Shimada, Hidenori Ojima, Yae Kanai, Nobuyoshi Hiraoka

PATHOLOGY INTERNATIONAL (WILEY-BLACKWELL) 60 ( 10 ) 681 - 684 2010.10

Accepted, ISSN 13205463

Serous cystic neoplasm (SCN) of the pancreas is a benign epithelial neoplasm, except in extremely rare malignant cases. Development of SCN in tissues other than the pancreas has been never reported. Here we present the first reported case of SCN in an intrapancreatic accessory spleen (IPAS). A 54-year-old female patient with von Hippel-Lindau (VHL) syndrome was found to have pancreatic tail mass. Pathologically the 25-mm solid mass was an IPAS showing proliferation of clear cuboidal tumor cells without atypia, forming numerous small cysts. The tumor cells were rich in cytoplasmic glycogen and distributed in the splenic tissue almost diffusely. Immunohistochemically, tumor cells were positive for cytokeratins, MUC6, and neuron-specific enolase, and negative for neuroendocrine markers. From these findings, we diagnosed the lesion as SCN in IPAS. This tumor is suggested to develop as a VHL-associated SCN from coexisting pancreatic tissue in IPAS rather than as a metastatic tumor.

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Solitary hepatic lymphangioma: Report of a case

Matsumoto, Takuya, Ojima, Hidenori, Akishima-Fukasawa, Yuri, Hiraoka, Nobuyoshi, Onaya, Hiroaki, Shimada, Kazuaki, Mizuguchi, Yasunori, Sakurai, Shintaro, Ishii, Toshiharu, Kosuge, Tomoo, Kanai, Yae

SURGERY TODAY (SPRINGER) 40 ( 9 ) 883 - 889 2010.09

Research paper (scientific journal), ISSN 0941-1291

A 52-year-old woman presented with upper abdominal pain. Abdominal ultrasonography showed a 4-cm well-defined mass containing solid and cystic components in segment IV of the liver, and contrast-enhanced T1-weighted magnetic resonance imaging revealed heterogeneous enhancement within the tumor, indicating a solid or fibrous component. There were no cystic lesions in any other organs. A partial hepatectomy was performed, based on a preoperative diagnosis of sclerosing hemangioma and biliary cystadenoma or cystadenocarcinoma. Pathologically, the tumor appeared to be a multilocular and cystic lesion lined by attenuated endothelial- like cells with no atypia. Immunohistochemistry demonstrated the endothelial-like cells to be positive for the lymphatic-specific markers D2-40, LYVE-1, and Prox-1, which proved helpful for confirming the diagnosis as solitary hepatic lymphangioma. This case is presented with details of the pathologic and radiologic findings, because solitary hepatic lymphangioma is an extremely rare tumor and no previous reports have provided details of the immunohistochemical characteristics.

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Mice-lacking LMP2, immuno-proteasome subunit, as an animal model of spontaneous uterine leiomyosarcoma

Hayashi, Takuma, Horiuchi, Akiko, Sano, Kenji, Hiraoka, Nobuyoshi, Kanai, Yae, Shiozawa, Tanri, Tonegawa, Susumu, Konishi, Ikuo

PROTEIN & CELL (HIGHER EDUCATION PRESS) 1 ( 8 ) 711 - 717 2010.08

Research paper (scientific journal), ISSN 1674-800X

Uterine tumors are the most common type of gynecologic neoplasm. Uterine leiomyosarcoma (LMS) is rare, accounting for 2% to 5% of tumors of the uterine body. Uterine LMS develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Radiographic evaluation combined with PET/CT can be useless in the diagnosis and surveillance of uterine LMS. Importantly, a diagnostic biomarker, which distinguishes malignant LMS and benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS in order to establish a method of treatment. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of similar to 40% by 14 months of age. It is therefore of interest whether human uterine LMS shows a loss of LMP2 expression. We found LMP2 expression is absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is potentially a diagnostic biomarker for uterine LMS, and gene therapy with LMP2-encording DNA may be a new therapeutic approach.

