Research Institute for Clinical Oncology

Saitama, Japan

Research Institute for Clinical Oncology

Saitama, Japan
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Suganuma M.,Research Institute for Clinical Oncology | Saha A.,Tokushima Bunri University | Fujiki H.,Tokushima Bunri University
Cancer Science | Year: 2011

Green tea is now recognized as the most effective cancer preventive beverage. In one study, 10 Japanese-size cups of green tea daily supplemented with tablets of green tea extract limited the recurrence of colorectal polyps in humans to 50%. Thus, cancer patients who consume green tea and take anticancer drugs will have double prevention. We studied the effects of combining (-)-epigallocatechin gallate (EGCG) and anticancer drugs, focusing on inhibition of cell growth and induction of apoptosis. Numerous anticancer drugs, such as tamoxifen, COX-2 inhibitors, and retinoids were used for the experiments, and the combination of EGCG and COX-2 inhibitors consistently induced the enhancement of apoptosis. To study the mechanism of the enhancement, we paid special attention to the enhanced expressions of DDIT3 (growth arrest and DNA damage-inducible 153, GADD153), GADD45A, and CDKN1A (p21/WAF1/CIP1) genes, based on our previous evidence that a combination of EGCG and sulindac specifically induced upregulated expression of GADD153 and p21 genes in PC-9 lung cancer cells. The synergistic enhancements of apoptosis and GADD153 gene expression in human non-small cell lung cancer cells by the combination of EGCG and celecoxib were mediated through the activation of the MAPK signaling pathway. This article reviews the synergistic enhancement of apoptosis, gene expression, and anticancer effects using various combinations of EGCG and anticancer drugs, including the combination of (-)-epicatechin (EC) and curcumin. Based on the evidence, we present a new concept: green tea catechins as synergists with anticancer drugs. © 2010 Japanese Cancer Association.


Fujiki H.,Tokushima Bunri University | Suganuma M.,Research Institute for Clinical Oncology
Anti-Cancer Agents in Medicinal Chemistry | Year: 2011

Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A - toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin-LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is "possibly carcinogenic to humans and that nodularin is "not classifiable as to carcinogenicity". Our studies revealed that chemical tumor promoters are inducers of TNF-α in the cells of target tissues and that TNF-α is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF-α and IL-1. The carcinogenic features of TNF-α are described in this review, and the TNF-α inducing protein (Tipα) of Helicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development. © 2011 Bentham Science Publishers Ltd.


Ohtake F.,University of Tokyo | Fujii-Kuriyama Y.,University of Tokyo | Kawajiri K.,Research Institute for Clinical Oncology | Kato S.,University of Tokyo
Journal of Steroid Biochemistry and Molecular Biology | Year: 2011

The arylhydrocarbon receptor (AhR) is a ligand-dependent transcription factor mediating the adverse effects of dioxins. Although cross-talk of dioxins with estrogen and androgen signaling pathways are well described, the underlying molecular mechanisms have been largely elusive. Recent studies showed that modulation of estrogen/androgen signaling by dioxins is exerted in part through direct association of AhR with estrogen (ER) or androgen (AR) receptors. Agonist-bound AhR and ERα work as a functional unit to regulate expression of target genes. In addition to such genomic actions, AhR mediates non-genomic actions of AhR-ligands through the assembly of a CUL4B-based ubiquitin ligase complex and promotes the degradation of ERα and AR. These findings reveal the roles of the ubiquitin system in sensing and biological response to environmental chemicals, in which AhR acts as a ubiquitin ligase component to enhance the destruction of specific substrates. © 2011 Elsevier Ltd. All rights reserved.


Fujii-Kuriyama Y.,University of Tokyo | Fujii-Kuriyama Y.,Tokyo Medical and Dental University | Kawajiri K.,Research Institute for Clinical Oncology
Proceedings of the Japan Academy Series B: Physical and Biological Sciences | Year: 2010

The aryl hydrocarbon receptor (AhR) was originally identified as a ligandactivated transcription factor that is involved in the induction of xenobiotic-metabolizing Cytochrome P4501A1 (CYP1A1). For several decades, AhR has been studied in relation to toxicology and pharmacology. With recent discoveries on novel AhR functions, AhR research has expanded into multiple aspects of physiology, such as reproduction, innate immunity and tumor suppression. In this review, we summarize and discuss recent progress in mechanistic and functional studies on AhR with particular emphasis on physiological processes. © 2010 The Japan Academy.


