The Cancer Chemotherapy Center

Tokyo, Japan

The Cancer Chemotherapy Center

Tokyo, Japan
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PubMed | Tokyo Women's Medical University, Tottori University, Keio University, Hiroshima University and 4 more.
Type: Journal Article | Journal: PloS one | Year: 2014

Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.


PubMed | Institute of Microbial Chemistry BIKAKEN and The Cancer Chemotherapy Center
Type: Journal Article | Journal: PloS one | Year: 2015

Fibroblast-like stromal cells modulate cancer cells through secreted factors and adhesion, but those factors are not fully understood. Here, we have identified critical stromal factors that modulate cancer growth positively and negatively. Using a cell co-culture system, we found that gastric stromal cells secreted IL-6 as a growth and survival factor for gastric cancer cells. Moreover, gastric cancer cells secreted PGE2 and TNF that stimulated IL-6 secretion by the stromal cells. Furthermore, we found that stromal cells secreted glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Extracellular GAPDH, or its N-terminal domain, inhibited gastric cancer cell growth, a finding confirmed in other cell systems. GAPDH bound to E-cadherin and downregulated the mTOR-p70S6 kinase pathway. These results demonstrate that stromal cells could regulate cancer cell growth through the balance of these secreted factors. We propose that negative regulation of cancer growth using GAPDH could be a new anti-cancer strategy.


Hiramatsu M.,The Cancer Institute | Hiramatsu M.,Jikei University School of Medicine | Ninomiya H.,The Cancer Institute | Inamura K.,The Cancer Institute | And 10 more authors.
Lung Cancer | Year: 2010

The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with EGFR or KRAS mutations have been widely studied using cancer cell lines, although it is still uncertain in primary tumors.To study the activation status of main components of growth factor-induced pathways, phosphorylated Akt (pAkt), extracellular signal-regulated kinases 1 and 2 (pERK) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas. Also, thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were examined.Advanced tumor stages (p<0.001), negative TTF-1 expression (p<0.001) and Akt activation (p=0.015) were independent and significant poor prognostic markers. Akt activation related to advanced stage (p=0.021), invasiveness (p=0.004), and not to mutations. TTF-1 expression associated with never-smoker (p=0.013), pre- or minimally invasiveness (p<0.001) and EGFR mutations (p=0.017) as well as with pERK (p=0.039) expression. EGFR mutations did not correlated with pAkt and pERK expression, which was different from the results based on cultured cells, while KRAS mutations were solely and significantly linked to ERK activation (p=0.009).In lung adenocarcinoma, tumors with TTF-1 expression have distinct characteristics regarding mutations, signal protein activation and clinical issues. Moreover, this property was revealed to be important in outcome estimation at any tumor stage, whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin. The signal proteins were differently related to mutation status from cultured cells. © 2010 Elsevier Ireland Ltd.


PubMed | The Cancer Chemotherapy Center, Kyoto University and Tokyo Medical University
Type: Journal Article | Journal: Molecular cancer therapeutics | Year: 2014

Tivantinib (ARQ197) was first reported as a highly selective inhibitor of c-MET and is currently being investigated in a phase III clinical trial. However, as recently reported by us and another group, tivantinib showed cytotoxic activity independent of cellular c-MET status and also disrupted microtubule dynamics. To investigate if tivantinib exerts its cytotoxic activity by disrupting microtubules, we quantified polymerized tubulin in cells and xenograft tumors after tivantinib treatment. Consistent with our previous report, tivantinib reduced tubulin polymerization in cells and in mouse xenograft tumors in vivo. To determine if tivantinib directly binds to tubulin, we performed an in vitro competition assay. Tivantinib competitively inhibited colchicine but not vincristine or vinblastine binding to purified tubulin. These results imply that tivantinib directly binds to the colchicine binding site of tubulin. To predict the binding mode of tivantinib with tubulin, we performed computer simulation of the docking pose of tivantinib with tubulin using GOLD docking program. Computer simulation predicts tivantinib fitted into the colchicine binding pocket of tubulin without steric hindrance. Furthermore, tivantinib showed similar IC50 values against parental and multidrug-resistant cells. In contrast, other microtubule-targeting drugs, such as vincristine, paclitaxel, and colchicine, could not suppress the growth of cells overexpressing ABC transporters. Moreover, the expression level of ABC transporters did not correlate with the apoptosis-inducing ability of tivantinib different from other microtubule inhibitor. These results suggest that tivantinib can overcome ABC transporter-mediated multidrug-resistant tumor cells and is potentially useful against various tumors.


Nakazawa Y.,The Cancer Chemotherapy Center | Nakazawa Y.,University of Tokyo | Takagi S.,The Cancer Chemotherapy Center | Sato S.,The Cancer Chemotherapy Center | And 5 more authors.
Cancer Science | Year: 2011

