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Papers - KANAI Yae

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肝癌バイオマーカー候補因子microRNA-500の同定と解析(Identification of a novel liver cancer biomarker candidate, miR-500, designated as an oncofetal microRNA)

小坂展慶, 山本雄介, 宮島篤, 小泉史明, 水谷隆之, 金井弥栄, 落谷孝広

日本癌学会総会記事 (日本癌学会) 67回 413 - 413 2008.09

Accepted, ISSN 0546-0476

Molecular mechanisms of uterine leiomyosarcomas: involvement of defect in LMP2 expression.

Hayashi T, Shimamura Y, Saegusa T, Horiuchi A, Kobayashi Y, Hiraoka N, Kanai Y, Aburatani H, Sano K, Konishi I

Gene regulation and systems biology (Gene Regulation and Systems Biology) 2008 ( 2 ) 297 - 305 2008.07

Accepted

Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass. Typical presentations with hypercalcemia or eosinophilia have been reported. Radiographic evaluation with combined positron emission tomography/computed tomography may assist in the diagnosis and surveillance of women with uterine LMS. A recently developed risk-assessment index is highly predictive of disease-specific survival. Ovarian preservation does not appear to negatively impact outcome, and the addition of adjuvant therapy after surgical treatment does not seem to improve survival. It is noteworthy that LMP2-deficient mice exhibit spontaneous development of uterine LMS with a disease prevalence of approximately 37% by 12 months of age. The LMP2 gene is transcribed from a promoter containing an interferon (IFN)-gamma-response factor element; thus, the IFN-gamma-signal strongly induces LMP2 expression. Furthermore, a recent report demonstrated the loss of ability to induce LMP2 expression, which is an interferon (IFN)-gamma-inducible factor, in human uterine LMS tissues and cell lines. Analysis of human uterine LMS shows somatic mutations in the IFN gamma signalling pathway, thus the loss of LMP2 induction is attributable to a defect in the earliest steps of the IFN-gamma signalling pathway. The discovery of an impaired key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

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Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer

Kikuchi, Ryoko, Tsuda, Hitoshi, Kozaki, Ken-ichi, Kanai, Yae, Kasamatsu, Takahiro, Sengoku, Kazuo, Hirohashi, Setsuo, Inazawa, Johji, Imoto, Issei

CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 68 ( 13 ) 5067 - 5075 2008.07

Research paper (scientific journal), ISSN 0008-5472

Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family, the members of which are implicated in various biological processes, although its receptor remains unknown. We identified a homozygous loss of ANGPTL2 (9q33.3) in the course of screening a panel of ovarian cancer (OC) cell lines for genomic copy-number aberrations using in-house array-based comparative genomic hybridization. ANGPTL2 mRNA expression was observed in normal ovarian tissue and immortalized normal ovarian epithelial cells, but was reduced in some OC lines without its homozygous deletion (18 of 23 lines) and restored after treatment with 5-aza 2'-deoxycytidine. The methylation status of sequences around the ANGPTL2 CpG-island with clear promoter activity inversely correlated with expression. ANGPTL2 methylation was frequently observed in primary OC tissues as well. In an immunohistochemical analysis of primary OCs, ANGPTL2 expression was frequently reduced (51 of 100 cases), and inversely correlated with methylation status. Patients with OC showing reduced ANGPTL2 immunoreactivity had significantly worse survival in the earlier stages (stages I and II), but better survival in advanced stages (stages III and IV). The restoration of ANGPTL2 expression or treatment with conditioned medium containing ANGPTL2 inhibited the growth of OC cells originally lacking the expression of this gene, whereas the knockdown of endogenous ANGPTL2 accelerated the growth of OC cells with the expression of ANGPTL2. These results suggest that, at least partly, epigenetic silencing by hypermethylation of the ANGPTL2 promoter leads to a loss of ANGPTL2 function, which may be a factor in the carcinogenesis of OC in a stage-dependent manner.

