Details of a Researcher - NISHIHARA, Hiroshi

Papers - NISHIHARA, Hiroshi

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バイオマーカーによる診断、その他個別化病理診断の基盤作成胃癌におけるシグナル伝達分子のImmunoprofilingの検討(Diagnosis by biomaker, others Immunoprofiling of signaling molecule for gastric cancer: Pathological basis for Taylor made medicine)

西原広史, 菅野宏美, 石川麻倫, 大場彩音, 田中伸哉

日本癌学会総会記事 ((一社)日本癌学会) 69回 232 - 233 2010.08

ISSN 0546-0476

Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice.

Yanagi T, Akiyama M, Nishihara H, Ishikawa J, Sakai K, Miyamura Y, Naoe A, Kitahara T, Tanaka S, Shimizu H

The American journal of pathology (1) 177 ( 1 ) 106 - 118 2010.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 0002-9440

Harlequin ichthyosis (HI) is caused by loss-of-function mutations in the keratinocyte lipid transporter ABCA12. The patients often die in the first 1 or 2 weeks of life, although HI survivors' phenotypes improve within several weeks after birth. In order to clarify the mechanisms of phenotypic recovery, we studied grafted skin and keratinocytes from Abca12-disrupted (Abca12(-/-)) mice showing abnormal lipid transport. Abca12(-1-) neonatal epidermis showed significantly reduced total ceramide amounts and aberrant ceramide composition. Immunofluorescence and immunoblotting of Abca12(-1-) neonatal epidermis revealed defective profilaggrin/filaggrin conversion and reduced protein expression of the differentiation-specific molecules, loricrin, kallikrein 5, and transglutaminase 1, although their mRNA expression was up-regulated. In contrast, Abca12(-1-) skin grafts kept in a dry environment exhibited dramatic improvements in all these abnormalities. Increased transepidermal water loss, a parameter representing barrier defect, was remarkably decreased in grafted Abca12(-1-) skin. Ten-passage sub-cultured Abca12(-/-)keratinocytes showed restoration of intact ceramide distribution, differentiation-specific protein expression and profilaggrin/filaggrin conversion, which were defective in primary-cultures. Using cDNA microarray analysis, lipid transporters including four ATP-binding cassette transporters were up-regulated after sub-culture of Abca12(-/-) keratinocytes compared with primary-culture. These results indicate that disrupted keratinocyte differentiation during the fetal development is involved in the pathomechanism of HI and, during maturation, Abca12(-/-) epidermal keratinocytes regain normal differentiation processes. This restoration may account for the skin phenotype improvement observed in HI survivors. (Am J Pathol 2010, 177:106-118; DOI: 10.2353/ajpath.2010.091120)

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Controlled storage of ferrocene derivatives as redox-active molecules in dendrimers.

Ochi Y, Suzuki M, Imaoka T, Murata M, Nishihara H, Einaga Y, Yamamoto K

Journal of the American Chemical Society 132 ( 14 ) 5061 - 9 2010.04

Accepted, ISSN 0002-7863

Dendritic polyphenylazomethines (DPA) could encapsulate ferroceniums by complexation of the electron-donating skeleton of the DPA imines. Upon addition of ferroceniums to a series of dendritic polyphenylazomethines (DPAGX, where X is the generation number, X = 1-4), the UV-vis spectra showed changes in a manner similar to that observed for the complexation of metal ions with DPAGX. Stepwise shifts in the isosbestic point were consistently observed with the number of imine groups in the first and second layers of the generation-4 dendrimer (DPAG4). DPAG2 and DPAG3 were also found to trap 6 equiv of ferroceniums. To investigate the complexation, UV-vis spectroscopy, 57Fe MoÌssbauer spectroscopy, electrospray ionization-mass spectroscopy (ESI-MS), cyclic voltammetry (CV), and fluorescence spectroscopy were performed. We confirmed that neutral ferrocenes cannot complex with the imine group while ferroceniums can. Utilizing the redox property of ferrocenes, we were able to electrochemically control the encapsulation and release of ferrocenes into the DPA in a manner similar to redox-responsive proteins such as ferritin. In addition to ferrocenes, oligoferrocenes could also be trapped in the DPA. The biferrocene cation(1+) was particularly suitable for electrochemical switching due to its stable mixed valence condition. The terferrocene dication(2+) encapsulated into DPAG4 could be fabricated into a thin film, which exhibited the near-infrared absorption of an intervalence charge-transfer (IV-CT) band, pointing the way toward the use of such systems in material science. © 2010 American Chemical Society.

