Researchers Database

nakaya takeo

    DeprtmentofPathology(DivisionofhumanPathology) Associate Professor
Last Updated :2021/12/07

Researcher Information


Research funding number

  • 80512277

J-Global ID

Research Interests

  • がん分子創薬   創薬病理学   大腸癌   蛋白間相互作用阻害薬   病理診断学   New Cancer Therapy   Stem cell   腫瘍抑制   がん   KLF5   EBウイルス   癌幹細胞   LMP2A   

Research Areas

  • Life sciences / Experimental pathology
  • Life sciences / Tumor biology
  • Life sciences / Pharmaceuticals - chemistry and drug development
  • Life sciences / Human pathology

Published Papers

  • Takeo Nakaya, Koji Kamiya, Michio Nakaya, Kentaro Tsuji, Toshiro Niki, Mamitaro Ohtsuki, Akira Tanaka
    Medicine 99 (29) e20867  2020/07 [Refereed][Not invited]
    RATIONALE: Phagocytosis is an important physiological process for eliminating unnecessary substances or dead cells after tissue damage, such as inflammation or infarction. Phagocytosis was previously considered to be mainly performed by professional phagocytotic cells, such as macrophages. In contrast, we previously demonstrated that the phagocytosis of dead cells and unnecessary substances by myofibroblasts is as important as that by professional phagocytotic cells in myocardial infarction. Based on our discovery, we speculated that phagocytosis by myofibroblasts may be a more common pathological phenomenon also in other diseases than previously believed. PATIENT CONCERNS: A 44-year-old male patient with atopic dermatitis developed a cutaneous reddish nodule with an underlying induration on his thigh. INTERVENTIONS: The cutaneous lesion was surgically removed. DIAGNOSES: Histopathological examination demonstrated that the cutaneous lesion had solid infiltration by inflammatory cells, namely, plasma cells, histiocytes, and lymphocytes, in the dermis. The cutaneous lesion included mucinosis in the dermis. Inside the mucinosis, we detected cells with clear areas of mucinous substances. Some of the cells were α-smooth muscle actin-positive myofibroblasts. Electron microscopic images demonstrated that there were collagen bands in the cells with mucinous engulfment. Based on these pieces of evidence, we conclude that these mucinous phagocytotic cells were myofibroblasts, not professional phagocytotic cells, such as macrophages. OUTCOMES: There was no recurrence of the lesion. LESSONS: The clinical appearance of this case resembled that of previously reported solitary cutaneous focal mucinoses. However, our case had distinctive characteristics, such as the phagocytosis of mucinous substances by myofibroblasts, multiple mucinous lesions in a single eruption, and the presence of inflammatory cells, which have not been previously reported. For this distinct cutaneous lesion, a clear dermatological and pathological name has yet to be determined. We propose "myofibroblast phagocytic cutaneous mucinosis" as a candidate name. In addition, our discoveries suggest that phagocytosis by myofibroblasts is not rare but rather is a common pathological phenomenon that has been undetected or unrecognized.
  • Yuma Horii, Michio Nakaya, Hiroki Ohara, Hiroaki Nishihara, Kenji Watari, Akiomi Nagasaka, Takeo Nakaya, Yuki Sugiura, Toshiaki Okuno, Tomoaki Koga, Akira Tanaka, Takehiko Yokomizo, Hitoshi Kurose
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 (6) 8749 - 8763 2020/05 [Refereed][Not invited]
    Leukotriene B4 receptor 1 (BLT1), a high-affinity G-protein-coupled receptor for leukotriene B4 (LTB4 ), is expressed on various inflammatory cells and plays critical roles in several inflammatory diseases. In myocardial infarction (MI), various inflammatory cells are known to be recruited to the infarcted area, but the function of BLT1 in MI is poorly understood. Here, we investigated the role of BLT1 in MI and the therapeutic effect of a BLT1 antagonist, ONO-4057, on MI. Mice with infarcted hearts showed increased BLT1 expression and LTB4 levels. BLT1-knockout mice with infarcted hearts exhibited attenuated leukocyte infiltration, proinflammatory cytokine production, and cell death, which led to reduced mortality and improved cardiac function after MI. Bone-marrow transplantation studies showed that BLT1 expressed on bone marrow-derived cells was responsible for the exacerbation of inflammation in infarcted hearts. Furthermore, ONO-4057 administration attenuated the inflammatory responses in hearts surgically treated for MI, which resulted in reduced mortality and improved cardiac function after MI. Our study demonstrated that BLT1 contributes to excessive inflammation after MI and could represent a new therapeutic target for MI.
  • 小児の終糸脂肪腫にmyxopapillary ependymoma様の上衣成分を伴った1例
    辻 賢太郎, 仁木 利郎, 大城 久, 柴原 純二, 廣田 由佳, 仲矢 丈雄, 河田 浩敏, 田中 亨, 福嶋 敬宜
    日本病理学会会誌 (一社)日本病理学会 109 (1) 385 - 385 0300-9181 2020/03
  • Kentaro Tsuji, Takeo Nakaya, Kentaro Ashizawa, Fumihiro Arai, Noriyoshi Fukushima, Akira Gomi, Shintaro Sugita, Tadashi Hasegawa, Akira Tanaka
    Pathology international 70 (2) 123 - 125 1320-5463 2020/02 [Refereed][Not invited]
  • 膵癌は、他の独立した癌病巣・線維化病変に、それらの形成する微小環境を乗っ取り、転移しやすい(Pancreatic carcinoma metastasis to other carcinoma lesions and fibrotic regions, overtaking the stromal microenvironment)
    仲矢 丈雄, 大城 久, 斎藤 匠, 佐久間 康成, 曽我部 将哉, 山本 真一, 辻 賢太郎, 仲矢 道雄, 遠藤 俊輔, 堀江 久永, 佐田 尚宏, 仁木 利郎, 田中 亨
    日本癌学会総会記事 78回 E - 2106 0546-0476 2019/09