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CUB-domain-containing protein 1 regulates peritoneal dissemination of gastric scirrhous carcinoma

Uekita, Takamasa, Tanaka, Masamitsu, Takigahira, Misato, Miyazawa, Yuri, Nakanishi, Yukihiro, Kanai, Yae, Yanagihara, Kazuyoshi, Sakai, Ryuichi

AMERICAN JOURNAL OF PATHOLOGY (AMER SOC INVESTIGATIVE PATHOLOGY, INC) 172 ( 6 ) 1729 - 1739 2008.06

Research paper (scientific journal), ISSN 0002-9440

CUB-domain-containing protein 1 (CDCP1) is a type-I transmembrane protein that is highly expressed in colon, breast, and lung cancers. We recently revealed that CDCP1 is associated with and phosphorylated by Src family kinases and is involved in the regulation of anchorage independence of certain lung cancer cell lines. in this study, we examined whether CDCP1 is involved in the regulation of tumor progression of scirrhous gastric cancer, which is a diffusely infiltrative carcinoma with high invasion potential. Expression and phosphorylation levels of CDCP1 correlated with the invasive potential of scirrhous; gastric cancers. Reduction of CDCP1 expression by siRNA suppressed migration, invasion, and anchorage independence without affecting the proliferation of highly invasive scirrhous gastric cancer cells. However, CDCP1 overexpression promoted gastric cancer cell migration with low potential of invasion. Loss of CDCP1 suppressed invasion and dissemination of cancer cells that were orthotopically implanted in the gastric wall of nude mice. Expression and phosphorylation of CDCP1 were also detected in cancer cells of surgically resected tissues of human scirrhous gastric cancer by immunohistochemical analysis. Our results suggest that CDCP1 promotes invasion and peritoneal dissemination of cancer cells through the regulation of cell migration and anchorage independence. Therefore, it is both a potential prognostic and therapeutic target in certain types of gastrointestinal cancers, and suppression of its phosphorylation might be a useful strategy for modulating cancer metastasis.

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Overexpression of HDACs: a prognostic marker for gastric cancer identified by tissue microarray

Kanai, Yae

LANCET ONCOLOGY 9 ( 2 ) 91 - 93 2008.02

Research paper (scientific journal), ISSN 1470-2045

Minimally invasive intraductal papillary-mucinous carcinoma of the pancreas: Clinicopathologic study of 104 intraductal papillary-mucinous neoplasms

Nara, Satoshi, Shimada, Kazuaki, Kosuge, Tonioo, Kanai, Yae, Hiraoka, Nobuyoshi

AMERICAN JOURNAL OF SURGICAL PATHOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 32 ( 2 ) 243 - 255 2008.02

Research paper (scientific journal), ISSN 0147-5185

Invasive intraductal papillary-mucinous carcinoma (I-IPMC) is a heterogeneous entity with various postoperative outcomes. The aim of this study is to characterize early-stage I-IPMC with nonaggressive characteristics. One hundred and four patients with intraductal papillary-mucinous neoplasm (IPMN) were clinicopathologically investigated. The lesions were classified into 53 noninvasive IPMNs (adenoma, borderline, and,noninvasive IPMC) and 51 I-IPMCs on the basis of the WHO classification. I-IPMCs were divided further into 26 minimally invasive IPMCs (MI-IPMCs) and 25 invasive carcinomas originating in IPMC (IC-IPMCs) by new diagnostic criteria proposed in this study. We examined invasiveness of I-IPMC on 4 patterns, and defined simple and practical diagnostic criteria of minimal invasion for each invasive pattern. The disease-specific survival rates after 3, 5, and 10 years were 100%, 100%, and 100% for both noninvasive IPMN and MI-IPMC, and 51%, 38%, and 0% for IC-IPMC. The overall and disease-specific survival rates for MI-IPMC were both significantly better than those for IC-IPMC (P < 0.001), but there was no significant difference between noninvasive IPMN and MI-IPMC. Multivariate analysis showed that the factors indicative of poor prognosis were a diagnosis of I-IPMC classified as IC-IPMC and a high level of serum carbohydrate antigen 19-9. The prognosis of IC-IPMC was not significantly different from that of pancreatic ductal carcinoma in each of the corresponding tumor-node-metastasis stages. These findings suggest that a category of MI-IPMC provides more accurate and useful information of the stage and the aggressiveness of I-IPMC.