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Significance of PGP9.5 Expression in Cancer-Associated Fibroblasts for Prognosis of Colorectal Carcinoma

Akishima-Fukasawa, Yuri, Ino, Yoshinori, Nakanishi, Yukihiro, Miura, Ayaka, Moriya, Yoshihiro, Kondo, Tadashi, Kanai, Yae, Hirohashi, Setsuo

AMERICAN JOURNAL OF CLINICAL PATHOLOGY (AMER SOC CLINICAL PATHOLOGY) 134 ( 1 ) 71 - 79 2010.07

Research paper (scientific journal), ISSN 0002-9173

To assess the expression of a cancer-associated fibroblasts (CAFs) marker as an indicator of prognosis, we raised anti protein gene product 9.5 (PGP9.5) monoclonal antibody against cultured fibroblasts. PGP9.5 expression in cultured normal fibroblasts was increased by transforming growth factor 13 stimulation, indicating the phenotypic alteration to activated fibroblast. We immunohistochemically evaluated PGP9.5 expression with the CAFs of 110 colorectal cancer cases under T3 stage. PGP9.5 immunoreactivity in 30% or more of CAFs was defined as high PGP9.5 expression, and the other cases were considered as having low PGP9.5 expression.
Patients with high PGP9.5 expression (42.7%) had significantly shorter survival and a higher incidence of recurrence than the low PGP9.5 expression group (P=.002 and P < .001, respectively). Multivariate analysis indicated PGP9.5 expression as an independent prognostic factor for overall and recurrence-free survival partly as well as lymph node metastasis. These results indicate that PGP9.5 expression in CAFs is a helpful finding to represent the overall biologic behavior of advanced colorectal cancer.

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Metaplastic carcinoma of the breast

Okada, Nao, Hasebe, Takahiro, Iwasaki, Motoki, Tamura, Nobuko, Akashi-Tanaka, Sadako, Hojo, Takashi, Shibata, Tatsuhiro, Sasajima, Yuko, Kanai, Yae, Kinoshita, Takayuki

HUMAN PATHOLOGY (W B SAUNDERS CO-ELSEVIER INC) 41 ( 7 ) 960 - 970 2010.07

Research paper (scientific journal), ISSN 0046-8177

The purposes of this study were to investigate whether the biological characteristics or outcomes of patients with metaplastic carcinoma, invasive ductal carcinoma, or invasive lobular carcinoma of the breast differ; to determine whether the metaplastic carcinoma subtypes have similar malignant potentials; and to identify accurate predictors of outcome in patients with metaplastic carcinoma. The subject comprised 6137 invasive ductal carcinoma patients, 301 invasive lobular carcinoma patients, and 46 metaplastic carcinoma patients of the breast. The metaplastic carcinomas were classified according to the World Health Organization classification. Multivariate analyses clearly demonstrated that the metaplastic carcinoma patients had a significantly poorer outcome than the invasive ductal carcinoma patients or the invasive lobular carcinoma patients independent of the nodal status or age not exceeding 39 years, whereas patients with triple-negative metaplastic carcinomas or triple-negative invasive lobular carcinomas had a poorer outcome than those with triple-negative invasive ductal carcinomas. Although no significant differences in clinical outcome were observed among the metaplastic carcinoma subtypes in multivariate analyses, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant outcome predictors for metaplastic carcinoma patients. In conclusion, the results of this study clearly demonstrated that metaplastic carcinoma is more aggressive than invasive ductal carcinoma or invasive lobular carcinoma. Although the metaplastic carcinoma subtypes had no prognostic significance, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant predictors of outcome among metaplastic carcinoma patients. (C) 2010 Elsevier Inc. All rights reserved.

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Pancreatic Ducts as an Important Route of Tumor Extension for Acinar Cell Carcinoma of the Pancreas

Ban, Daisuke, Shimada, Kazuaki, Sekine, Shigeki, Sakamoto, Yoshihiro, Kosuge, Tomoo, Kanai, Yae, Hiraoka, Nobuyoshi

AMERICAN JOURNAL OF SURGICAL PATHOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 34 ( 7 ) 1025 - 1036 2010.07