  • Kentaro Tsuji, Atsushi Ito, Shinsuke Kurokawa, Takeo Nakaya, Taichiro Yoshimoto, Hirotoshi Kawata, Mio Tamba-Sakaguchi, Noriyoshi Fukushima, Hisashi Oshiro
    Medicine 98 (32) e16643  2019/08 [Refereed][Not invited]
    RATIONALE: Primary carcinosarcoma of the upper urinary tract is rare. Ureteral duplication is one of the most common urinary tract malformations. Additionally, the association between ureteral duplication and malignancy is unknown. To the best of our knowledge, no cases of malignant tumors diagnosed as carcinosarcoma with ureteral duplication have been reported. We herein report the case of a patient with carcinosarcoma of the ureteropelvic junction associated with incomplete ureteral duplication. PATIENT CONCERNS: A 60-year-old Japanese woman presented with painless gross hematuria. She had a history of total hysterectomy and chemotherapy for endometrioid carcinoma 5 years before. She had no history of occupational chemical exposure. DIAGNOSES: Radiographic imaging revealed right incomplete ureteral duplication, hydronephrosis, and a polypoid tumor in the ureteropelvic junction of the lower moiety of the right kidney. Urine cytology showed a small amount of degenerated atypical epithelial and nonepithelial cells. The transureteral biopsy specimen showed dysplastic urothelial cells and atypical myoid spindle cells. These findings were indefinite for malignancy. INTERVENTIONS: The patient underwent right nephroureterectomy. Pathological examination of the resected tumor showed a biphasic neoplasm composed of carcinomatous and sarcomatous components. The sarcomatous component was immunohistochemically positive for vimentin, desmin, h-caldesmon, and α-SMA and negative for pancytokeratin (AE1/AE3), low molecular weight cytokeratin (CAM 5.2), EMA, E-cadherin, GATA3, uroplakin 2, and p63. Based on these findings, we diagnosed the tumor as carcinosarcoma. OUTCOMES: The postoperative course was uneventful. No additional therapy was administered. The patient has remained alive without recurrence for 21 months since surgery. LESSONS: Carcinosarcoma can arise from ureteral duplication. Although the majority of carcinosarcomas of the upper urinary tract are diagnosed at an advanced stage and have a poor prognosis, some can have a less aggressive course. Further studies are needed to determine the association between ureteral duplication and malignancy.
  • Takeo Nakaya, Masaya Sogabe, Shin-Ichi Yamamoto, Kentaro Tsuji, Michio Nakaya, Toshiro Niki, Shunsuke Endo, Akira Tanaka
    Medicine 98 (24) e15888  2019/06 [Refereed][Not invited]
    RATIONALE: Suppression and of cancer metastasis is one of the most important issues in cancer care. Considering the typical clinical course of metastases, cancer cells might prefer certain environments or conditions. However, favorable environments for cancer metastasis have not been clearly identified. We had previously described a case of dual, yet separate, pancreatic and colon cancer, in which the metastatic pancreatic cancer was localized at the invasive portion of the colon cancer. We hypothesized that metastatic pancreatic cancer took over the colon cancer microenvironment. PATIENT CONCERNS: We experienced an another case of double cancer in a 65-year-old man who had lung squamous cell carcinoma and an independent pancreatic adenocarcinoma that metastasized to the liver as well as to the lung cancer lesion and pulmonary fibrotic regions associated with pneumothorax and bronchiolization. INTERVENTIONS: The pneumothorax could not be controlled by conservative treatment. Thus, an emergency surgery with partial resection of the lower lobe of right lung was performed. DIAGNOSES: We found multiple pancreatic cancer metastases in the lung cancer and fibrotic lesions in the surgical specimen. However, we detected no metastasis in normal lung tissues except inside small arteries, although the lung cancer and fibrotic tissue areas were smaller than the normal lung tissue areas in the surgical specimen. OUTCOMES: The patient died 50 days after the surgery. LESSONS: This case may thus provide evidence to strengthen our hypothesis that pancreatic cancer prefers to metastasize to other independent cancer lesions, overtaking the cancer microenvironment constructed by other independent cancers. The lung cancer microenvironment, rich in myofibroblasts and/or cancer-associated fibroblasts, might be suitable for pancreatic carcinoma metastasis. In addition, we propose the hypothesis that compared with normal tissues, noncancerous fibrotic lesions are preferable destinations for cancer metastasis. Furthermore, metastasis of pancreatic carcinoma to lung cancer and fibrotic tissues might be more common, although such cases have not been previously reported.
  • 間質微小環境の乗っ取りによる膵癌から原発性結腸癌への転移(Metastasis of pancreatic cancer in primary colon cancer by overtaking the stromal microenvironment)
    仲矢 丈雄, 大城 久, 斎藤 匠, 佐久間 康成, 堀江 久永, 佐田 尚宏, 田中 亨
    日本病理学会会誌 108 (1) 303 - 303 0300-9181 2019/04
  • Rapid Growth of Pelvic Cyst during Pregnancy: A Case Report.
    Fujimoto Y, Takahashi H, Horie K, Nakaya T, Niki T, Fujiwara H, Matsubara S
    Case Rep Obstet Gynecol. 2019 3120921  2019 [Refereed][Not invited]
  • Iwasaki K, Morimoto M, Ota G, Koinuma K, Horie H, Sata N, Nakaya T