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A new formula for predicting liver metastasis in patients with colorectal cancer: Immunohistochemical analysis of a large series of 439 surgically resected cases

Ochiai, Hiroki, Nakanishi, Yukihiro, Fukasawa, Yuri, Sato, Yasunori, Yoshimura, Kimio, Moriya, Yoshihiro, Kanai, Yae, Watanabe, Masahiko, Hasegawa, Hirotoshi, Kitagawa, Yuko, Kitajima, Masaki, Hirohashi, Setsuo

ONCOLOGY (KARGER) 75 ( 1-2 ) 32 - 41 2008

Research paper (scientific journal), ISSN 0030-2414

Objective: The purpose of this study was to establish a new formula predicting liver metastasis in patients with colorectal cancer (CRC). Methods: Nine previously reported predictive markers for liver metastasis and/or prognosis (COX-2, dysadherin, E-cadherin, beta-catenin, Ki-67, p53, laminin5 gamma 2, matrilysin and MUC-1) were immunohistochemically investigated in 439 consecutive patients with CRC. We tried to determine the combination of molecules which best predicted liver metastasis. A formula for predicting liver metastasis was constructed using a training cohort comprising 150 cases, and applied to a validation cohort comprising 190 cases and another comprising 99 cases from an outside hospital. Results: A combination of dysadherin, E-cadherin and matrilysin was identified to be best for predicting liver metastasis (area under the curve value, 0.807). The predictive formula: 3 x dysadherin score [0 for low expression (<= 50% of tumor cells positive) or 1 for high expression (> 50%)] + 4 x E-cadherin score [0 for preserved (> 80% of tumor cells positive) or 1 for reduced (<= 80%)] + 2 x matrilysin score [0 for low expression (<= 30% of tumor cells positive) or 1 for high expression (> 30%)] was able to discriminate patients with liver metastasis in the training cohort with a sensitivity of 85.7% and a specificity of 58.9%. The discriminative capacity of the formula was validated in the first cohort with a sensitivity of 87.0% and a specificity of 66.5%, and in the second cohort with a sensitivity of 80% and a specificity of 60.0%. Conclusions: We have established a formula for predicting liver metastasis in patients with CRC, and confirmed that it has a high sensitivity potentially useful for clinical application. Copyright (C) 2008 S. Karger AG, Basel.

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A Novel Diagnostic Biomaker, LMP2, for Human Uterine Leiomyosarcoma

Hayashi, Takuma, Kobayashi, Yukihiro, Horiuchi, Akiko, Hiraoka, Nobuyoshi, Kanai, Yae, Konishi, Ikuo, Sano, Kenji