Research paper (scientific journal), ISSN 0147-5185

Acinar cell carcinoma (ACC) of the pancreas is very rare, which usually grows expansively. Recently, a variant of ACC with predominant growth in the pancreatic ducts has been proposed, and is speculated to have potentially less aggressive behavior. The aim of this study was to investigate how the pancreatic duct system is related to the growth and extension of ACC. We reviewed the detailed gross and histologic features of 13 cases of ACC, of which 7 (54%) showed intraductal polypoid growth (IPG) of the tumor in the large pancreatic ducts with a mean IPG length of 24.8 mm. Tumors with IPG were found to spread characteristically along the pancreatic ducts as extending polypoid projections, filling the ducts and destroying the duct walls, although tumors did not tend to extend beyond the pancreatic parenchyma. Comparison of the clinicopathologic characteristics showed that ACC with IPG had less infiltrative features including lymphatic, venous, and neural invasion, formation of tumor thrombus in the portal vein, nodal metastasis, and invasion beyond the pancreas to the surrounding organs; death in only 1 case (14%) of ACC with IPG was the result of ACC itself. In contrast, ACC without IPG frequently showed more infiltrative growth, and was the cause of death in 50% of patients with this type of tumor. Intraductal dissemination of ACC in pancreatic ducts was proven in 1 case of ACC with IPG. These findings suggest that a significant proportion of ACC shows IPG, which is potentially linked to less aggressive clinicopathologic characteristics.

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DNA methylation profiles in precancerous tissue and cancers: carcinogenetic risk estimation and prognostication based on DNA methylation status

Arai, Eri, Kanai, Yae

EPIGENOMICS (FUTURE MEDICINE LTD) 2 ( 3 ) 467 - 481 2010.06

Research paper (scientific journal), ISSN 1750-1911

Alterations in DNA methylation, which are associated with DNA methyltransferase abnormalities and result in silencing of tumor-related genes and chromosomal instability, are involved even in precancerous changes in various organs. DNA methylation alterations also account for the histological heterogeneity and clinicopathological diversity of human cancers. Therefore, we have analyzed DNA methylation on a genome-wide scale in clinical tissue samples. Our approach using the bacterial artificial chromosome array-based methylated CpG island amplification method has revealed that DNA methylation alterations correlated with the future development of more malignant cancers are already accumulated at the precancerous stage in the kidney, liver and urinary tract. DNA methylation profiles at precancerous stages are basically inherited by the corresponding cancers developing in individual patients. Such DNA methylation alterations may confer vulnerability to further genetic and epigenetic alterations, generate more malignant cancers, and thus determine patient outcome. On the basis of bacterial artificial chromosome array-based methylated CpG island amplification data, indicators for carcinogenetic risk estimation have been established using liver tissue specimens from patients with hepatitis virus infection, chronic hepatitis and liver cirrhosis or histologically normal urothelia, and for prognostication using biopsy or surgically resected specimens from patients with renal cell carcinoma, hepatocellular carcinoma and urothelial carcinoma. Such genome-wide DNA methylation profiling has now firmly established the clinical relevance of translational epigenetics.

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CUB Domain-Containing Protein 1, a Prognostic Factor for Human Pancreatic Cancers, Promotes Cell Migration and Extracellular Matrix Degradation

Miyazawa, Yuri, Uekita, Takamasa, Hiraoka, Nobuyoshi, Fujii, Satoko, Kosuge, Tomoo, Kanai, Yae, Nojima, Yoshihisa, Sakai, Ryuichi

CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 70 ( 12 ) 5136 - 5146 2010.06

Research paper (scientific journal), ISSN 0008-5472

CUB domain-containing protein 1 (CDCP1) is a membrane protein that is highly expressed in several solid cancers. We reported previously that CDCP1 regulates anoikis resistance as well as cancer cell migration and invasion, although the underlying mechanisms have not been elucidated. In this study, we found that expression of CDCP1 in pancreatic cancer tissue was significantly correlated with overall survival and that CDCP1 expression in pancreatic cancer cell lines was relatively high among solid tumor cell lines. Reduction of CDCP1 expression in these cells suppressed extracellular matrix (ECM) degradation by inhibiting matrix metalloproteinase-9 secretion. Using the Y734F mutant of CDCP1, which lacks the tyrosine phosphorylation site, we showed that CDCP1 regulates cell migration, invasion, and ECM degradation in a tyrosine phosphorylation-dependent manner and that these CDCP1-associated characteristics were inhibited by blocking the association of CDCP1 and protein kinase C delta (PKC delta). CDCP1 modulates the enzymatic activity of PKC delta through the tyrosine phosphorylation of PKC delta by recruiting PKC delta to Src family kinases. Cortactin, which was detected as a CDCP1-dependent binding partner of PKC delta, played a significant role in migration and invasion but not in ECM degradation of pancreatic cells. These results suggest that CDCP1 expression might play a crucial role in poor outcome of pancreatic cancer through promotion of invasion and metastasis and that molecules blocking the expression, phosphorylation, or the PKC delta-binding site of CDCP1 are potential therapeutic candidates. Cancer Res; 70(12); 5136-46. (C) 2010 AACR.