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DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma.

Wang L, Nishihara H, Kimura T, Kato Y, Tanino M, Nishio M, Obara M, Endo T, Koike T, Tanaka S

Biochemical and biophysical research communications (1) 395 ( 1 ) 111 - 115 2010.04

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

DOCK2; a member of the CDM protein family, regulates cell motility and cytokine production through the activation of Rac in mammalian hematopoietic cells and plays a pivotal role in the modulation of the immune system. Here we demonstrated the alternative function of DOCK2 in hematopoietic tumor cells, especially in terms of its association with the tumor progression.
Immunostaining for DOCK2 in 20 cases of human B cell lymphoma tissue specimens including diffuse large B cell lymphoma and follicular lymphoma revealed the prominent expression of DOCK2 in all of the lymphoma cells. DOCK2-knockdown (KD) of the B cell lymphoma cell lines, Ramos and Raji, using the lentiviral shRNA system presented decreased cell proliferation compared to the control cells. Furthermore, the tumor formation of DOCK2-KD Ramos cell in nude mice was significantly abrogated. Western blotting analysis and pull-down assay using GST-PAK-RBD kimeric protein suggested the presence of DOCK2-Rac-ERK pathway regulating the cell proliferation of these lymphoma cells. This is the first report to clarify the prominent role of DOCK2 in hematopoietic malignancy. (C) 2010 Elsevier Inc. All rights reserved.

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Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks.

Tabu K, Kimura T, Sasai K, Wang L, Bizen N, Nishihara H, Taga T, Tanaka S

Molecular cancer (BIOMED CENTRAL LTD) 9 39 2010.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1476-4598

Background: An increasing number of studies support the presence of stem-like cells in human malignancies. These cells are primarily responsible for tumor initiation and thus considered as a potential target to eradicate tumors. CD133 has been identified as an important cell surface marker to enrich the stem-like population in various human tumors. To reveal the molecular machinery underlying the stem-like features in tumor cells, we analyzed a promoter of CD133 gene using human colon carcinoma Caco-2 and synovial sarcoma Fuji cells, which endogenously express CD133 gene.
Results: A reporter analysis revealed that P5 promoter, located far upstream in a human CD133 gene locus, exhibits the highest activity among the five putative promoters (P1 to P5). Deletion and mutation analysis identified two ETS binding sites in the P5 region as being essential for its promoter activity. Electrophoretic mobility shift assays demonstrated the specific binding between nuclear factors and the ETS binding sequence. Overexpression of dominant-negative forms of Ets2 and Elk1 resulted in the significant decrease of P5 activity. Furthermore, treatment of Fuji cells with a specific MEK/ERK inhibitor, U0126, also markedly decreased CD133 expression, but there was no significant effect in Caco-2 cells, suggesting cell type-specific regulation of CD133 expression. Instead, the side population, another hallmark of TSLCs, was dramatically diminished in Caco-2 cells by U0126. Finally, Ras-mediated oncogenic transformation in normal human astrocytes conferred the stem-like capability to form neurosphere-like colonies with the increase of CD133 mRNA expression.
Conclusions: In conclusion, the Ras/ERK pathway at least in part contributes to the maintenance and the acquisition of stem-like hallmarks, although the extent of its contribution is varied in a cell type-specific manner. These findings could help our comprehensive understanding of tumor stemness, and also improve the development of eradicative therapies against human malignancies.

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Sudden death of a patient with pandemic influenza (A/H1N1pdm) virus infection by acute respiratory distress syndrome.