Fujiki H.,Research Institute for Clinical Oncology | Sueoka E.,Saga University | Suganuma M.,Research Institute for Clinical Oncology
Journal of Cancer Research and Clinical Oncology | Year: 2013

Purpose: The classic two-stage chemical carcinogenesis in rodents is not directly linked to multistage carcinogenesis in humans. In light of our findings that tumor necrosis factor-α (TNF-α) is an endogenous tumor promoter and that TNF-α-inducing protein (Tipα) of Helicobacter pylori stimulates progression of cancer and epithelial-mesenchymal transition, we think it is necessary to re-examine the concept of tumor promoter, from chemicals to inflammatory proteins. Topics and results: This paper begins with "inflammation," discovered by Virchow, studies of Yamagiwa and Tsutsui, and briefly reviews numerous topics, such as (1) the classic concept of tumor promoter, (2) tumor promotion on mouse skin induced by protein kinase C activators and okadaic acid class compounds, (3) organ specificity of tumor promoters, presenting numerous tumor promoters in various organs, (4) unique tumor promotion induced by inhibitors of protein phosphatases 1 and 2A in mouse skin, rat glandular stomach, and rat liver, (5) the significant role of TNF-α in tumor-promoting inflammation, (6) progression induced by Tipα of H. pylori, and (7) enhancement of cancer treatment efficacy with the combination of anticancer drugs and green tea catechins, to inhibit tumor-promoting inflammation. Conclusion: Human cancer development involves both durable genetic changes caused by carcinogens and proinflammatory cytokines, and simultaneous inflammation in progression induced by proinflammatory cytokines and chemokines. © 2013 Springer-Verlag Berlin Heidelberg.


Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/-). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. We recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes.


Izumi H.,Research Institute for Clinical Oncology | Kaneko Y.,Research Institute for Clinical Oncology
Cancer Research | Year: 2014

Asymmetric cell division (ACD) is a physiologic process during development and tissue homeostasis. ACD produces two unequal daughter cells: one has stem/progenitor cell activity and the other has potential for differentiation. Recent studies showed that misregulation of the balance between self-renewal and differentiation by ACD may lead to tumorigenesis in Drosophila neuroblasts. However, it is still largely unknown whether human cancer stem-like cells exhibit ACD or not. Here, using human neuroblastoma cells as an ACD model, we found that MYCN accumulates at spindle poles by GSK-3β phosphorylation during mitosis. In parallel, the ACD-related ubiquitin ligase Trim32 was recruited to spindle poles by CDK1/cyclin B-mediated phosphorylation. Trim32 interacted with MYCN at spindle poles during mitosis, facilitating proteasomal degradation of MYCN at spindle poles and inducing ACD. Trim32 also suppressed sphere formation of neuroblastoma-initiating cells, suggesting that the mechanisms of ACD produce differentiated neuroblastoma cells that will eventually die. Thus, Trim32 is a positive regulator of ACD that acts against MYCN and should be considered as a tumor-suppressor candidate. Our findings offer novel insights into the mechanisms of ACD and clarify its contributions to human tumorigenesis. © 2014 AACR.


Matsushima Y.,Research Institute for Clinical Oncology
Experimental Animals | Year: 2012

Breeding of fancy mice has been a tradition in Japan. Recent progress in animal science has shed a new light on Japanese wild-derived mice as tools for discovery of new disease models because these mice, Mus musculus molossinus, are genetically far remote from the majority of available laboratory mice. After decades of effort, five inbred strains of mice have been established from pairs of wild mice trapped in Tohoku, northeastern Japan, namely KOR1/Stm, KOR5/Stm, KOR7/Stm, AIZ/Stm, and MAE/Stm. They carried numerous mutations, leading to a variety of diseases. During the inbreeding of KOR1, the first spontaneous mutation was found in the Apoe (apolipoprotein E) gene, and the mutant was later designated as spontaneous hyperlipidemic (SHL). Thereafter, a number of other mutations were discovered among wild-derived inbred strains, including atopic dermatitis, microphthalmia, dominant white spots, sebaceous gland abnormalities, and audible song-like vocalization. Furthermore, to examine the possible effects of the genetic background for these mutant genes, sets of congenic strains were generated, in which the mutant gene was introduced into at least 3 different strains of laboratory mice, including BALB/c and C57BL/6. These congenic strains have now been established as novel disease models. These wild-derived inbred strains serve as a treasure trove for novel disease models. Most of them have been deposited in the Riken BioResource Center (BRC), and some are also available from commercial breeders. © 2012 Japanese Association for Laboratory Animal Science.