    Medicine 97 (30) e11357  2018 [Refereed][Not invited]
    RATIONALE: Although systemic lupus erythematosus (SLE) can be complicated by various gastrointestinal tract diseases, it is rarely associated with lupus enteritis and protein-losing enteropathy (PLE). We report here the successful surgical treatment of lupus enteritis and therapy-resistant and refractory PLE in a patient with SLE. We also provide a review of relevant literature. PATIENT CONCERNS: A 16-year-old girl presenting with polyarthritis, malar rash, and palmar erythema was indicated for steroid therapy on the basis of positive results for antinuclear, anti-Smith, and antiphospholipid antibodies, which confirmed the diagnosis of SLE. During the course of steroid therapy, the patient developed acute abdomen and hypoalbuminemia. DIAGNOSES: Computed tomography and Tc-labeled human serum albumin scintigraphy revealed abnormal findings, and a diagnosis of lupus enteritis and PLE was made. Steroid treatment was continued but no significant improvement was observed, and the patient was referred and admitted to our hospital. Double-balloon enteroscopy revealed multiple ischemic stenoses and mucosal necroses in the small intestine, suggesting that PLE was associated with ischemic enteritis due to antiphospholipid syndrome. The patient received steroids, immunosuppressive drugs, and antithrombotic therapy, with no improvement in symptoms. Thus, the disease was judged to be refractory and resistant to medical therapy, and the patient was indicated for surgical treatment. INTERVENTIONS: Partial small intestinal resection was performed by removing the segment of the small intestine presenting PLE lesions, and a double-end ileostomy was created. OUTCOMES: Multiple stenotic lesions were confirmed in the resected segment. Histopathology evaluation revealed marked inflammatory cell infiltration in the intestinal tract wall and recanalization of the vessels, suggesting a circulatory disorder caused by vasculitis and antiphospholipid syndrome. Postoperatively, the clinical course was good. Serum albumin levels and body weight increased as nutritional status improved significantly. Secondary enteroenterostomy with ileostomy closure could be performed at 2 months after the initial surgery. LESSONS: Timely surgical treatment can be successful in managing therapy-resistant and refractory PLE in patients with SLE.
  • Nakaya T, Oshiro H, Saito T, Sakuma Y, Horie H, Sata N, Tanaka A
    Int J Clin Exp Pathol. 11 (6) 3141 - 3146 2018 [Refereed][Not invited]
    We report a unique case of a 74-old man, who presented with double cancers, showing metastasis of pancreatic cancer to colon cancer. Histopathological examination after surgery revealed that the patient had ascending colon cancer, which metastasized to the liver (pT4N0M1), as well as pancreatic cancer (pT2N1M1) that metastasized to the most invasive portion of the colon cancer, namely the serosal to subserosal layers. Although the mechanisms for this scenario have yet to be elucidated, we speculate that the metastatic pancreatic carcinoma overtook the stromal microenvironment of the colon cancer. Namely, the cancer microenvironment enriched by cancer-associated fibroblasts, which supported the colon cancer, might be suitable for the invasion and engraftment by pancreatic carcinoma. The similarity of histological appearance might make it difficult to distinguish metastatic pancreatic carcinoma within colon cancer. Furthermore, the metastasis of pancreatic carcinoma in colon carcinoma might be more common, despite it not having been previously reported.
  • Naomi Nakano, Takeo Nakaya, Koji Kamiya, Mayumi Komine, Satoru Murata, Hirotoshi Kawata, Shigeo Yokoyama, Akira Tanaka, Mamitaro Ohtsuki
    JOURNAL OF DERMATOLOGY 44 (11) 1327 - 1328 0385-2407 2017/11 [Refereed][Not invited]
  • Takeo Nakaya, Taiju Hyuga, Yukichi Tanaka, Shina Kawai, Hideo Nakai, Toshiro Niki, Akira Tanaka
    MEDICINE 96 (15) e6499  0025-7974 2017/04 [Refereed][Not invited]
    Background: Renal dysplasia is the most important cause of end-stage renal disease in children. The histopathological characteristic of dysplasia is primitive tubules with fibromuscular disorganization. Renal dysplasia often includes metaplastic cartilage. Metaplastic cartilage in renal dysplasia has been explained as occurring secondary to vesicoureteral reflux (VUR). Additionally, renal dysplasia is observed in renal dysplasia-associated syndromes, which are combinations of multiple developmental malformations and include VACTERL association. Case presentation: We observed the following multiple developmental malformations in a 108-day-old male infant during a nephrectomy: a nonfunctioning right kidney with VUR, hemidiaphragmatic eventration, a ventricular septal defect (VSD) with tetralogy of Fallot in the heart, cryptorchidism, and hyperdactylia. These developmental anomalies satisfied the diagnostic criteria for VACTERL association. A surgical specimen of the right nonfunctioning kidney revealed prominent cartilaginous metaplasia in the renal dysplasia with VUR. The densities of the ectopic cartilaginous lesions in this nonfunctioning kidney were extraordinarily high compared with other renal dysplasia cases. Giemsa banding of his genome produced normal results. The patient has not undergone further detailed genomic investigation. Conclusion: This case might be a novel type of VACTERL association, that is, renal dysplasia combined with prominent cartilaginous metaplasia, tetralogy of Fallot and VSD of the heart, hemidiaphragmatic eventration, and hyperdactylia.