TUMOR BIOLOGY (KARGER) 29 47 - 47 2008

Research paper (scientific journal), ISSN 1010-4283

Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state

Kanai, Yae, Hirohashi, Setsuo

CARCINOGENESIS (OXFORD UNIV PRESS) 28 ( 12 ) 2434 - 2442 2007.12

Research paper (scientific journal), ISSN 0143-3334

Alterations of DNA methylation are one of the most consistent epigenetic changes in human cancers. Human cancers generally show global DNA hypomethylation accompanied by region-specific hypermethylation. Alterations of DNA methylation may result in chromosomal instability as a result of changes in chromatin structure. DNA hypermethylation of CpG islands silences various tumor-related genes. Alterations of DNA methylation are frequently observed in cancers associated with chronic inflammation and/or persistent infection with viruses or other pathogenic microorganisms, such as hepatitis B or C viruses, Epstein-Barr virus, human papillomavirus and Helicobacter pylori, or with cigarette smoking. Accumulating evidence suggests that alterations of DNA methylation are involved even in the early and precancerous stages. On the other hand, in patients with cancers, aberrant DNA methylation is significantly associated with poorer tumor differentiation, tumor aggressiveness and poor prognosis. Precancerous conditions showing alterations of DNA methylation may progress rapidly and generate more malignant cancers. DNA methyltransferase (DNMT) 1 over-expression is not a secondary result of increased cell proliferative activity but is significantly correlated with the CpG island methylator phenotype, which is defined as frequent DNA hypermethylation of C-type CpG islands that are usually methylated in a cancer-specific (not age-dependent) manner. Splicing alteration of DNMT3b may result in chromosomal instability through DNA hypomethylation of pericentromeric satellite regions. Alteration of DNA methylation may become an indicator for carcinogenetic risk estimation and early diagnosis of cancers and a biological predictor of poor prognosis in patients with cancers. Correction of DNA methylation status may offer a new strategy for prevention and therapy of cancers.

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Molecular markers and changes of computed tomography appearance in lung adenocarcinoma with ground-glass opacity

Yoshida, Yukihiro, Kokubu, Akiko, Suzuki, Kenji, Kuribayashi, Hidehiko, Tsuta, Koji, Matsuno, Yoshihiro, Kusumoto, Masahiko, Kanai, Yae, Asamura, Hisao, Hirohashi, Setsuo, Shibata, Tatsuhiro

JAPANESE JOURNAL OF CLINICAL ONCOLOGY (OXFORD UNIV PRESS) 37 ( 12 ) 907 - 912 2007.12

Research paper (scientific journal), ISSN 0368-2811

Background: High-resolution computed tomography (HRCT) of lung adenocarcinoma at early stage shows pure ground-glass opacity (GGO) and most cases of pure GGO remain stable during follow-up. There is no consensus on the strategy for follow-up. Identification of the molecular mechanisms that are associated with the natural history of lung adenocarcinoma should provide useful information.
Methods: Twenty-three lung adenocarcinomas that were followed-up for more than 6 months pre-operatively by HRCT were included in this study. Patterns of radiological changes during the follow-up period were classified into three groups; type 1, pure GGO without consolidation; type 2, appearance or increase in consolidation within pure GGO; type 3, consolidation without pure GGO. Mutational analysis of the epidermal growth factor receptor (EGFR) and K-ras genes and immunohistochemical staining of p53 protein were performed.
Results: EGFR mutations were found in 17 cases (74%), and there was no K-ras mutation. Positive staining of p53 was found in 8 cases (35%). As for radiological findings during the follow-up period, the frequencies of EGFR mutations and positive p53 staining were 67 and 0% in type 1 (n = 9), 89 and 44% in type 2 (n = 9) and 60 and 80% in type 3 (n = 5).
Conclusions: EGFR mutations were frequently found in lung adenocarcinoma with GGO on HRCT in this study. Inactivation of p53 may be associated with the appearance of central consolidation within pure GGO on HRCT which reflects invasive features and may be useful as a molecular marker during the follow-up of pure GGO.

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Invasive biliary cystic tumor without ovarian-like stroma

Ishibashi, Yuji, Ojima, Hidenori, Hiraoka, Nobuyoshi, Sano, Tsuyoshi, Kosuge, Tomoo, Kanai, Yae