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Combined Functional Genome Survey of Therapeutic Targets for Hepatocellular Carcinoma

Satow, Reiko, Shitashige, Miki, Kanai, Yae, Takeshita, Fumitaka, Ojima, Hidenori, Jigami, Takafumi, Honda, Kazufumi, Kosuge, Tomoo, Ochiya, Takahiro, Hirohashi, Setsuo, Yamada, Tesshi

CLINICAL CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 16 ( 9 ) 2518 - 2528 2010.05

Research paper (scientific journal), ISSN 1078-0432

Purpose: The outcome of patients with advanced hepatocellular carcinoma (HCC) has remained unsatisfactory. Patients with HCC suffer from chronic hepatitis or liver cirrhosis, and their reserve liver function is often limited.
Experimental Design: To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we searched for genes that were upregulated in 20 cases of HCC [namely, discovery sets 1 (n = 10) and 2 (n = 10)] in comparison with corresponding nontumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome.
Results: Eleven transcripts whose expression was significantly increased in HCC were subjected to siRNA-based secondary screening of genes required for HCC cell proliferation as well as quantitative reverse transcription-PCR analysis [validation sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted four genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice.
Conclusions: The four genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Although many important genes must have been overlooked, the selected genes were biologically relevant. The combination of genome-wide expression and functional screening described here is a rapid and comprehensive approach that could be applied in the identification of therapeutic targets in any type of human malignancy. Clin Cancer Res; 16(9); 2518-28. (C) 2010 AACR.

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Establishment of six new human biliary tract carcinoma cell lines and identification of MAGEH1 as a candidate biomarker for predicting the efficacy of gemcitabine treatment

Ojima, Hidenori, Yoshikawa, Daitaro, Ino, Yoshihiro, Shimizu, Hiroko, Miyamoto, Masashi, Kokubu, Akiko, Hiraoka, Nobuyoshi, Morofuji, Noriaki, Kondo, Tadashi, Onaya, Hiroaki, Okusaka, Takuji, Shimada, Kazuaki, Sakamoto, Yoshihiro, Esaki, Minoru, Nara, Satoshi, Kosuge, Tomoo, Hirohashi, Setsuo, Kanai, Yae, Shibata, Tatsuhiro

CANCER SCIENCE (WILEY-BLACKWELL PUBLISHING, INC) 101 ( 4 ) 882 - 888 2010.04

Research paper (scientific journal), ISSN 1347-9032

The aim of this study was to establish new biliary tract carcinoma (BTC) cell lines and identify predictive biomarkers for the potential effectiveness of gemcitabine therapy. Surgical specimens of BTC were transplanted directly into immunodeficient mice to establish xenografts, then subjected to in vitro cell culture. The gemcitabine sensitivity of each cell line was determined and compared with the genome-wide gene expression profile. A new predictive biomarker candidate was validated using an additional cohort of gemcitabine-treated BTC cases. From 55 BTC cases, we established 19 xenografts and six new cell lines. Based on their gemcitabine sensitivity, 10 BTC cell lines (including six new and four publicly available ones) were clearly categorized into two groups, and MAGEH1 mRNA expression in the tumor cells showed a significant negative correlation with their sensitivity to gemcitabine. Immunohistochemically, MAGEH1 protein was detected in three (50%) out of six sensitive cell lines, and four (100%) out of four resistant cell lines. In the validation cohort of gemcitabine-treated recurrence cases, patients were categorized into "effective'' and "non-effective'' groups according to the RECIST guidelines for assessment of chemotherapeutic effects. MAGEH1 protein expression was detected in two (40%) out of five "effective'' cases and all four (100%) "non-effective'' cases. We have established a new BTC bioresource that covers a wide range of biological features, including drug sensitivity, and is linked with clinical information. Negative expression of MAGEH1 protein serves as a potential predictive marker for the effectiveness of gemcitabine therapy in BTC. (Cancer Sci 2010; 101: 882-888)

