Kanagawa Cancer Center Research Institute

Yokohama-shi, Japan

Kanagawa Cancer Center Research Institute

Yokohama-shi, Japan
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Narimatsu H.,Kanagawa Cancer Center Research Institute
International Journal of Molecular Sciences | Year: 2017

The progression of many common disorders involves a complex interplay of multiple factors, including numerous different genes and environmental factors. Gene-environmental cohort studies focus on the identification of risk factors that cannot be discovered by conventional epidemiological methodologies. Such epidemiological methodologies preclude precise predictions, because the exact risk factors can be revealed only after detailed analyses of the interactions among multiple factors, that is, between genes and environmental factors. To date, these cohort studies have reported some promising results. However, the findings do not yet have sufficient clinical significance for the development of precise, personalized preventive medicine. Especially, some promising preliminary studies have been conducted in terms of the prevention of obesity. Large-scale validation studies of those preliminary studies, using a prospective cohort design and long follow-ups, will produce useful and practical evidence for the development of preventive medicine in the future. © 2017 by the authors; licensee MDPI, Basel, Switzerland.


Koizume S.,Kanagawa Cancer Center Research Institute | Miyagi Y.,Kanagawa Cancer Center Research Institute
International Journal of Molecular Sciences | Year: 2017

Tissue factor (TF) is a cell surface receptor for coagulation factor VII (fVII). The TF-activated fVII (fVIIa) complex is an essential initiator of the extrinsic blood coagulation process. Interactions between cancer cells and immune cells via coagulation factors and adhesion molecules can promote progression of cancer, including epithelial ovarian cancer (EOC). This process is not necessarily advantageous, as tumor tissues generally undergo hypoxia due to aberrant vasculature, followed by reduced access to plasma components such as coagulation factors. However, hypoxia can activate TF expression. Expression of fVII, intercellular adhesion molecule-1 (ICAM-1), and multiple pro-inflammatory cytokines can be synergistically induced in EOC cells in response to hypoxia along with serum deprivation. Thus, pro-inflammatory responses associated with the TF-fVIIa–ICAM-1 interaction are expected within hypoxic tissues. Tumor tissue consists of multiple components such as stromal cells, interstitial fluid, albumin, and other micro-factors such as proton and metal ions. These factors, together with metabolism reprogramming in response to hypoxia and followed by functional modification of TF, may contribute to coagulation factor-driven inflammatory responses in EOC tissues. The aim of this review was to describe potential coagulation factor-driven inflammatory responses in hypoxic EOC tissues. Arguments were extended to clinical issues targeting this characteristic tumor environment. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.


Takahashi K.,Kanagawa Cancer Center Research Institute | Tanaka T.,Kanagawa Cancer Center Research Institute | Suzuki K.,Kanagawa Cancer Center Research Institute
Cellular Signalling | Year: 2010

Membrane targeting of WAVE2 along microtubules is mediated by a motor protein kinesin and requires Pak1, a downstream effector of Rac1. However, the mechanism by which WAVE2 targeting to the leading edge is directionally controlled remains largely unknown. Here we demonstrate that EB1, a microtubule plus-end-binding protein, constitutively associates with stathmin, a microtubule-destabilizing protein, in human breast cancer cells. Stimulation of the cells with insulin-like growth factor I (IGF-I) induced Pak1-dependent binding of the EB1-stathmin complex to microtubules that bear WAVE2 and colocalization of the complex with WAVE2 at the leading edge. Depletion of EB1 by small interfering RNA (siRNA) abrogated the IGF-I-induced WAVE2 targeting and stathmin binding to microtubules. On the other hand, chemotaxis chamber assays indicated that the IGF-I receptor (IGF-IR) was locally activated in the region facing toward IGF-I. In addition, IGF-I caused phosphatidylinositol 3-kinase (PI 3-kinase)-dependent production of phosphatidylinositol 3,4,5-triphosphate (PIP3) near activated IGF-IR and WAVE2 colocalization with it. Collectively, WAVE2-membrane targeting is directionally controlled by binding of the EB1-stathmin complex to WAVE2-bearing microtubules and by the interaction between WAVE2 and PIP3 produced near IGF-IR that is locally activated by IGF-I. © 2009 Elsevier Inc. All rights reserved.


