研究者詳細 - 井山　諭

論文 - 井山　諭

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Pneumothorax as an Adverse Event in Patients with Lung Metastasis of Soft Tissue Sarcoma under Eribulin Treatment

Kohichi Takada, Kazuyuki Murase, Hajime Nakamura, Naotaka Hayasaka, Yohei Arihara, Satoshi Iyama, Hiroshi Ikeda, Makoto Emori, Shintaro Sugita, Katsuyuki Nakamura, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Internal Medicine ( Japanese Society of Internal Medicine ) 58 ( 20 ) 3009 - 3012 2019年10月

DOI

Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer

Hajime Nakamura, Kohichi Takada, Yohei Arihara, Naotaka Hayasaka, Kazuyuki Murase, Satoshi Iyama, Masayoshi Kobune, Koji Miyanishi, Junji Kato

Cancer Gene Therapy ( Springer Science and Business Media LLC ) 26 ( 9-10 ) 313 - 322 2019年09月

DOI

EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells

Shogo Miura, Masayoshi Kobune, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Kazuyuki Murase, Akari Goto, Hiroshi Ikeda, Kohichi Takada, Koji Miyanishi, Junji Kato

Blood Cells, Molecules, and Diseases ( Elsevier BV ) 78 1 - 8 2019年09月

DOI

Blastic plasmacytoid dendritic cell neoplasm(BPDCN)の1例

執行延明, 西田彩華, 菅野莉英, 藤岡茉生, 大橋隆宏, 堀本浩平, 加藤潤史, 肥田時征, 宇原久, 井山諭, 前田和男, 須釜佑介

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 9 ) 1910 - 1910 2019年08月

Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells.

Naotaka Hayasaka, Kohichi Takada, Hajime Nakamura, Yohei Arihara, Yutaka Kawano, Takahiro Osuga, Kazuyuki Murase, Shohei Kikuchi, Satoshi Iyama, Makoto Emori, Shintaro Sugita, Tadashi Hasegawa, Akira Takasawa, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Scientific reports 9 ( 1 ) 5759 - 5759 2019年04月 [査読有り] [国際誌]

An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.

DOI PubMed

miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells.

Masahiro Yoshida, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Hiroshi Ikeda, Akari Goto, Yutaka Kawano, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Junji Kato, Masayoshi Kobune

PloS one 14 ( 3 ) e0213220 2019年 [査読有り] [国際誌]

We and others have demonstrated that various abnormalities of the bone marrow (BM) mesenchymal stromal cells (MSCs) such as aberrant cytokine expression, abnormal hedgehog signaling, and impaired miRNA biogenesis are observed in patients with acute myeloid leukemia (AML). However, underlying mechanisms to induce the dysfunction of BM MSCs have not yet been clarified. We previously showed that AML cells release abundant exosomal miR-7977, which, in turn, enters BM mesenchymal stromal cells (MSCs). However, the precise function of miR-7977 is not known. In this study, we performed transduction of a miR-7977 mimic into MSCs, compared transcriptomes between control-transduced (n = 3) and miR-7977-transduced MSCs (n = 3), and conducted pathway analysis. The array data revealed that the expression of 0.05% of genes was reduced 2-fold and the expression of 0.01% of genes was increased 2-fold. Interestingly, approximately half of these genes possessed a miR-7977 target site, while the other genes did not, suggesting that miR-7977 regulates the gene expression level directly and indirectly. Gene set enrichment analysis showed that the gene sets of Yes-associated protein 1 (YAP1) _up were significantly enriched (p<0.001, q<0.25), suggesting that miR-7977 modulates the Hippo-YAP signaling pathway. Visualization of pathway and network showed that miR-7977 significantly reduced the expression of Hippo core kinase, STK4. miR-7977 inactivated the Hippo-YAP signaling pathway as proven by GFP-tagged YAP nuclear trans localization and TEAD reporter assay. The miR-7977-transduced MSC cell line, HTS-5, showed elevated saturation density and enhanced entry into the cell cycle. These results suggest that miR-7977 is a critical factor that regulates the Hippo-YAP signaling pathway in BM-MSCs and may be involved in the upregulation of leukemia-supporting stroma growth.