PATHOLOGY INTERNATIONAL (BLACKWELL PUBLISHING) 57 ( 12 ) 794 - 798 2007.12

Research paper (scientific journal), ISSN 1320-5463

Presented herein is a rare case of invasive biliary cystic tumor without an ovarian-like stroma, and the apparent sequence underlying its malignant transformation, which was identified on detailed histological examination. A 54-year-old woman was incidentally diagnosed as having a cystic tumor in segment VIII of the liver, and central biseg-mentectomy was performed. Macroscopically the tumor measured 4.6 x 3.5 cm; and unilocular cystic and solid areas were seen on cut surface. Microscopically the tumor showed three types of neoplasia: adenoma and tubulopapillary adenocarcinoma in the cystic area, and invasive adenocarcinoma in the solid area. The relative area of the tumor occupied by each of these histological types was approximately 3%, 50% and 47%, respectively. Moreover, transitional zones between adenoma and tubulopapillary adenocarcinoma, and between tubulopapillary adenocarcinoma and invasive adenocarcinoma were noted. The immunohistochemical expression of Ki-67 and p53 increased gradually from adenoma through to tubulopapillary adenocarcinoma, and was highest in invasive adenocarcinoma. MUC1 was positive, and MUC2 and MUC5AC were both negative. No ovarian-like stroma or communication with the bile ducts around the tumor was found in any area of the specimen. On the basis of the World Health Organization histological classification and these pathological findings, the present case was diagnosed as invasive-type biliary cystadenocarcinoma.

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Sensitive detection of FGFR3 mutations in bladder cancer and urine sediments by peptide nucleic acid-mediated real-time PCR clamping

Miyake, Makito, Sugano, Kokichi, Kawashima, Kiyotaka, Ichikawa, Hiroki, Hirabayashi, Kaoru, Kodama, Tetsuro, Fujimoto, Hiroyuki, Kakizoe, Tadao, Kanai, Yae, Fujimoto, Kiyohide, Hirao, Yoshihiko

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (ACADEMIC PRESS INC ELSEVIER SCIENCE) 362 ( 4 ) 865 - 871 2007.11

Research paper (scientific journal), ISSN 0006-291X

Somatic mutations of the fibroblast growth factor receptor 3 (FGFR3) gene were detected by peptide nucleic acid (PNA)-mediated real-time PCR clamping. Mutation was detected in negative control containing only wild-type DNA due to a misincorporation of dNTPs to PNA binding sites when the amount of template DNA was decreased to 1 ng. Thus, the amount of template DNA was critical determinant of the assay sensitivity in PNA-mediated PCR clamping. Assay conditions were optimized to detect FGFR3 mutations in exons 7, 10, and 15, at a concentration of more than 1% mutated DNA using 50 ng of genomic DNA as the template. Mutations were detected in 12 of 13 (92.3%) tumor tissues and 11 of 13 (84.6%) urine samples from patients with superficial bladder cancer, while no mutations were detected in tissues and/or urine samples from patients with muscle-invasive bladder cancer or chronic cystitis. (c) 2007 Elsevier Inc. All rights reserved.

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Promoter hypermethylation contributes to frequent inactivation of a putative conditional tumor suppressor gene connective tissue growth factor in ovarian cancer

Kikuchi, Ryoko, Tsuda, Hitoshi, Kanai, Yae, Kasamatsu, Takahiro, Sengoku, Kazuo, Hirohashi, Setsuo, Inazawa, Johji, Imoto, Issei

CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 67 ( 15 ) 7095 - 7105 2007.08

Research paper (scientific journal), ISSN 0008-5472

Connective tissue growth factor (CTGF) is a secreted protein belonging to the CCN family, members of which are implicated in various biological processes. We identified a homozygous loss of CTGF (6q23.2) in the course of screening a panel of ovarian cancer cell lines for genomic copy number aberrations using in-house array-based comparative genomic hybridization. CTGF mRNA expression was observed in normal ovarian tissue and immortalized ovarian epithelial cells but was reduced in many ovarian cancer cell lines without its homozygous deletion (12 of 23 lines) and restored after treatment with 5-aza 2 '-deoxycytidine. The methylation status around the CTGF CpG island correlated inversely with the expression, and a putative target region for methylation showed promoter activity. CTGF methylation was frequently observed in primary ovarian cancer tissues (39 of 66, 59%) and inversely correlated with CTGF mRNA expression. In an immunohistochemical analysis of primary ovarian cancers, CTGF protein expression was frequently reduced (84 of 103 cases, 82%). Ovarian cancer tended to lack CTGF expression more frequently in the earlier stages (stages I and II) than the advanced stages (stages III and IV). CTGF protein was also differentially expressed among histologic subtypes. Exogenous restoration of CTGF expression or treatment with recombinant CTGF inhibited the growth of ovarian cancer cells lacking its expression, whereas knockdown of endogenous CTGF accelerated growth of ovarian cancer cells with expression of this gene. These results suggest that epigenetic silencing by hypermethylation of the CTGF promoter leads to a loss of CTGF function, which may be a factor in the carcinogenesis of ovarian cancer in a stage-dependent and/or histologic subtype-dependent manner.