Takiyama A, Wang L, Tanino M, Kimura T, Kawagishi N, Kunieda Y, Katano H, Nakajima N, Hasegawa H, Takagi T, Nishihara H, Sata T, Tanaka S

Japanese journal of infectious diseases (1) 63 ( 1 ) 72 - 74 2010.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 1344-6304

We describe an autopsy case of a patient with pandemic influenza (A/H1N1pdm) virus infection in Japan, who developed rapidly progressive viral pneumonia exhibiting diffuse alveolar damage. A 41-year-old female visited our hospital with a fever of 38.7 degrees C. She was a public health nurse with no underlying disease and had had contact with a group of elementary school students who had been infected with the influenza (A/H1N1pdm) virus I week earlier. She was prescribed oseltamivir and returned to the hotel where she was staying alone. The next day, she was found dead in her hotel room. At autopsy, both lungs were voluminous and microscopic examination revealed acute-stage, severe diffuse alveolar damage with remarkable mononuclear cell infiltration and hyaline membrane formation in the lungs. CD8-positive T lymphocytes were dominantly observed. Immunohistochemically, influenza A viral protein was confirmed in the damaged type 11 pneumocytes and also in the infiltrated macrophages. Real-time RT-PCR analysis of both pre- and post-mortem pharyngeal swabs confirmed a novel influenza (A/H1N1pdm) virus infection. This is the second autopsy case of influenza (A/H1N1pdm) virus infection in Japan, and the findings indicated that the patient died due to an exceptionally rapid progression of viral pneumonia. This case indicates that patients with influenza (A/H1N1pdm) virus infection should be carefully monitor for acute respiratory distress syndrome.

Treating "intractable" tumours using nanoDDS and TGF-beta inhibitor

Kano M.R, Nishihara H, Kataoka K, Miyazono K

European Cells and Materials 20 ( SUPPL.3 ) 2010

Joint Work, Accepted

A case of central nervous system lymphomatoid granulomatosis; characteristics of PET imaging and pathological findings.

Nishihara H, Nakasato M, Sawa H, Murakami H, Yamamoto D, Moriyama K, Kato N, Hashimoto I, Kamada H, Tanaka S

Journal of neuro-oncology (2) 93 ( 2 ) 275 - 278 2009.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0167-594X

Lymphomatoid granulomatosis (LYG) in the central nervous system (CNS) is an uncommon lymphoproliferative disorder with low grade malignant potential. Here we report a case of CNS-LYG, in particular, its characteristics of radioisotope imaging and pathological findings. A 65-year-old man complained of visual disturbance and homonymous hemianopsia was designated. CT and MRI revealed an edematous, enhanced irregular and nodular lesion in the right occipital and parietal lobes. Although 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan showed low uptake in the lesion, Methionine (MET)-PET scan indicated high uptake. Proton magnetic resonance spectroscopy ((1)H-MRS) at 3T revealed a decrease of the peak of the N-acetylaspartate (NAA), suggesting a possible neoplastic lesion. The patient was diagnosed with CNS-LYG based on the surgically removed material showing perivascular infiltration of CD3-positive small T-lymphocytes with granulomatous lesions. The post-operative steroid therapy was effective and the recurrence or exacerbation has not been observed by radiological imaging until now.

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Human synovial sarcoma proto-oncogene Syt is essential for early embryonic development through the regulation of cell migration.

Kimura T, Sakai M, Tabu K, Wang L, Tsunematsu R, Tsuda M, Sawa H, Nagashima K, Nishihara H, Hatakeyama S, Nakayama K, Ladanyi M, Tanaka S, Nakayama KI

Laboratory investigation; a journal of technical methods and pathology (6) 89 ( 6 ) 645 - 656 2009.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0023-6837

SYT-SSX protein, resulted from chromosomal translocation, causes synovial sarcoma, which is a malignant tumor accounting for 10% of soft tissue sarcoma. However, biological functions of SYT (synovial sarcoma translocation), also known as SS18, are largely unclear, whereas it has been proven that Syt-null mice die at early stages of embryonic development. Here, we generated Syt-deficient mice and confirmed the reported phenotypes, including growth retardation, open neural tube and haplo-insufficient lethality, and therefore, there is no doubt that Syt is essential for embryonic development. However, placental defects, described in the earlier report, were rarely seen in our mice and we frequently observed cardiac defect in Syt-deficient mice. As the mechanisms responsible for embryonic lethality seem to be complicate, we performed additional experiments. By using primary cultured embryonic fibroblasts, we showed that Syt(-/-) MEFs deregulate actin organization and suppressed cell migration. These observations suggest that Syt may contribute to the signaling pathway important for various cellular functions in vivo and in vitro, and we propose that Syt-deficient MEFs would be a powerful means to understand the biological roles of SYT in vitro. Laboratory Investigation (2009) 89, 645-656; doi:10.1038/labinvest.2009.25; published online 30 March 2009

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Crk adaptor protein-induced phosphorylation of Gab1 on tyrosine 307 via Src is important for organization of focal adhesions and enhanced cell migration.