DOI PubMed

Denosumab prevents bone loss in newly diagnosed malignant lymphoma patients undergoing corticosteroid-containing chemotherapy: A prospective, non-randomized study

Ayumi Tatekoshi, Tsutomu Sato, Satoshi Iyama, Kohichi Takada, Kazuyuki Murase, Masahiro Yoshida, Soushi Ibata, Akari Hashimoto, Yusuke Kamihara, Hiroto Horiguchi, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Sapporo Medical journal ( Sapporo Medical University ) 87 ( 1-6 ) 35 - 47 2018年12月

Background: Malignant lymphoma patients have a high risk of bone mineral density (BMD) loss caused by corticosteroid-containing chemotherapy. Bisphosphonates have been used to prevent bone loss: however, little is known about effects of denosumab, a fully humanized monoclonal antibody inhibiting osteoclast-mediated bone resorption. Methods: This clinical trial was conducted in newly diagnosed lymphoma patients undergoing corticosteroidcontaining chemotherapy. BMD was evaluated at baseline, and patients with a lumbar spine T-score of < -1 were subcutaneously administered once with 60 mg of denosumab ("Denosumab" group). Patients with a T-score > -1 were allocated to the "No treatment" group. BMD was reevaluated at 24 weeks after enrollment. Bone turnover markers (BTMs) were collected at 0,2, and 24 weeks. Results: Forty-three patients were enrolled (19 in the "Denosumab" group and 24 in the "No treatment" group). Patients in the "No treatment" group had decreased T-scores for the lumbar spine or femoral neck (P < 0.0001 or P = 0.0029, respectively) at 24 weeks after enrollment, whereas both T-scores were stable in the "Denosumab" group. Of the 18 patients in the "Denosumab" group, 12 had a T-score change from baseline (AT-score) of > 0, whereas the remaining six patients had a AT-score < 0. These six patients had severely low T-scores at enrollment. Osteoclastic BTMs were strongly suppressed during the 24 weeks in the "Denosumab" group. The probability of major osteoporotic fracture or hip fracture in the "No treatment?' group increased during the 24 weeks (P = 0.0195 or P = 0.0289, respectively), whereas pretreatment with denosumab prevented increased risks of both types of fractures. Conclusions: Our data suggests that BMD screening at diagnosis of lymphoma should be considered so that the bone health of lymphoma survivors can be improved with denosumab.

DOI

Long-term prognosis of human herpesvirus 6 reactivation following allogeneic hematopoietic stem cell transplantation.

Kotoe Iesato, Tsukasa Hori, Yuko Yoto, Masaki Yamamoto, Natsuko Inazawa, Kenichi Kamo, Hiroshi Ikeda, Satoshi Iyama, Naoki Hatakeyama, Akihiro Iguchi, Junichi Sugita, Ryoji Kobayashi, Nobuhiro Suzuki, Hiroyuki Tsutsumi

Pediatrics international : official journal of the Japan Pediatric Society 60 ( 6 ) 547 - 552 2018年06月 [査読有り] [国際誌]

BACKGROUND: Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently have HHV-6 reactivation typically during the early phase following HSCT. The long-term clinical complications and prognosis, however, remain unclear. METHODS: Between September 2010 and October 2012, whole blood samples from 105 patients collected weekly from prior to 6 weeks after HSCT underwent multiplex polymerase chain reaction (PCR) to screen for viral DNA, followed by real-time PCR for quantitative estimation. In 48 patients, only HHV-6 was detected in at least one sample. In 30 patients, no viral DNA was detected. Long-term clinical records were reviewed in March 2016. All 48 HHV-6-positive patients, and 24 patients in whom no viral DNA detected, were followed up. RESULTS: Median maximum HHV-6 DNA load in the blood of the HHV-6 reactivation group (n = 48) was 11 800 copies/μg peripheral blood leukocyte DNA (range, 52-310 000 000). Hemophagocytic syndrome (HPS) was diagnosed in two subjects with HHV-6 reactivation. Acute graft-versus-host disease (GVHD) developed more frequently in patients with HHV-6 reactivation than in patients without viral reactivation (P = 0.002), but there was no difference in incidence of chronic GVHD. There was no difference in engraftment of neutrophils and platelets between groups. There was also no difference in overall survival between groups. Onset of HPS, however, was associated with lower overall survival (P = 0.009). CONCLUSIONS: Human herpesvirus 6 reactivation was associated with acute GVHD, but not with chronic GVHD, engraftment or overall survival. Onset of HPS, however, predicts lower overall survival.