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Intraductal carcinosarcoma with a heterologous mesenchymal component originating in intraductal papillary-mucinous carcinoma (IPMC) of the pancreas with both carcinoma and osteosarcoma cells arising from IPMC cells

Okamura, Jun, Sekine, Shigeki, Nara, Satoshi, Ojima, Hidenori, Shimada, Kazuaki, Kanai, Yae, Hiraoka, Nobuyoshi

JOURNAL OF CLINICAL PATHOLOGY (B M J PUBLISHING GROUP) 63 ( 3 ) 266 - 269 2010.03

Research paper (scientific journal), ISSN 0021-9746

Carcinosarcoma of the pancreas is extremely rare and its histogenesis is still unclear. This is a report on a 64-year-old female patient with an intraductal carcinosarcoma arising from intraductal papillary-mucinous carcinoma (IPMC) in the pancreas tail. The carcinosarcoma grew as a polypoid mass within the main pancreatic duct. Histologically, the tumour consisted of adenocarcinoma covering the luminal surface of the lesion with minimal stromal invasion, and osteosarcoma occupying the stroma. Immunohistochemical and gene mutation analyses revealed that both the carcinomatous and sarcomatous tumour cells of the carcinosarcoma, as well as the IPMC cells, expressed TP53 and had identical mutations in KRAS and TP53 genes, indicating that these two neoplastic components of the carcinosarcoma shared a common tumorigenesis and arose from the IPMC. This is the first report of a carcinosarcoma originating in IPMC. These findings imply that carcinosarcoma with a heterologous mesenchymal component is of ductal origin.

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Long-term Recurrence-free Survival in a Patient with Primary Hepatic Carcinosarcoma: Case Report with a Literature Review

Yamamoto, Yusuke, Ojima, Hidenori, Shimada, Kazuaki, Onaya, Hiroaki, Hiraoka, Nobuyoshi, Mizuguchi, Yasunori, Kosuge, Tomoo, Kanai, Yae

JAPANESE JOURNAL OF CLINICAL ONCOLOGY (OXFORD UNIV PRESS) 40 ( 2 ) 166 - 173 2010.02

Research paper (scientific journal), ISSN 0368-2811

A 72-year-old man was found to have a 40 mm mass in liver segment VIII during follow-up abdominal ultrasonography for type C viral hepatitis. Abdominal ultrasound showed a well-defined mass containing a cystic component, and computed tomographic hepatic arteriography showed heterogeneous enhancement except for cystic necrosis. Under a pre-operative diagnosis of atypical hepatocellular carcinoma (HCC), partial resection of liver segment VIII was performed. The encapsulated tumor consisted of a peripheral solid component with a central necrotic area. Histologically, the solid component had a two-layer structure, an HCC component in the external area and a sarcomatous component with neoplastic osteoid formation in the internal area, showing histological transition. Immunohistochemically, the HCC component was positive for hepatocyte antigen and negative for vimentin. The Ki-67 labeling index was found to increase from 5% to 58% with increasing histologic atypia. The sarcomatous component was positive for vimentin and negative for pan-keratin and hepatocyte antigen, with a Ki-67 labeling index of > 90%. These findings led to a diagnosis of primary hepatic carcinosarcoma. Although previously reported patients with hepatic carcinosarcoma showed early metastasis with a very poor outcome, this patient has remained free of recurrence for 30 months, which is the longest recurrence-free survival time recorded for this type of cancer. Since relatively early-stage hepatic carcinosarcoma rarely seems to present as a small tumor showing a concentric growth pattern, we report this case with a review of the literature.

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前立腺がん神経温存手術の適応選択に3T MRI拡散強調画像を用いた術前局在診断はどの程度有用か?

原智彦, 三宅基隆, 中西弘之, 河原貴史, 熊谷伸, 堀淳一, 新井恵吏, 金井弥栄, 鶴崎正勝, 込山元清, 中川徹, 藤元博行

日本泌尿器科学会雑誌 ((一社)日本泌尿器科学会) 101 ( 2 ) 290 - 290 2010.02

ISSN 0021-5287

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