Watanabe T, Tsuda M, Makino Y, Konstantinou T, Nishihara H, Majima T, Minami A, Feller SM, Tanaka S

Cell research (5) 19 ( 5 ) 638 - 650 2009.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1001-0602

Upon growth factor stimulation, the scaffold protein, Gab1, is tyrosine phosphorylated and subsequently the adaptor protein, Crk, transmits signals from Gab1. We have previously shown that Crk overexpression, which is detectable in various human cancers, induces tyrosine phosphorylation of Gab1 without extracellular stimuli. In the present study, the underlying mechanisms were further investigated. Mutational analyses of CrkII demonstrated that the SH2 domain, but not the SH3(N) or the regulatory Y221 residue of CrkII, is critical for the induction of Gab1-Y307 phosphorylation. SH2 mutation of CrkII also decreased the interaction with Gab1. In GST pull-down assay, Crk-SH2 bound to wild-type Gab1, whereas Crk-SH3(N) interacted with the Gab1 mutant, which lacks the clustered tyrosine region (residues 242-410). Tyrosine phosphorylation of Gab1 was induced by all Crk family proteins, but not other SH2-containing signalling adaptors. Src-family kinase inhibitor, PP2, abrogates Crk-induced tyrosine phosphorylations of Gab1. Y307 phosphorylation was undetectable in fibroblasts lacking Src, Yes, and Fyn, even upon overexpression of Crk, whereas cells lacking only Yes and Fyn still contained Gab1 with phosphorylated Y307. Furthermore, Crk induced the phosphorylation of Src-Y416; accordingly the interaction between Crk and Csk was increased. The Gab1-Y307F mutant failed to localize near the plasma membrane even upon HGF stimulation and decreased cell migration. Moreover, Gab1-Y307F disturbed the localization of Crk, FAK, and paxillin, which are the typical components of focal adhesions. Taken together, these results indicate that Crk facilitates tyrosine phosphorylation of Gab1-Y307 through Src, contributing to the organization of focal adhesions and enhanced cell migration, thereby possibly promoting human cancer development.

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Colonic metastasis from primary carcinoma of the lung: Report of a case and review of Japanese literature

Hiromi Ono, Mihiro Okabe, Takashi Kimura, Masato Kawakami, Kenji Nakamura, Yasushi Danjo, Hidero Takasugi, Hiroshi Nishihara

Clinical Journal of Gastroenterology 2 ( 2 ) 89 - 95 2009.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1865-7257

We report a rare case of colonic metastasis from primary carcinoma of the lung. A 59-year-old man who underwent pulmonary surgery for lung cancer was referred to our hospital in June 2007. The patient complained of abdominal pain, and barium enema examination at another hospital had demonstrated a descending colon tumor. Postoperative histopathological and immunohistochemical findings indicated that the tumor was a colonic metastasis of lung cancer. Three months postoperatively, the cancer had metastasized to the brain, and the patient underwent radiotherapy. He survived for more than 1 year after colonic surgery. Clinically apparent metastases from lung cancer to the colon are rare, and in the 50 Japanese cases retrospectively investigated here, the prognosis was poor. © 2008 Springer.

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CNS lymphomatoid granulomatosis with lymph node and bone marrow involvements.

Takiyama A, Nishihara H, Tateishi U, Kimura T, Wang L, Marukawa K, Itoh T, Hashino S, Nagashima K, Tanaka S

Neuropathology : official journal of the Japanese Society of Neuropathology (6) 28 ( 6 ) 640 - 644 2008.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0919-6544

Lymphomatoid granulomatosis (LYG) in the CNS is an uncommon lymphoproliferative disease with characteristic angiocentric lymphoreticular proliferative and granulomatous lesions exhibiting low-grade malignant potential. Here we report a rare case of CNS-LYG, which disseminated to the lymph node and bone marrow. A 50-year-old man was diagnosed with CNS-LYG based on brain biopsy showing perivascular infiltration of CD3-positive small T-lymphocytes without overt nuclear atypism. Eight months after the initial neurological symptoms, inguinal lymph node swelling was found and histopathologically diagnosed as peripheral T-cell lymphoma. TCR gamma-gene rearrangement study using both paraffin-embedded specimens of brain and inguinal lymph node demonstrated an identical clonal band. Considering the clinical course, we concluded lymph node involvement of CNS-LYG, suggesting the malignant potential of CNS-LYG.