Kikuchi K.,Kanagawa Cancer Center Research Institute | Li X.,Kanagawa Cancer Center Research Institute | Zheng Y.,Kanagawa Cancer Center Research Institute | Takano Y.,Kanagawa Cancer Center Research Institute
FEBS Letters | Year: 2011

Invasion of MDA-MB-231 breast cancer cells into three-dimensional (3-D) type I-collagen matrices depends on TGF-α. We characterized the steps of invasion mediated by TGF-α. Cell migration, as observed by videomicroscopy, was effectively stimulated by collagen, suggesting that TGF-α may specifically participate in the invasion of a 3-D collagen matrix. We assessed the role of small GTPases of the Rho family in the invasion. Cdc42 was found to be necessary for invasion but dispensable for cell migration. These results suggest that TGF-α mediates invasion into 3-D collagen matrices by initiating the formation of protrusions into collagen, likely through activation of Cdc42. Structured summary: PAK physically interacts with Rac1 by pull down (View interaction) PAK physically interacts with CDC42 by pull down (View interaction). © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Koizume S.,Kanagawa Cancer Center Research Institute | Miyagi Y.,Kanagawa Cancer Center Research Institute
Genomics Data | Year: 2015

The tumor microenvironment is generally hypoxic because of the limited oxygen supply from inefficient or insufficient vasculature. Hypoxic tumor tissues are also poorly supplied with serum components. We have previously demonstrated that expression of the FVII gene is induced in response to hypoxia in ovarian clear cell carcinoma (CCC) cells. This gene activation is synergistically enhanced when cells are simultaneously subjected to serum starvation, and is dependent on the transcription factor Sp1 directly associating with the FVII promoter. We have identified additional genes activated via a similar Sp1-dependent mechanism by conducting cDNA microarray analysis (GSE55565). ICAM1, which encodes intercellular adhesion molecule-1 (ICAM-1), is one such gene. ICAM-1 confers an anti-apoptotic effect upon CCC cells in vitro and promotes growth of CCC tumors. Here we describe the transcriptome analysis performed in our recently published study (Koizume et al., 2015). We further show that autonomous activation of the TNFα-NFκB axis is responsible for the synergistic activation of ICAM1 under hypoxic and serum starvation conditions. This study provides additional information as to how CCC cell survival can be facilitated under conditions of serum starvation and hypoxia. © 2015.


Morimura S.,Kanagawa Cancer Center Research Institute | Takahashi K.,Kanagawa Cancer Center Research Institute
International Journal of Cell Biology | Year: 2011

Cell migration is considered necessary for the invasion that accompanies the directional formation of the cellular protrusions termed lamellipodia. In invasive breast cancer MDA-MB-231 cells, lamellipodia formation is preceded by translocation of the actin cytoskeletal regulatory protein WAVE2 to the leading edge. WAVE2 translocation and lamellipodia formation require many signaling molecules, including PI3K, Rac1, Pak1, IRSp53, stathmin, and EB1, but whether these molecules are necessary for invasion remains unclear. In noninvasive breast cancer MCF7 cells, no lamellipodia were induced by IGF-I, whereas in MDA-MB-231 cells, Rac1, stathmin, and EB1 were overexpressed. Depletion of Rac1 or stathmin by small interfering RNA abrogated the IGF-I-induced invasion of MDA-MB-231 cells; however, depletion of EB1 did not, indicating the necessity of Rac1 and stathmin but not EB1 for invasion. The signaling pathway leading to cell invasion may not be identical but shares some common molecules, leading to cell migration through lamellipodia formation. Copyright © 2011 Shigeru Morimura and Kazuhide Takahashi.


Morimura S.,Kanagawa Cancer Center Research Institute | Suzuki K.,Kanagawa Cancer Center Research Institute | Takahashi K.,Kanagawa Cancer Center Research Institute
Biochemical and Biophysical Research Communications | Year: 2011

Investigation of the mechanism underlying cell membrane-targeted WAVE2 capture by phosphatidylinositol 3,4,5-triphosphate (PIP 3) through IRSp53 revealed an unidentified 250-kDa protein (p250) bound to PIP 3. We identified p250 as nonmuscle myosin IIA heavy chain (MYH9) by mass spectrometry and immunoblot analysis using anti-MYH9 antibody. After stimulation with insulin-like growth factor I (IGF-I), MYH9 colocalized with PIP 3 in lamellipodia at the leading edge of cells. Depletion of MYH9 expression by small interfering RNA (siRNA) and inhibition of myosin II activity by blebbistatin abrogated the formation of actin filament (F-actin) arcs and lamellipodia induced by IGF-I. MYH9 was constitutively associated with WAVE2, which was dependent on myosin II activity, and the MYH9-WAVE2 complex colocalized to PIP 3 at the leading edge after IGF-I stimulation. These results indicate that MYH9 is required for lamellipodia formation since it provides contractile forces and tension for the F-actin network to form convex arcs at the leading edge through constitutive binding to WAVE2 and colocalization with PIP 3 in response to IGF-I. © 2010 Elsevier Inc.