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肝多段階発がん過程におけるFOXP3+制御性T細胞について(FOXP3+ Regulatory T Cells Affect the Development and Progression of Hepatocarcinogenesis)

小林規俊, 平岡伸介, 山上亘, 尾島英知, 金井弥栄, 小菅智男, 中島淳, 廣橋説雄

日本癌学会総会記事 ((一社)日本癌学会) 66回 42 - 42 2007.08

ISSN 0546-0476

Increased expression of DNA methyltransferase 1 (DNMT1) protein in uterine cervix squamous cell carcinoma and its precursor lesion

Sawada, Morio, Kanai, Yae, Arai, Eri, Ushijima, Saori, Ojima, Hidenori, Hirohashi, Setsuo

CANCER LETTERS (ELSEVIER IRELAND LTD) 251 ( 2 ) 211 - 219 2007.06

Research paper (scientific journal), ISSN 0304-3835

Aberrant DNA methylation has been shown to play important roles during multistage carcinogenesis in various human organs. The aim of this study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during cervical carcinogenesis. We carried out an immunohistochemical examination for DNMT1 in 34 samples of histologically normal squamous epithelium, 36 samples of low-grade cervical intraepithelial neoplasia (CIN), 61 samples of higher-grade CIN and 30 samples of squamous cell carcinoma of the uterine cervix. The DNMT1 protein expression score, reflecting the intensity and incidence of DNMT1 nuclear immunoreactivity, was increased even in low-grade CIN (P < 0.0001) in comparison with histologically normal squamous epithelium and was further increased in higher-grade CIN (P < 0.0001 compared to low-grade CIN). The DNMT1 protein expression score remained at a plateau in microinvasive carcinoma (Stage IA, P = 0.0690 compared to higher-grade CIN) and then decreased with cancer invasion (Stage IB or more, P = 0.0 176 compared to Stage IA), whereas the proliferating cell nuclear antigen (PCNA) labeling index did not decrease with cancer invasion (P = 0.8259 between Stage IA and Stage IB or more). Thus, the DNMT1 protein expression score and the PCNA labeling index were not mutually correlated in squamous cell carcinoma of the uterine cervix (P = 0.2304). These data suggest that progressively increasing expression of DNMT1 protein is not entirely a secondary result of increased cell proliferative activity, but is associated with an early step of multistage cervical carcinogenesis. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

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Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma: Identification of genetic indicators that predict patient outcome

Loukopoulos, Panayiotis, Shibata, Tatsuhiro, Katoh, Hiroto, Kokubu, Akiko, Sakamoto, Michiie, Yamazaki, Ken, Kosuge, Tomoo, Kanai, Yae, Hosoda, Fumie, Imoto, Issei, Ohki, Misao, Inazawa, Jyoji, Hirohashi, Setsuo