  • Hirotoshi Kawata, Tomoko Kamiakito, Takeo Nakaya, Maiko Komatsubara, Kenji Komatsu, Tatsuo Morita, Yasumitsu Nagao, Akira Tanaka
    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 165 (Pt B) 219 - 227 0960-0760 2017/01 [Refereed][Not invited]
    Endocrine resistance is a major problem in prostate cancer. Recent studies suggest that cellular plasticity plays a key role in therapy resistance. Yet little is known about the cellular changes of human prostate cancer after androgen deprivation therapy (ADT). In this study, we investigated cellular senescence, senescence-associated secretory phenotypes (SASPs), and anti-oxidant responses. Hormone ablation upregulated senescence-associated (SA)-beta-Gal activity in prostate glands, as well as the expressions of p27(KIP1) and p53, in a mouse castration model. In line with this, the expressions of p21(CIP1) and p27(KIP1) were significantly more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. In a study of SASP markers, the expressions of IL6 and IL8 were also more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. IL6, IL8, and MMP2 were expressed more strongly in human prostate cancer specimens resected after ADT than in untreated tumors. Of note, treatment with the anti-oxidant reagent NAC significantly suppressed SA-beta-Gal activity in androgen-sensitive human prostate cancer LNCaP cells. In immunohistochemical analyses on anti-oxidant response genes, NRF2 and NQO1 were more upregulated after hormone ablation in human prostate gland and carcinoma specimens after ADT than in untreated specimens or in murine prostate glands after castration. Taken together, these findings suggest that ADT induces cellular senescence processes accompanied by secretory phenotypes and anti-oxidant responses in prostate. These cellular changes may be attractive targets for preventing endocrine resistance in prostate cancer. (C) 2016 Elsevier Ltd. All rights reserved.
  • Michio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, Hitoshi Kurose
    JOURNAL OF CLINICAL INVESTIGATION 127 (1) 383 - 401 0021-9738 2017/01 [Refereed][Not invited]
    Myocardial infarction (MI) results in the generation of dead cells in the infarcted area. These cells are swiftly removed by phagocytes to minimize inflammation and limit expansion of the damaged area. However, the types of cells and molecules responsible for the engulfment of dead cells in the infarcted area remain largely unknown. In this study, we demonstrated that cardiac myofibroblasts, which execute tissue fibrosis by producing extracellular matrix proteins, efficiently engulf dead cells. Furthermore, we identified a population of cardiac myofibroblasts that appears in the heart after MI in humans and mice. We found that these cardiac myofibroblasts secrete milk fat globule-epidermal growth factor 8 (MFG-E8), which promotes apoptotic engulfment, and determined that serum response factor is important for MFG-E8 production in myofibroblasts. Following MFG-E8-mediated engulfment of apoptotic cells, myofibroblasts acquired antiinflammatory properties. MFG-E8 deficiency in mice led to the accumulation of unengulfed dead cells after MI, resulting in exacerbated inflammatory responses and a substantial decrease in survival. Moreover, MFG-E8 administration into infarcted hearts restored cardiac function and morphology. MFG-E8-producing myofibroblasts mainly originated from resident cardiac fibroblasts and cells that underwent endothelial-mesenchymal transition in the heart. Together, our results reveal previously unrecognized roles of myofibroblasts in regulating apoptotic engulfment and a fundamental importance of these cells in recovery from MI.
  • Giant solitary fibrous tumor of the pleura with high-grade sarcomatous overgrowth accompanied by lipid-rich, rhabdomyosarcomatous, and pleomorphic components: A case report.
    Nakaya T, Oshiro H, Takigami A, Kanai Y, Tetsuka K, Hagiwara K, Fujii H, Endo S, Tanaka A
    Medicine 96 (50) e8926  2017 [Refereed][Not invited]
  • Takeo Nakaya, Shuichiro Kobayashi, Satoshi Kitahara, Akira Tanaka, Hiroshi Kamma, Akio Komatsu
    Human Pathology: Case Reports 5 29 - 33 2214-3300 2016/09 [Refereed][Not invited]
    We experienced the giant seminoma with 18 × 10 × 10 cm sized and about 2.6 kg weight of 25 year old patient. We intensively examined the histological tissue type distributions in this giant seminoma. Most of the tumor consisted of seminoma components. In addition, the tumor included the very small fragments of yolk sac tumor and embryonal carcinoma component at the root part of the seminoma mass. This shows that intensive histological examination may contribute to the finding of other embryonic component of the large seminoma. This may show that leaving the seminoma growing may generate the other embryonic tumor component, not always big enough to find out in a routine procedure, during the growth, in the different way from the original mixed cell germ tumor.