Takahashi K.,Kanagawa Cancer Center Research Institute | Suzuki K.,Kanagawa Cancer Center Research Institute
Cellular Signalling | Year: 2010

Membrane targeting of WAVE2 along microtubules to phosphatidylinositol 3,4,5-triphosphate (PIP 3) in response to an extracellular stimulus requires Rac1, Pak1, stathmin, and EB1. However, whether WAVE2 interacts directly with PIP 3 or not remains unclear. We demonstrate that insulin-like growth factor I (IGF-I) induces WAVE2 membrane targeting, accompanied by phosphorylation of Pak1 at serine 199/204 (Ser199/204) and stathmin at Ser38 in the inner cytoplasmic region. This is spatially independent of the membrane region where the IGF-I receptor (IGF-IR) is locally activated. WAVE2, phosphorylated Pak1, and phosphorylated stathmin located at the microtubule ends began to accumulate at the leading edge of cells in close proximity to PIP 3 that was produced in a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent manner. The PIP 3-beads binding assay revealed that insulin receptor substrate p53 (IRSp53) and actin rather than WAVE2 bound to PIP 3. IRSp53 constitutively associated with WAVE2 and these two proteins colocalized with PIP 3 at the leading edge after IGF-I stimulation. Suppression of IRSp53 expression by two independent small interfering RNAs (siRNAs) completely inhibited IGF-I-induced membrane targeting and local accumulation of WAVE2 at the leading edge of cells. We propose that IRSp53 constitutively forms a complex with WAVE2 and is crucial for membrane targeting followed by local accumulation of WAVE2 at the leading edge of cells through linking WAVE2 to PIP 3 that is produced near locally activated IGF-IR in response to IGF-I. © 2010 Elsevier Inc.


Takahashi K.,Kanagawa Cancer Center Research Institute
Journal of Oncology | Year: 2012

E-cadherin is one of the key molecules in the formation of cell-cell adhesion and interacts intracellularly with a group of proteins collectively named catenins, through which the E-cadherin-catenin complex is anchored to actin-based cytoskeletal components. Although cell-cell adhesion is often disrupted in cancer cells by either genetic or epigenetic alterations in cell adhesion molecules, disruption of cell-cell adhesion alone seems to be insufficient for the induction of cancer cell migration and invasion. A small GTP-binding protein, Rac1, induces the specific cellular protrusions lamellipodia via WAVE2, a member of WASP/WAVE family of the actin cytoskeletal regulatory proteins. Biochemical and pharmacological investigations have revealed that WAVE2 interacts with many proteins that regulate microtubule growth, actin assembly, and membrane targeting of proteins, all of which are necessary for directional cell migration through lamellipodia formation. These findings might have important implications for the development of effective therapeutic agents against cancer cell migration and invasion. Copyright © 2012 Kazuhide Takahashi.


Katayama K.,Kanagawa Cancer Center Research Institute | Narimatsu H.,Kanagawa Cancer Center Research Institute
PLoS ONE | Year: 2016

Owing to the increasing number of elderly "baby boomers" in Japan, the number of cancer patients is also expected to increase. Approximately 2 million baby boomers from nearby local areas are residing in metropolitan areas; hence, the geographical distribution of cancer patients will probably markedly change. We assessed the expected number of breast cancer (BC) patients in different regions (urban, outer city, town, rural) using estimates of the nation's population and Kanagawa Cancer Registry data. To estimate future BC incidence for each region, we multiplied the 2010 rate by the predicted female population for each region according to age group. The incidence cases of BC in those aged ≥65 years is expected to increase in all areas; in particular, compared to rates in 2010, the BC incidence in urban areas was predicted to increase by 82.6% in 2035 and 102.2% in 2040. Although the incidence in all BC cases in urban areas showed an increasing trend, until peaking in 2040 (increasing 31.2% from 2010), the number of BC patients would continue to decrease in other areas. The number of BC patients per capita BC specialist was 64.3 patients in 2010; this value would increase from 59.3 in 2010 to 77.7 in 2040 in urban areas, but would decrease in other areas. Our findings suggest that the number of elderly BC patients is expected to increase rapidly in urban areas and that the demand for BC treatment would increase in the elderly population in urban areas. © 2016 Katayama, Narimatsu.

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