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Harlequin ichthyosis model mouse reveals alveolar collapse and severe fetal skin barrier defects.

Yanagi T, Akiyama M, Nishihara H, Sakai K, Nishie W, Tanaka S, Shimizu H

Human molecular genetics (19) 17 ( 19 ) 3075 - 3083 2008.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0964-6906

Harlequin ichthyosis (HI), which is the most severe genodermatosis, is caused by loss-of-function mutations in ABCA12, a member of the ATP-binding cassette transporter family. To investigate the pathomechanism of HI and the function of the ABCA12 protein, we generated ABCA12-deficient mice (Abca12(-/-)) by targeting Abca12. Abca12(-/-) mice closely reproduce the human HI phenotype, showing marked hyperkeratosis with eclabium and skin fissure. Lamellar granule abnormalities and defective ceramide distribution were remarkable in the epidermis. Skin permeability assay of Abca12(-/-) fetuses revealed severe skin barrier dysfunction after the initiation of keratinization. Surprisingly, the Abca12(-/-) mice also demonstrated lung alveolar collapse immediately after birth. Lamellar bodies in alveolar type II cells of the Abca12(-/-) mice lacked normal lamellar structures. The level of surfactant protein B, an essential component of alveolar surfactant, was reduced in the Abca12(-/-) mice. Fetal therapeutic trials with systemic administration of retinoid or dexamethasone, which are effective for HI and respiratory distress, respectively, to the pregnant mother mice neither improved the skin phenotype nor extended the survival period. Our HI model mice reproduce the human HI skin phenotype soon after the initiation of fetal skin keratinization and provide evidence that ABCA12 plays pivotal roles in lung and skin barrier functions.

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Promoter hypomethylation regulates CD133 expression in human gliomas.

Tabu K, Sasai K, Kimura T, Wang L, Aoyanagi E, Kohsaka S, Tanino M, Nishihara H, Tanaka S

Cell research (10) 18 ( 10 ) 1037 - 1046 2008.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1001-0602

Brain tumor-initiating cells (BTICs) have been enriched using antibodies against the cell surface protein CD133; however, the biological relevance and the regulatory mechanism of CD133 expression in human gliomas are not yet understood. In this study, we initially demonstrated that CD133 was overexpressed in high-grade human glioblastomas where CD133-positive cells were focally observed as a micro-cluster. In addition, CD133 transcripts with exon 1A, 1B, or 1C were predominantly expressed in glioblastomas. To elucidate the mechanism regulating this aberrant expression of CD133, three proximal promoters (P1, P2, and P3) containing a CpG island were isolated. In U251MG and T98G glioblastoma cells, the P1 region flanking exon 1A exhibited the highest activity among the three promoters, and this activity was significantly inactivated by in vitro methylation. After treatment with the demethylating agent 5-azacytidine and/or the histone deacetylase inhibitor valproic acid, the expression level of CD133 mRNA was significantly restored in glioma cells. Importantly, hypomethylation of CpG sites within the P1, P2, and P3 regions was observed by bisulfite sequencing in human glioblastoma tissues with abundant CD133 mRNA. Taken together, our results indicate that DNA hypomethylation is an important determinant of CD133 expression in glioblastomas, and this epigenetic event may be associated with the development of BTICs expressing CD133.

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Hypopharyngeal squamous cell carcinoma producing both granulocyte colony-stimulating factor and parathyroid hormone-related protein.