DOI PubMed

High expression of nucleoporin 133 mRNA in bone marrow CD138+ cells is a poor prognostic factor in multiple myeloma

Soushi Ibata, Masayoshi Kobune, Shohei Kikuchi, Masahiro Yoshida, Shogo Miura, Hiroto Horiguchi, Kazuyuki Murase, Satoshi Iyama, Kohichi Takada, Koji Miyanishi, Junji Kato

Oncotarget ( Impact Journals LLC ) 9 ( 38 ) 25127 - 25135 2018年05月 [査読有り]

Recent advances in plasma cell biology and molecularly-targeted therapy enable us to employ various types of drugs including immunomodulatory drugs, proteasome inhibitors, and immunotherapy. However, the optimal therapeutic strategies to introduce these drugs for heterogeneous patients with multiple myeloma (MM) have not yet been clarified. In the present study, we attempted to identify a new factor indicating poor prognosis in CD138+ myeloma cells using accumulated Gene Expression Omnibus (GEO) datasets from studies of MM and to assess the relationship between gene expression and survival using MAQC-II Project Myeloma (GSE24080). Five GEO datasets (GSE5900, GSE58133, GSE68871, GSE57317 and GSE16791) which were analyzed by the same microarray platform (GLP570) were combined into one MM database including various types of MM. However, we found that gene expression levels were quite heterogeneous. Hence, we focused on the differentially-expressed genes (DEGs) between newlydiagnosed MM and relapsed/refractory MM and found that the expression levels of more than 20 genes changed two-fold or more. Additionally, pathway analysis indicated that six pathways including Hippo signaling were significantly enriched. Then, we applied all DEGs and genes associated with core enrichment for GSE24080 to evaluate their involvement in disease prognosis. We found that nucleoporin 133 (NUP133) is an independent poor prognostic factor by Cox proportional hazard analysis. These results suggested that high expression of NUP133 could be useful when choosing the appropriate MM therapy and may be a new target of MM therapy.

DOI

ART療法中に多発血栓症を併発した悪性リンパ腫患者の一例

池田博, 吉田正宏, 舘越鮎美, 菊地尚平, 村瀬和幸, 高田弘一, 井山諭, 小船雅義, 村上則子, 宮越郁子, 又村了輔, 國本雄介, 加藤淳二

日本エイズ学会誌 ( (一社)日本エイズ学会 ) 19 ( 4 ) 501 - 501 2017年11月

Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma

Yohei Arihara, Kohichi Takada, Yusuke Kamihara, Naotaka Hayasaka, Hajime Nakamura, Kazuyuki Murase, Hiroshi Ikeda, Satoshi Iyama, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Junji Kato

ONCOTARGET ( IMPACT JOURNALS LLC ) 8 ( 39 ) 65889 - 65899 2017年09月 [査読有り]

Reactive oxygen species (ROS) are normal byproducts of a wide variety of cellular processes. ROS have dual functional roles in cancer cell pathophysiology. At low to moderate levels, ROS act as signaling transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS induce cell death. In multiple myeloma (MM), ROS overproduction is the trigger for apoptosis induced by several anticancer compounds, including proteasome inhibitors. However, no drugs for which oxidative stress is the main mechanism of action are currently used for treatment of MM in clinical situations. In this study, we demonstrate that the p53-activating small molecule CP-31398 (CP) effectively inhibits the growth of MM cell lines and primary MM isolates from patients. CP also suppresses the growth of MM xenografts in mice. Mechanistically, CP was found to induce intrinsic apoptosis in MM cells via increasing ROS production. Interestingly, CP-induced apoptosis occurs regardless of the p53 status, suggesting that CP has additional mechanisms of action. Our findings thus indicate that CP could be an attractive candidate for treatment of MM patients harboring p53 abnormalities; this satisfies an unmet clinical need, as such individuals currently have a poor prognosis.

DOI PubMed

[A Case of Chronic Myelogenous Leukemia That Developed Fibrous Pericarditis Owing to Nilotinib Use].

Miura S, Murase K, Sakurada A, Takada K, Iyama S, Sato T, Sato Y, Miyanishi K, Kobune M, Muranaka A, Tachibana K, Kato J

Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 6 ) 529 - 531 2017年06月 [査読有り] [国内誌]

A 64-year-old man was diagnosed with chronic-phase chronic myelogenous leukemia(CML)in May 2009. He was treated with imatinib and achieved complete cytogenetic response(CCyR)in 2 months. After 4 months of treatment, he developed interstitial pneumonia and became intolerant to imatinib. He was then switched to nilotinib from October of the same year. In June 2013, he was diagnosed with drug-induced pericarditis resulting from nilotinib use, and thus, nilotinib was discontinued. Subsequently, he was followed up without specific treatment for CML. In January 2014, he was admitted to the Dept. of Cardiovascular, Renal and Metabolic Medicine at our hospital because of heart failure. After examinations of cardiac function, he was diagnosed with constrictive pericarditis. Therefore, pericardiolysis was performed by the Dept. of Cardiovascular Surgery at our hospital. Pathologic findings showed hyaline-like fibrous tissue proliferation in the pericardium, which was diagnosed as fibrous pericarditis induced by nilotinib. We report a case of chronic myelogenous leukemia that developed fibrous pericarditis owing to nilotinib use.