  • Hisashi Oshiro, Masahiro Miura, Hiroaki Iobe, Tomoo Kudo, Yoshihito Shimazu, Takaaki Aoba, Koji Okudela, Kiyotaka Nagahama, Kentaro Sakamaki, Maki Yoshida, Toshitaka Nagao, Takeo Nakaya, Atsushi Kurata, Osamu Ohtani
    Lymphatic research and biology 13 (2) 137 - 45 2015/06 [Refereed][Not invited]
    BACKGROUND: Lymphatic stomata are small lymphatic openings in the serosal membrane that communicate with the serosal cavity. Although these stomata have primarily been studied in experimental mammals, little is known concerning the presence and properties of lymphatic stomata in the adult human pleura. Thus, adult human pleurae were examined for the presence or absence of lymphatic stomata. METHODS AND RESULTS: A total of 26 pulmonary ligaments (13 left and 13 right) were obtained from 15 adult human autopsy cases and examined using electron and light microscopy. The microscopic studies revealed the presence of apertures fringed with D2-40-positive, CD31-positive, and cytokeratin-negative endothelial cells directly communicating with submesothelial lymphatics in all of the pulmonary ligaments. The apertures' sizes and densities varied from case to case according to the serial tissue section. The medians of these aperture sizes ranged from 2.25 to 8.75 μm in the left pulmonary ligaments and from 2.50 to 12.50 μm in the right pulmonary ligaments. The densities of the apertures ranged from 2 to 9 per mm(2) in the left pulmonary ligaments and from 2 to 18 per mm(2) in the right pulmonary ligaments. However, no significant differences were found regarding the aperture size (p=0.359) and density (p=0.438) between the left and the right pulmonary ligaments. CONCLUSIONS: Our study revealed that apertures exhibit structural adequacy as lymphatic stomata on the surface of the pulmonary ligament, thereby providing evidence that lymphatic stomata are present in the adult human pleura.
  • Takeo Nakaya, Kiyoko Morita, Atsushi Kurata, Tetsuo Ushiku, Takashi Igarashi, Masahiko Kuroda, Masashi Fukayama
    HUMAN PATHOLOGY 45 (8) 1773 - 1777 0046-8177 2014/08 [Refereed][Not invited]
    Kaposiform hemangioendothelioma is a vascular tumor categorized as intermediate malignancy. We experienced an autopsy of a female baby with kaposiform hemangioendothelioma with Kasabach-Men-itt syndrome. She died of systemic bleeding tendency following disseminated intravascular coagulation at the age of 9 days. At autopsy, a huge main tumor, histologically kaposiform hemangioendothelioma, was discovered in the mediastinum between the right chest cavity and pericardium. Furthermore, kaposiform hemangioendothelioma with the same histology involved the lungs, heart, liver, subserosa of cardial part of the stomach, retroperitoneum around the right adrenal gland, broad ligament of the uterus, and muscular tissue around the thyroid. To date, a few previously reported cases of multifocal kaposiform hemangioendothelioma have demonstrated locally aggressive distributions mainly in bone and soft tissues. The present case with extensive distribution including visceral organs implies that kaposiform hemangioendothelioma may have higher potential to spread than considered before. (C) 2014 Elsevier Inc. All rights reserved.
  • Camille Belzil, Naoyuki Asada, Kei-ichiro Ishiguro, Takeo Nakaya, Kari Parsons, Valentina Pendolino, Gernot Neumayer, Marina Mapelli, Yoshihiro Nakatani, Kamon Sanada, Minh Dang Nguyen
    BIOLOGY OPEN 3 (6) 475 - 485 2046-6390 2014/06 [Refereed][Not invited]
    Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.
  • Takeo Nakaya, Seishi Ogawa, Ichiro Manabe, Masami Tanaka, Masashi Sanada, Toshiro Sato, Makoto M. Taketo, Kazuki Nakao, Hans Clevers, Masashi Fukayama, Masahiko Kuroda, Ryozo Nagai
    CANCER RESEARCH 74 (10) 2882 - 2891 0008-5472 2014/05 [Refereed][Not invited]
    The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5(+) crypt-base columnar cells, but core mechanisms and their contributions to intestinal cancer are not fully defined. In this study, we examined a hypothesized role for KLF5, a zinc-finger transcription factor that is critical to maintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in the mouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. In mice, inducible deletion of Klf5 in Lgr5(+) stem cells suppressed their proliferation and survival in a manner associated with nuclear localization of beta-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of beta-catenin in Lgr5(+) stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/beta-catenin pathway is the most frequently altered pathway in human colorectal cancer, our results argue that KLF5 acts as a fundamental core regulator of intestinal oncogenesis at the stem-cell level, and they suggest KLF5 targeting as a rational strategy to eradicate stem-like cells in colorectal cancer. (C) 2014 AACR.
  • Takeo Nakaya, Atsushi Kurata, Hirotsugu Hashimoto, Shigeo Nishimata, Yasuyo Kashiwagi, Koji Fujita, Hisashi Kawashima, Masahiko Kuroda
    PATHOLOGY INTERNATIONAL 64 (2) 75 - 80 1320-5463 2014/02 [Refereed][Not invited]