The platelet aggregation-inducing factor, Aggrus (also known as podoplanin), is reported to contribute to cancer metastasis by mediating cancer cell-platelet interaction. Aggrus has been shown to be upregulated in many different types of cancers. Thus, not only the functional inhibition of Aggrus, but also its application as a cancer-specific antigen has therapeutic potential. Among a series of anti-Aggrus mAb established previously, no mouse anti-human Aggrus mAb exists that possesses the ability to neutralize platelet aggregation. For precise preclinical examinations of mouse and monkey models, the establishment of Aggrus-neutralizing mouse mAb and their chimeric Abs is needed. In this study, we established two mouse anti-human Aggrus mAb, P2-0 and HAG-3. A precise analysis of their epitopes revealed that P2-0 recognized the conformation near the bioactive O-glycosylation site at the Thr 52 residue. In contrast, HAG-3 recognized the amino-terminus side at a short distance from the conformation recognized by P2-0. We observed that only P2-0 attenuated Aggrus-induced platelet aggregation and Aggrus binding to its platelet receptor, that is, the C-type lectin-like receptor-2. Consistent with these data, only P2-0 prevented the experimental metastasis of human Aggrus-overexpressing CHO cells. Subsequently, we cloned the complementary determining region of P2-0 and produced the murine/human chimeric P2-0 antibody. This chimeric antibody maintained its inhibitory activity of Aggrus-induced platelet aggregation and experimental metastasis. Thus, P2-0 and its chimeric antibody are expected to aid the development of preclinical and clinical examinations of Aggrus-targeted cancer therapy. © 2011 Japanese Cancer Association.


Miyata K.,The Cancer Chemotherapy Center | Takagi S.,The Cancer Chemotherapy Center | Sato S.,The Cancer Chemotherapy Center | Morioka H.,The Cancer Chemotherapy Center | And 4 more authors.
Cancer medicine | Year: 2014

Almost all highly metastatic tumor cells possess high platelet aggregating abilities, thereby form large tumor cell-platelet aggregates in the microvasculature. Embolization of tumor cells in the microvasculature is considered to be the first step in metastasis to distant organs. We previously identified the platelet aggregation-inducing factor expressed on the surfaces of highly metastatic tumor cells and named as Aggrus. Aggrus was observed to be identical to the marker protein podoplanin (alternative names, T1α, OTS-8, and others). Aggrus is frequently overexpressed in several types of tumors and enhances platelet aggregation by interacting with the platelet receptor C-type lectin-like receptor 2 (CLEC-2). Here, we generated a novel single-chain antibody variable region fragment (scFv) by linking the variable regions of heavy and light chains of the neutralizing anti-human Aggrus monoclonal antibody MS-1 with a flexible peptide linker. Unfortunately, the generated KM10 scFv failed to suppress Aggrus-induced platelet aggregation in vitro. Therefore, we performed phage display screening and finally obtained a high-affinity scFv, K-11. K-11 scFv was able to suppress Aggrus-induced platelet aggregation in vitro. Moreover, K-11 scFv prevented the formation of pulmonary metastasis in vivo. These results suggest that K-11 scFv may be useful as metastasis inhibitory scFv and is expected to aid in the development of preclinical and clinical examinations of Aggrus-targeted cancer therapies. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.


Haga N.,The Cancer Chemotherapy Center | Saito S.,The Cancer Chemotherapy Center | Tsukumo Y.,The Cancer Chemotherapy Center | Sakurai J.,The Cancer Chemotherapy Center | And 3 more authors.
Cancer Science | Year: 2010

Cancer cells consume large amounts of glucose because of their specific metabolic pathway. However, cancer cells exist in tumor tissue where glucose is insufficient. To survive, cancer cells likely have the mechanism to elude their glucose addiction. Here we show that functional mitochondria are essential if cancer cells are to avoid glucose addiction. Cancer cells with dysfunctional mitochondria, such as mitochondrial DNA-deficient Ρ;0 cells and electron transport chain blocker-treated cells, were highly sensitive to glucose deprivation. Our data demonstrated that this sensitization was associated with failure of the unfolded protein response (UPR), an adaptive response mediated by the endoplasmic reticulum (ER). This study suggests a link between mitochondria and the ER during the UPR under glucose deprivation conditions and that mitochondria govern cell fate, not only through ATP production and apoptosis regulation, but also through modulating the UPR for cell survival. © 2010 Japanese Cancer Association.


PubMed | The Cancer Chemotherapy Center
Type: Journal Article | Journal: Cancer science | Year: 2011

The platelet aggregation-inducing factor, Aggrus (also known as podoplanin), is reported to contribute to cancer metastasis by mediating cancer cell-platelet interaction. Aggrus has been shown to be upregulated in many different types of cancers. Thus, not only the functional inhibition of Aggrus, but also its application as a cancer-specific antigen has therapeutic potential. Among a series of anti-Aggrus mAb established previously, no mouse anti-human Aggrus mAb exists that possesses the ability to neutralize platelet aggregation. For precise preclinical examinations of mouse and monkey models, the establishment of Aggrus-neutralizing mouse mAb and their chimeric Abs is needed. In this study, we established two mouse anti-human Aggrus mAb, P2-0 and HAG-3. A precise analysis of their epitopes revealed that P2-0 recognized the conformation near the bioactive O-glycosylation site at the Thr(52) residue. In contrast, HAG-3 recognized the amino-terminus side at a short distance from the conformation recognized by P2-0. We observed that only P2-0 attenuated Aggrus-induced platelet aggregation and Aggrus binding to its platelet receptor, that is, the C-type lectin-like receptor-2. Consistent with these data, only P2-0 prevented the experimental metastasis of human Aggrus-overexpressing CHO cells. Subsequently, we cloned the complementary determining region of P2-0 and produced the murine/human chimeric P2-0 antibody. This chimeric antibody maintained its inhibitory activity of Aggrus-induced platelet aggregation and experimental metastasis. Thus, P2-0 and its chimeric antibody are expected to aid the development of preclinical and clinical examinations of Aggrus-targeted cancer therapy.

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