PubMed

低分子化合物CP-31398は多発性骨髄腫に対して活性酸素種依存的なアポトーシスを誘導する

在原洋平, 高田弘一, 神原悠輔, 河野豊, 早坂尚貴, 中村元, 菊地尚平, 村瀬和幸, 井山諭, 池田博, 佐藤勉, 宮西浩嗣, 小船雅義, 加藤淳二

International Journal of Myeloma ( 日本骨髄腫学会 ) 7 ( 1 ) 76 - 76 2017年04月 [査読有り]

A Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma

Satoshi Iyama, Tsutomu Sato, Hirofumi Ohnishi, Yuji Kanisawa, Shuichi Ohta, Takeshi Kondo, Akio Mori, Yutaka Tsutsumi, Hiroyuki Kuroda, Yasutaka Kakinoki, Satoshi Yamamoto, Tohru Takahashi, Motohiro Shindo, Yoshihiro Torimoto, Kazuya Sato, Hiroshi Iwasaki, Yoshihito Haseyama, Kyuhei Kohda, Yasuhiro Nagamachi, Yasuo Hirayama, Hajime Sakai, Yasuji Hirata, Takashi Fukuhara, Hiroshi Ikeda, Masayoshi Kobune, Junji Kato, Mitsutoshi Kurosawa

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA ( CIG MEDIA GROUP, LP ) 17 ( 1 ) 23 - 30 2017年01月 [査読有り]

担当区分：筆頭著者 , 責任著者

Mogamulizumab recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab for ATL treatment in patients in Japan and found that mogamulizumab is an effective therapeutic strategy in ATL. Some concern exists that the use of mogamulizumab in patients undergoing hematopoietic stem cell transplantation patients might cause severe graft-versus-host disease. Determining the optimum number of mogamulizumab administrations should be a priority for future studies. Background: Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C-C chemokine receptor 4, recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan. Materials and Methods: A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study. Results: Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35-86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3-4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non-HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21-53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III-IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively. Conclusion: Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre-HSCT mogamulizumab treatment regimen is thus a priority. (C) 2016 Elsevier Inc. All rights reserved.

DOI PubMed

A phase II trial of small-dose bortezomib, lenalidomide and dexamethasone (sVRD) as consolidation/maintenance therapy in patients with multiple myeloma

Soushi Ibata, Tsutomu Sato, Hiroyuki Kuroda, Yasuhiro Nagamachi, Satoshi Iyama, Akihito Fujimi, Yusuke Kamihara, Yuichi Konuma, Masahiro Yoshida, Ayumi Tatekoshi, Akari Hashimoto, Hiroto Horiguchi, Kaoru Ono, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Masayoshi Kobune, Yasuo Hirayama, Junji Kato

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER ) 78 ( 5 ) 1041 - 1049 2016年11月 [査読有り]

Consolidation/maintenance therapy induces deep remission in patients with multiple myeloma (MM); however, the most suitable regimen has been under investigation. The combination therapy with bortezomib, lenalidomide and dexamethasone (VRD) is a powerful regimen for relapsed/refractory as well as newly diagnosed MM as an induction therapy. However, severe adverse events (AEs) may become a problem when VRD is introduced without dose reduction as a consolidation/maintenance therapy. In this single-arm phase II study, we evaluated the efficacy of small-dose VRD regimen (sVRD) in the consolidation/maintenance setting. Sixteen patients who had partial response (PR) or better after any induction therapy were enrolled. Patients received at least six 28-day cycles of subcutaneous bortezomib (1.3 mg/m(2) on days 1 and 15), lenalidomide (10 mg on days 1-21) and dexamethasone (40 mg on days 1, 8, 15 and 22). The overall response rate and the complete response (CR) rate were 100 and 43.8 %, respectively. In particular, one patient with CR and two patients with very good PR at enrollment achieved stringent CR during 6 courses of sVRD. With a median follow-up time of 29.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached, while the PFS and OS rates at 2.5 years were 66.6 and 77.3 %, respectively. Univariate analysis demonstrated that disease progression as a reason for discontinuation of sVRD had a negative impact on OS. There were no grade 3 or 4 hematologic or nonhematologic AEs. Our sVRD regimen as a consolidation/maintenance therapy was highly effective and well tolerable.