CANCER SCIENCE (BLACKWELL PUBLISHING) 98 ( 3 ) 392 - 400 2007.03

Research paper (scientific journal), ISSN 1347-9032

We analyzed the subchromosomal numerical aberrations of 44 surgically resected pancreatic adenocarcinomas by array-based comparative genomic hybridization. The aberration profile ranged widely between cases, suggesting the presence of multiple or complementary mechanisms of evolution in pancreatic cancer, and was associated with lymph node metastasis and venous or serosal invasion. A large number of small loci, previously uncharacterized in pancreatic cancer, showed non-random loss or gain. Frequent losses at 1p36, 4p16, 7q36, 9q34, 11p15, 11q13, 14q32-33, 16p13, 17p11-13, 17q11-25, 18q21-tel, 19p13, 21q22 and 22q11-12, and gains at 1q25, 2p16, 2q21-37, 3q25, 5p14, 5q11-13, 7q21, 7p22, 8p22, 8q21-23, 10q21, 12p13, 13q22, 15q13-22 and 18q11 were identified. Sixteen loci were amplified recurrently. We identified novel chromosomal alterations that were significantly associated with a range of malignant phenotypes. Gain of LUNX, HCK, E2F1 and DNMT3b at 20q11, loss of p73 at 1p36 and gain of PPM1D at 17q23 independently predicted patient outcome. Expression profiling of amplified genes identified Smurf1 and TRRAP at 7q22.1, BCAS1 at 20q13.2-3, and VCL at 10q22.1 as potential novel oncogenes. Our results contribute to a complete description of genomic structural aberrations and the identification of potential therapeutic targets and genetic indicators that predict patient outcome in pancreatic adenocarcinoma.

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FOXP3(+) regulatory T cells affect the development and progression of hepatocarcinogenesis

Kobayashi, Noritoshi, Hiraoka, Nobuyoshi, Yamagami, Wataru, Ojima, Hidenori, Kanai, Yae, Kosuge, Tomoo, Nakajima, Atsushi, Hirohashi, Setsuo

CLINICAL CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 13 ( 3 ) 902 - 911 2007.02

Research paper (scientific journal), ISSN 1078-0432

Purpose: Tumor-infiltrating lymphocytes represent the host immune response to cancer. CD4(+) CD25(+) FOXP3(+) regulatory T cells (Tregs) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Tregs and CD8(+) T cells during hepatocarcinogenesis.
Experimental Design: We examined the infiltration of FOXP3(+) Tregs and CD8(+) Tcells in the tumor stroma and nontumorous liver parenchyma using 323 hepatic nodules including precursor lesions, early hepatocellular carcinoma (HCC), and advanced HCC, along with 39 intrahepatic cholangiocarcinomas and 59 metastatic liver adenocarcinomas. We did immunohistochemical comparative studies.
Results: The prevalence of Tregs was significantly higher in HCC than in the nontumorous liver (P < 0.001). The patient group with a high prevalence of Tregs infiltrating HCC showed a significantly lower survival rate (P = 0.007). Multivariate analysis revealed that the prevalence of Tregs infiltrating HCC was an independent prognostic factor. The prevalence of Tregs increased in a stepwise manner (P < 0.001) and that of CD8(+) T cells decreased during the progression of hepatocarcinogenesis (P < 0.001). Regardless of the presence of hepatitis virus infection or histopathologic evidence of hepatitis, the prevalence of Tregs was significantly increased in nontumorous liver bearing primary hepatic tumors.
Conclusions: Tregs play a role in controlling the immune response to HCC during the progression of hepatocarcinogenesis. It has been suggested that primary hepatic cancers develop in liver that is immunosuppressed by a marked infiltration of Tregs. A high prevalence of Tregs infiltrating HCC is thought to be an unfavorable prognostic indicator.

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Prognostic value of tumor architecture, tumor-associated vascular characteristics, and expression of angiogenic molecules in pancreatic endocrine tumors

Takahashi, Yu, Akishima-Fukasawa, Yuri, Kobayashi, Noritoshi, Sano, Tsuyoshi, Kosuge, Tomoo, Nimura, Yuji, Kanai, Yae, Hiraoka, Nobuyoshi

CLINICAL CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 13 ( 1 ) 187 - 196 2007.01