Tamura K, Yoshinaga T, Tanino M, Kimura T, Yamada N, Nishimura M, Fukuda S, Nishihara H, Shindoh M, Tanaka S

Pathology international (10) 58 ( 10 ) 652 - 656 2008.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1320-5463

A 57-year-old woman was admitted to Hokkaido University Hospital because of dysphagia. Laryngoscopy indicated hypopharyngeal tumor histologically diagnosed as squamous cell carcinoma (SCC). A combination of radiotherapy and chemotherapy was performed for 2 months, and the hypopharyngeal lesion completely regressed. After 4 months, fever, anorexia, and malaise appeared, and chest X-ray and CT indicated two large tumors in the right lung. Transbroncheal lung biopsy (TBLB) specimens were diagnosed as SCC. Laboratory data showed high levels of serum granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP). Subsequently, positron emission tomography (PET) showed multiple metastases to several organs including the liver, spine, skull, and thigh. Two months after readmission, the patient died with no success of chemotherapy. At autopsy, the lung tumor was clearly positive for both G-CSF and PTHrP on immunohistostaining. Retrospectively, examination showed that the primary pharyngeal tumor was focally positive for these two cytokines. Thus, a certain population of hypopharyngeal cancer producing G-CSF and PTHrP, spread to various organs and contributed to the rapid progression and poor prognosis. This case is presented with a discussion of several other cases in the literature.

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Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O6-methylguanine-DNA methyltransferase status in glioma: relationship between immunohistochemistry and methylation analysis.

Sasai K, Nodagashira M, Nishihara H, Aoyanagi E, Wang L, Katoh M, Murata J, Ozaki Y, Ito T, Fujimoto S, Kaneko S, Nagashima K, Tanaka S

The American journal of surgical pathology (8) 32 ( 8 ) 1220 - 1227 2008.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0147-5185

Evaluation of O-6-methylguanine-DNA methyltransferase (MGMT) expression is important for antiglioma therapy as many clinical trials have demonstrated that promoter hypermethylation and low level expression of MGMT are associated with an enhanced response to alkylating agents. However, here we report that the current strategies used to evaluate MGMT status in gliomas are unreliable. We observed discordance in the MGMT expression status when immunohistochemical evaluation and polymerase chain reaction-based methylation assessments were used: 73% of gliomas with methylated MGMT promoter had substantial numbers of MGMT-immunopositive tumor cells. Furthermore, when MGMT expression was tested in tumor homogenates using reverse transcription-polymerase chain reaction, 43% of tumors were found positive, in comparison to only 24%, when histologic samples were assayed immunohistochemically. To explain these inconsistencies we undertook a detailed immunohistochemical evaluation of tumor samples and found that some gliomas demonstrated remarkably high expression of MGMT in the entire tumor whereas others contained only a small immunopositive area. Additionally, we found that gliomas contained various types of non-neoplastic cells expressing MGMT, including lymphocytes, vascular endothelial cells, and macrophages/microglias, which contribute to overall MGMT expression detected in tumor homogenates, and thus result in overestimation of tumor NIGMT expression. Therefore, to correctly establish MGMT expression in the tumor, which could be informative of glioma sensitivity to alkylating agents, exclusion of non-neoplastic brain components from analysis is required.

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A case of cerebral ganglioneuronal tumor in the parietal lobe of an adult.

Nishihara H, Ozaki Y, Ito T, Yoshinaga T, Tabu K, Tanino M, Nagashima K, Tanaka S

Brain tumor pathology (1) 25 ( 1 ) 45 - 49 2008

Research paper (scientific journal), Joint Work, Accepted, ISSN 1433-7398

Central nervous system (CNS) neuroblastoma/ganglioneuroblastoma is one of the embryonal tumors with neuronal differentiation found in young adults, but it is most common in children, especially in those below the age of 5 years, whereas extraventricular neurocytoma, a rare neuroepithelial tumor with neuronal differentiation, mostly affects young adults. Here we present a rare case of cerebral ganglioneuronal tumor that occurred in a 32-year-old woman. The patient suffered from tonic convulsion, and computed tomography demonstrated a well-demarcated, round tumor 3.3 cm in size with marked calcification in the right parietal lobe. Histological analysis revealed diffuse infiltration of small, round cells with scattered large ganglion-like cells. Immunohistochemically, the tumor cells did not react with any neuronal molecules, except for chromogranin A in ganglion-like large tumor cells, but electron microscopy demonstrated the presence of synapse-like nerve terminal structures without mature postsynaptic density, suggesting the presence of neoplastic tumor components with neuronal differentiation; thus, this tumor was diagnosed as CNS ganglioneuroblastoma with possible low-grade malignancy because the Mib-1 labeling index was less than 3%-4%. Here we discuss the histological entity of cerebral ganglioneuronal tumors, including extraventricular neurocytoma.

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Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4.