The concept of cancer and inflammation has a long history. Virchow's irritation theory based on human cancer engendered the essential role of inflammation in carcinogenesis. Drs. Yamagiwa and Ichikawa first published a comprehensive paper entitled "Experimental study on the pathogenesis of epithelial tumors" (I report) in 1915 in German, and went on to publish five more reports (1915-1924) under the same title. They succeeded in demonstrating that inflammation is an important carcinogenic factor, and the mechanisms are now being investigated by numerous scientists all over the world. In order to introduce Yamagiwa's work to modern cancer researchers, the essentials of their six reports have been translated into English as a short review. Scientists' comments on Yamagiwa's contribution are attached by way of introduction. Drs. Yamagiwa and Ichikawa first published a comprehensive paper entitled "Experimental study on the pathogenesis of epithelial tumors" in 1915 in German. The essentials of their six reports under the same title have been translated into English as a short review. Scientists' comments on Yamagiwa's contribution are attached by way of introduction. © 2013 The Authors.


Fujiki H.,Research Institute for Clinical Oncology | Watanabe T.,Research Institute for Clinical Oncology | Suganuma M.,Research Institute for Clinical Oncology
Journal of Cancer Research and Clinical Oncology | Year: 2014

Purpose: Cell-surface nucleolin in human gastric cancer cell lines is a receptor for TNF-α-inducing protein (Tipα) of Helicobacter pylori. The binding complex of nucleolin and Tipα is internalized into the cells and then induces tumor progression of human gastric cancer. Surface nucleolin is also a receptor of human immunodeficiency virus-1, and the anti-HIV pseudopeptide (HB-19) showed anti-carcinogenic activity in vivo. Surface nucleolin has dual functions depending on the ligands: In order to understand the mechanisms of surface nucleolin, it is necessary to review surface nucleolin and its relation to carcinogenic ligands and anti-carcinogenic ligands. Other ligands can be grouped among disease-related ligands, which is an important new topic for the prevention of various ailments. Results and discussion: This paper mainly deals with two ligands of surface nucleolin, Tipα and pseudopeptide HB-19. The binding complex of nucleolin and Tipα induces expression of TNF-α and chemokine genes and activates NF-κB in gastric cancer cells of humans and mice. However, when human gastric cancer cell line MKN-1 was transfected with nucleolin-targeted siRNA, the result was inhibition of cell migration and elongation induced by Tipα. The amount of surface nucleolin was reduced in membrane fraction of the nucleolin knockdown MKN-1 cells, but the amount of nucleolin in the cytosol or nuclear fractions of the cells did not change. The results indicate that surface nucleolin acts as a carcinogenic mediator for Tipα of H. pylori. In contrast, both the viral external envelop glycoprotein gp120 of HIV and the anti-HIV pseudopeptide HB-19 bind to surface nucleolin. Through this binding, treatment with HB-19 inhibited tumor development in human breast cancer cell line MDA-MB-231 and rhabdoid tumor cell line derived from Wilms's tumor in xenograft nude mouse models. The results show that surface nucleolin acts as an anti-carcinogenic mediator for HB-19. Conclusion: Based on these discrete functions of surface nucleolin, the binding complex of carcinogenic ligands and surface nucleolin seems to be competing with that of anti-carcinogenic ligands and surface nucleolin. Moreover, carcinogenic ligands derived from endogenous sources play a significant role in human cancer development, and the interaction of surface nucleolin with disease-related ligands will be a new research subject for the prevention and treatment of various ailments. © 2014 The Author(s).

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