    Shwachman-Diamond syndrome, which is characterized by pancreatic fatty degeneration, skeletal growth retardation, and hematological dysfunction, is a congenital disease caused by SBDS gene mutations. Although hematological disorders often accompany this syndrome, carcinomas associated with this syndrome have not been reported except in one breast cancer and one moderately differentiated pancreatic cancer case. We report on an autopsy of a 24-year-old case of pancreatoduodenal carcinoma in Shwachman-Diamond syndrome. The histology of the tumor was undifferentiated carcinoma, which seems to have originated from either the pancreatic duct or the duodenal epithelium. The tumor was intermingled with two pathological changes characteristic of Shwachman-Diamond syndrome: fatty degeneration of the pancreas and inflammation of the villous stroma of the duodenum. Considering that SBDS protein regulates mitosis and its suppression causes genomic instability, this case might provide an example of carcinogenesis based on genomic instability, together with degenerative changes and chronic inflammation, at a very young age.
  • Takeo Nakaya, Kei-ichiro Ishiguro, Camille Belzil, Anna M. Rietsch, Qunyan Yu, Shin-ichi Mizuno, Roderick T. Bronson, Yan Geng, Minhng Da Nguyen, Koichi Akashi, Piotr Sicinski, Yoshihiro Nakatani
    PLoS ONE 8 (6) e66269  1932-6203 2013/06 [Refereed][Not invited]
    p600 is a multifunctional protein implicated in cytoskeletal organization, integrin-mediated survival signaling, calcium-calmodulin signaling and the N-end rule pathway of ubiquitin-proteasome-mediated proteolysis. While push, the Drosophila counterpart of p600, is dispensable for development up to adult stage, the role of p600 has not been studied during mouse development. Here we generated p600 knockout mice to investigate the in vivo functions of p600. Interestingly, we found that homozygous deletion of p600 results in lethality between embryonic days 11.5 and 13.5 with severe defects in both embryo and placenta. Since p600 is required for placental development, we performed conditional disruption of p600, which deletes selectively p600 in the embryo but not in the placenta. The conditional mutant embryos survive longer than knockout embryos but ultimately die before embryonic day 14.5. The mutant embryos display severe cardiac problems characterized by ventricular septal defects and thin ventricular walls. These anomalies are associated with reduced activation of FAK and decreased expression of MEF2, which is regulated by FAK and plays a crucial role in cardiac development. Moreover, we observed pleiotropic defects in the liver and brain. In sum, our study sheds light on the essential roles of p600 in fetal development. © 2013 Nakaya et al.
  • Takeo Nakaya, Yoshinao Kikuchi, Akiko Kunita, Shumpei Ishikawa, Keisuke Matsusaka, Rumi Hino, Hiroyuki Aburatani, Masashi Fukayama
    VIRUS RESEARCH 174 (1-2) 108 - 115 0168-1702 2013/06 [Refereed][Not invited]
    Epstein-Barr virus (EBV) is a representative human oncogenic virus that causes malignancies of various cell lineages. LMP2A, an EBV-encoded latent membrane protein, is expressed in EBV-associated malignancies of various cell lineages. LMP2A caused visible tumor formation transplanted in nude mice when transferred to immortalized non-transformed fibroblasts, NIH3T3. LMP2A-expressing cells showed higher ability of colony formation in soft agar than empty vector-transfected control cells, although the expression of LMP2A did not cause focus transformation in low serum concentrations. LMP2A expression increased the size of Hoechst 33,342 dye excreting side population (SP), in which cancer-initiating cells or cancer stem-like cells were enriched. SP increase by LMP2A was also responsible for colony formation in soft agar. The LMP2A-mediated SP increase depended on the activations of Stat3, MEK/ERK, and PI3K pathways, and on upregulation of HMGA2. Enrichment of SP, stem-like cells, by LMP2A promoted the transformation capability of LMP2A from non-transformed cells. The enrichment of stem-like cell population by a virus-encoded factor might explain the oncogenic functions of oncogenic viruses. (C) 2013 Elsevier B.V. All rights reserved.
  • Michio Nakaya, Mitsuru Tajima, Hidetaka Kosako, Takeo Nakaya, Akiko Hashimoto, Kenji Watari, Hiroaki Nishihara, Mina Ohba, Shiori Komiya, Naoki Tani, Motohiro Nishida, Hisaaki Taniguchi, Yoji Sato, Mitsuru Matsumoto, Makoto Tsuda, Masahiko Kuroda, Kazuhide Inoue, Hitoshi Kurose
    NATURE COMMUNICATIONS 4 1532  2041-1723 2013/02 [Refereed][Not invited]
    Efficient engulfment of apoptotic cells is critical for maintaining tissue homoeostasis. When phagocytes recognize 'eat me' signals presented on the surface of apoptotic cells, this subsequently induces cytoskeletal rearrangement of phagocytes for the engulfment through Rac1 activation. However, the intracellular signalling cascades that result in Rac1 activation remain largely unknown. Here we show that G-protein-coupled receptor kinase 6 (GRK6) is involved in apoptotic cell clearance. GRK6 cooperates with GIT1 to activate Rac1, which promotes apoptotic engulfment independently from the two known DOCK180/ELMO/Rac1 and GULP1/Rac1 engulfment pathways. As a consequence, GRK6-deficient mice develop an autoimmune disease. GRK6-deficient mice also have increased iron stores in splenic red pulp in which F4/80(+) macrophages are responsible for senescent red blood cell clearance. Our results reveal previously unrecognized roles for GRK6 in regulating apoptotic engulfment and its fundamental importance in immune and iron homoeostasis.