Research paper (scientific journal), ISSN 1078-0432

Purpose: It is difficult to predict the biological behavior of pancreatic endocrine tumors (PETs). Our aim was to evaluate the prognostic significance of certain variables in PETs.
Experimental Design: The following variables were examined in 37 patients with PETs and then compared with other clinicopathologic characteristics: histologic tumor structure; microvessel density (MVD) measured by three different methods, including a unique method involving calculation of solid area MVD; endothelial proliferation; and the immunohistochemical expression of vascular endothelial growth factor-A and CXC chemokine CXCL-12. Intratumoral vascular structures were analyzed by double immunofluorescence using 30-mu m-thick sections.
Results: The presence of focal and intensive solid growth of tumor cells (large solid nests; P=0.003), low solid area MVD (P=0.002), a high endothelial cell proliferation index (EPI; P=0.005), and high expression of CXCL-12 in PET cells (P=0.018) were significant unfavorable prognostic indicators. The predominant structure of the overall tumor histology and the expression of vascular endothelial growth factor-A did not separate aggressive PETs. In areas of focal solid growth, tumor-associated blood vessels had obviously low MVD and high EPI, and their structures were poorly formed with highly abnormal features, in comparison with other areas. High expression of CXCL-12 in tumor cells was significantly associated with variables representing tumor growth, hematogenous tumor spread, low MVD, high EPI, and the presence of large solid nests.
Conclusions: This study has provided novel findings on the prognostic features of tumor architecture and tumor-associated angiogenesis in PETs. CXCL-12 is the first candidate molecule in association with neoangiogenesis in PETs.

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Primary adenocarcinoma of the rete testis with preceding diagnosis of pulmonary metastases

Nakagawa, Tohru, Hiraoka, Nobuyoshi, Ihara, Fumie, Komiyama, Motokiyo, Kanai, Yae, Matsuno, Yoshihiro

INTERNATIONAL JOURNAL OF UROLOGY (BLACKWELL PUBLISHING) 13 ( 12 ) 1532 - 1535 2006.12

Research paper (scientific journal), ISSN 0919-8172

We report a case of primary adenocarcinoma of the rete testis in a 55-year-old man with pulmonary metastases that were detected 11 months prior to the diagnosis of the primary lesion. Primary adenocarcinoma of the rete testis is an extremely rare malignant tumor with a poor outcome. The most common primary symptom is a scrotal mass, often accompanied by hydrocele and chronic epididymitis. The diagnosis is often delayed because of non-specific clinical presentation and symptoms. We cannot forget that rete testis is a possible primary site for a primary, unknown metastatic adenocarcinoma.

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Genetic inactivation of the APC gene contributes to the malignant progression of sporadic hepatocellular carcinoma: A case report

Katoh, Hiroto, Shibata, Tatsuhiro, Kokubu, Akiko, Ojima, Hidenori, Kosuge, Tomoo, Kanai, Yae, Hirohashi, Setsuo

GENES CHROMOSOMES & CANCER (WILEY-LISS) 45 ( 11 ) 1050 - 1057 2006.11

Research paper (scientific journal), ISSN 1045-2257

Although activated Wnt/beta-catenin pathway is considered to be one of the main driving forces of hepatocarcinogenesis, no somatic mutations of the adenomatous polyposis coli (APC) gene have been found in sporadic hepatocellular carcinoma (HCC) to date. Here we present a case of a sporadic nodule-in-nodule-type HCC that provides the first evidence that biallelic genetic inactivation of the APC gene contributed to the development of the tumor. High-density array-based comparative genomic hybridization (aCGH) was performed to clarify genome-wide chromosomal structural alteration profiles of both early and advanced components of this nodule-in-nodule HCC. aCGH analysis revealed a chromosomal loss of the AIPC gene locus only in the inner advanced component of this tumor. Direct sequencing of the remaining allele revealed a nonsense mutation at codon 682 in the Armadillo repeats, resulting in a truncated protein that lacked all of the beta-catenin-binding motifs. Nonsense mutations at this location are rare among other types of cancer. In conclusion, combined with an immunohistochemical analysis of the beta-catenin protein, this case provides the first evidence that genetic inactivation of the APC gene can play a significant role in the progression of sporadic HCC, probably by activating the Wnt/beta-catenin pathway. (c) 2006 Wiley-Liss, Inc.

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