Wang L, Tabu K, Kimura T, Tsuda M, Linghu H, Tanino M, Kaneko S, Nishihara H, Tanaka S

Biochemical and biophysical research communications (4) 362 ( 4 ) 976 - 981 2007.11

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

Signaling adaptor protein Crk has been shown to be involved in pathogenesis of human cancers including brain tumor where Crk was reported to be overexpressed. In this study, we addressed whether Crk is indispensable for malignant phenotype of brain tumor. In 20 surgical specimens of glioma, mRNA of both CrkI and CrkII was found to be elevated in malignant tumor. To define a precise role of Crk, we have established Crk-knockdown cell lines of glioblastoma KMG4 by siRNA, and early phase of cell adhesion to laminin was found to be suppressed. Wound healing assay revealed the decreased cell motility in Crk knockdown cells, and suppression of both anchorage-dependent and -independent growth were demonstrated in these cells. Furthermore, in vivo tumor forming potential was also markedly suppressed. These results suggest that Crk is required for early attachment to laminin, cell motility, and growth of glioblastoma cell line KMG4. (C) 2007 Elsevier Inc. All rights reserved.

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Immunohistochemical and gene rearrangement studies of central nervous system lymphomatoid granulomatosis.

Nishihara H, Tateishi U, Itoh T, Nagashima K, Tanaka S

Neuropathology : official journal of the Japanese Society of Neuropathology (5) 27 ( 5 ) 413 - 418 2007.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0919-6544

Lymphomatoid granulomatosis (LYG) is a rare multisystem disorder with characteristic angiocentric lymphoproliferative features, most frequently involving the lung, skin, and rarely the CNS. LYG has been classified into three subtypes based on the relative proportions of atypical and inflammatory infiltrating cells. Most systemic LYGs have been shown to be EBV-associated, T-cell rich, B-cell proliferative disorders. Here, we present four cases of LYG arising from the CNS and have analyzed them by immunohistochemistry to assess the phenotype of the infiltrate, and by PCR-SSCP (single-strand conformation polymorphism) analysis for immunoglobulin heavy chain (IgH) and T-cell receptor (TcR) gamma gene rearrangements. Three cases revealed perivascular infiltration of T-cell dominant lymphoid cells, two cases showed monoclonal TcR gamma gene rearrangement, while the remaining case had a B-cell immunophenotype and monoclonal IgH gene rearrangement with EBV genome expression. This is the first report of a gene rearrangement study on CNS-LYG. We confirm that some cases of CNS-LYG are derived from T-cell monoclonal lymphoproliferative disease, although this disease should be classified as a borderline malignancy and should be separated from overt malignant lymphoma of CNS.

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Type I interferon prolongs cell cycle progression via p21WAF1/CIP1 induction in human colon cancer cells.

Katayama T, Nakanishi K, Nishihara H, Kamiyama N, Nakagawa T, Kamiyama T, Iseki K, Tanaka S, Todo S

International journal of oncology (3) 31 ( 3 ) 613 - 620 2007.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 1019-6439

Type I interferon (IFN) was originally identified as an immunomodulatory cytokine because of its antiviral activity. Further characterization of its biological effects revealed a prominent role in the direct control of cell growth and potent immunomodulatory and antiangiogenic actions. IFN-alpha and IFN-SS had both been classified as type I IFN, but differences in their antitumor activities were reported. We confirmed the difference in the antiproliferative activities of IFN-alpha 2b and IFN-SS toward HT29 and SW480 cells. IFN treatment was observed to prolong cell cycle progression; in particular, the accumulation of S-phase population was one of the most characteristic changes. The prolongation of S-phase progression and transition into G2/M-phase was suggested to be a crucial action of type I IFN on colon cancer. Additionally, IFN activated the p21 promoter gene and induced p21(WAFl/CIP1) expression. Furthermore, the cell cycle prolongation effect of IFN was suppressed when p21 expression was downregulated. Therefore, we confirmed that p21(WAFl/CIP1) was a crucial target molecule for the effects of IFN on the cell cycle. Additionally, the ability of p21 induction differed between IFN-alpha 2b and IFN-SS and correlated with their inhibitory activities toward cell growth. We conclude that type I IFN prolongs cell cycle progression by p21(WAFl/CIP1) induction in human colon cancer cells.

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