  • Epstein-Barrウイルス因子LMP2AのCancer Initiating Cells制御による発癌促進機構
    仲矢 丈雄, 菊地 良直, 松坂 恵介, 石川 俊平, 日野 るみ, 坂谷 貴司, 油谷 浩幸, 深山 正久
    日本病理学会会誌 (一社)日本病理学会 99 (1) 196 - 196 0300-9181 2010/03 [Refereed][Not invited]
  • EBウイルスの膜タンパクLMP2Aにより促進される発癌過程の解明(Oncogenic molecular and cellular processes promoted by EBV-encoded membrane protein LMP2A)
    仲矢 丈雄, 菊地 良直, 石川 俊平, 松坂 恵介, 日野 るみ, 坂谷 貴司, 油谷 浩幸, 深山 正久
    日本癌学会総会記事 68回 76 - 77 0546-0476 2009/08 [Refereed][Not invited]
  • Rumi Hino, Hiroshi Uozaki, Noriko Murakami, Tetsuo Ushiku, Aya Shinozaki, Shumpei Ishikawa, Teppei Morikawa, Takeo Nakaya, Takashi Sakatani, Kenzo Takada, Masashi Fukayama
    CANCER RESEARCH 69 (7) 2766 - 2774 0008-5472 2009/04 [Refereed][Not invited]
    CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBV-associated gastric carcinoma (GC). Aberrant promoter methylation and expression loss of PTEN were evaluated in cancer tissues of GC by methylation-specific PCR and immunohistochemistry, respectively, showing that both abnormalities occurred concurrently in EBV-associated GC. PTEN abnormalities were reiterated in GC cell tines MKN-1 and MKN-7 infected with recombinant EBV, and DNA methyltransferase I (DNMT1) was commonly overexpressed in both cell lines. Stable and transient transfection systems in MKN-1 similarly showed that viral latent membrane protein 2A (LMP2A) up-regulated DNMT1, leading to an increase in methylation of the PTEN promoter. Importantly, the level of phosphorylate signal transducer and activator of transcription 3 (pSTAT3) increased in the nuclei of LMP2A-expressing GC cells, and knockdown of STAT3 counteracted LMP2A-mediated DNMT1 overexpression. Immunohistochemistry for both pSTAT3 and DNMT1 showed diffuse labeling in the nuclei of the cancer cells in GC tissues, especially in EBV-associated GC. Taken together, LMP2A induces the phosphorylation of STAT3, which activates DNMT1 transcription and causes PTEN expression loss through CpG island methylation of the PTEN promoter in EBV-associated GC. LMP2A plays an essential role in the epigenetic abnormalities in host stomach cells and in the development and maintenance of EBV-associated cancer. [Cancer Res 2009;69(7):2766-74]
  • T Nakaya, M Sato, N Hata, M Asagiri, H Suemori, S Noguchi, N Tanaka, T Taniguchi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 283 (5) 1150 - 1156 0006-291X 2001/05 [Refereed][Not invited]
    During viral infection, interferon-alpha/beta (IFN-alpha/beta) and many IFN-inducible genes are induced to elicit antiviral responses of the host. Using cells with a gene disruption(s) for the IRF family of transcription factors, we provide evidence that these genes, containing similar IRF-binding cis-elements, are classified into distinct groups, based on the gene induction pathway(s), The IFN-beta gene induction is dependent on either IRF-3 or IRF-7, whereas induction of the IFN-alpha gene family is IRF-7-dependent. On the other hand, ISG15, ISG54 and IP-10 are induced by either IRF-3 or IFN stimulated gene factor 3 (ISGF3). We also show that another group of genes is totally dependent on ISGF3, Thus, during viral infection, a given gene responds either directly to a virus or virus-induced IFN-alpha/beta or both through distinct pathways, The differential utilization of these induction pathways for these genes during viral infection may reflect their distinct functional roles in the efficient antiviral response. (C) 2001 Academic Press.
  • M Sato, H Suemori, N Hata, M Asagiri, K Ogasawara, K Nakao, T Nakaya, M Katsuki, S Noguchi, N Tanaka, T Taniguchi
    IMMUNITY 13 (4) 539 - 548 1074-7613 2000/10 [Refereed][Not invited]
    Induction of the interferon (IFN)-alpha/beta gene transcription in virus-infected cells is an event central to innate immunity. Mice lacking the transcription factor IRF-3 are more vulnerable to virus infection. In embryonic fibroblasts, virus-induced IFN-alpha/beta gene expression levels are reduced and the spectrum of the IFN-alpha mRNA subspecies altered. Furthermore, cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infections by any of the virus types tested. In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7. These results demonstrate the essential and distinct roles of the two factors, which together ensure the transcriptional efficiency and diversity of IFN-alpha/beta genes for the antiviral response.
  • M Sato, N Hata, M Asagiri, T Nakaya, T Taniguchi, N Tanaka
    FEBS LETTERS 441 (1) 106 - 110 0014-5793 1998/12 [Refereed][Not invited]
    The interferon regulatory factor (IRF) family of transcription factors regulate the interferon (IFN) system, among which IRF-3 is involved in the virus-induced IFN-beta gene expression. Here me show that another member IRF-7 is critical for the IFN-alpha gene induction. Unlike the IRF-3 gene, the IRF-7 gene is induced by IFNs through activation of the ISGF3 transcription factor, and IRF-7 undergoes virus-induced nuclear translocation. In cells lacking p48, an essential component of IFN stimulated gene factor 3 (ISGF3), ectopic expression of IRF-7 but not IRF-3 can rescue the deficiency to induce IFN-alpha genes. These results indicate that IRF-7 is a key factor in the positive feedback regulation of IFN-alpha/beta production. (C) 1998 Federation of European Biochemical Societies.