DOI PubMed

Phase I/IIa Study of Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease

Takeru Asano, Ken-Ichi Matsuoka, Satoshi Iyama, Kazuteru Ohashi, Yoshihiro Inamoto, Chikako Ohwada, Makoto Murata, Atsushi Satake, Chikamasa Yoshida, Koichi Nakase, Yasuo Mori, Mitsune Tanimoto

ACTA MEDICA OKAYAMA ( OKAYAMA UNIV MED SCHOOL ) 70 ( 5 ) 429 - 433 2016年10月 [査読有り]

Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT.

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma.

Kamihara Y, Takada K, Sato T, Kawano Y, Murase K, Arihara Y, Kikuchi S, Hayasaka N, Usami M, Iyama S, Miyanishi K, Sato Y, Kobune M, Kato J

Oncotarget 7 ( 39 ) 64330 - 64341 2016年09月 [査読有り] [国際誌]

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling.

DOI PubMed

Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer.

Osuga T, Takimoto R, Ono M, Hirakawa M, Yoshida M, Okagawa Y, Uemura N, Arihara Y, Sato Y, Tamura F, Sato T, Iyama S, Miyanishi K, Takada K, Hayashi T, Kobune M, Kato J

Journal of the National Cancer Institute 108 ( 9 ) 2016年09月 [査読有り] [国際誌]

BACKGROUND: Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-ß-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC. METHODS: In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided. RESULTS: We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P ≤ .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 ± 3.09; SN38-treated group [SN38], 3.53 ± 1.47; liposome-carrying, SN38-treated group [F0], 3.1 ± 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 ± 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001). CONCLUSIONS: Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

DOI PubMed

Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer

Takahiro Osuga, Rishu Takimoto, Michihiro Ono, Masahiro Hirakawa, Makoto Yoshida, Yutaka Okagawa, Naoki Uemura, Yohei Arihara, Yasushi Sato, Fumito Tamura, Tsutomu Sato, Satoshi Iyama, Koji Miyanishi, Kohichi Takada, Tsuyoshi Hayashi, Masayoshi Kobune, Junji Kato

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE ( OXFORD UNIV PRESS INC ) 108 ( 8 ) 2016年08月 [査読有り]

Background: Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-beta-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC. Methods: In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided. Results: We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P <= .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 +/- 3.09; SN38-treated group [SN38], 3.53 +/- 1.47; liposome-carrying, SN38-treated group [F0], 3.1 +/- 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 +/- 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001). Conclusions: Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

DOI PubMed

[Treatment Outcomes of Adult-Onset Ewing Sarcoma: A Single-Center Retrospective Study of Five Cases].

Murase K, Takada K, Kamihara Y, Usami M, Yoshida M, Tatekoshi A, Hashimoto A, Arihara Y, Hayasaka N, Miura S, Iyama S, Sato T, Sato Y, Miyanishi K, Kobune M, Emori M, Kaya M, Yamashita T, Sugita S, Hasegawa T, Kato J

Gan to kagaku ryoho. Cancer & chemotherapy 43 ( 8 ) 1015 - 8 2016年08月 [査読有り] [国内誌]

UNLABELLED: We report the treatment outcomes of 5 cases of adult-onset Ewing sarcoma(ES)managed between 2011 and 2014. We examined prognostic factors including the primary lesion, tumor size, metastatic status, and serum LDH levels. RESULTS: The locations of the primary lesions included the limbs in 1 case and the trunk in 4; the cases in the trunk had a worse prognosis than that in the limbs. Tumor size was greater than 8 cm in only 1 patient, who also displayed evidence of metastases at presentation and high LDH levels. All the patients received chemotherapy consisting of alternating vincristine, doxorubicin, and cyclophosphamide(VDC)and etoposide and ifosfamide(IE). Surgery was selected for the treatment of 4 patients, and radiotherapy was administered to 1 patient for local treatment of the tumor. A median follow-up duration of 31.6 months revealed the 2-year overall survival rate and progression-free survival rate to be 80.0%. CONCLUSIONS: The prognosis of patients with adult-onset ES is poor; however, combined modality therapy, including VDC-IE, was demonstrated to improve the outcome of patients in the present study. Nevertheless, the patient with tumor size exceeding 8 cm, metastasis, and high LDH levels, relapsed 1 year after treatment, as reported previously. Further investigation is required to clarify the factors affecting prognosis in adults, and to develop effective therapies for patients with a poor prognosis.

PubMed

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