Books etc

  • Precision Medicine
    Takeo Nakaya (Contributor遺伝子治療の概略)
    北隆館 2018/12
  • 化学
    仲矢丈雄, 黒田雅彦, 大木忠明 (Joint work次世代に向けた核酸医薬品の新技術)
    化学同人 2012/09
  • 病理画像診断これでスッキリ!
    仲矢 丈雄 (Joint work)
    メジカルビュー 2012
  • がんプロフェッショナル養成講座 腫瘍病理学
    仲矢 丈雄 (Joint work)
    文光堂 2008

Conference Activities & Talks

  • Small molecules mimicking KLF5 structure suppresses cancer cells in both in vivo and vitro without damaging normal cells.  [Invited]
    Nakaya T, Tsuji K, Tanaka A, Nagai R
    6th International Conference on Biology and Pathobiology of KLF/Sp Transcription Factors  2018/10
  • Small mimicries of KLF5 selectively suppress the survival and Wnt-KLF5 signal of colorectal cancer.  [Not invited]
    Nakaya T, Kasai M, Nakano H, Yoshimori A, Tanaka A, Kouji H, Nagai R
    第106回日本病理学会総会  2017/04
  • The protein interaction inhibitors of KLF5 suppress Wnt signal activation selectively in colorectal cancer cells.  [Not invited]
    Nakaya T, Nakano H, Kasai M, Yoshimori A, Tanaka A, Kouji H, Nagai R
    第75回日本癌学会学術総会  2016/10
  • The protein interaction inhibitors of KLF5 suppress Wnt signal activation selectively in colorectal cancer cells.  [Not invited]
    Nakaya T, Nagai R
    FASEB SRC, KLF and SP Transcription Factors In Disease And Regenerative Medicine  2016/08


  • KLF5は、腸管幹細胞の正常性と発癌能の調節に重要な因子として機能する(KLF5 functions as the master regulator of the integrity and oncogenicity of intestinal stem cells)
    仲矢 丈雄, 小川 誠司, 眞鍋 一郎, 田中 正視, 眞田 昌, 佐藤 俊朗, 武藤 誠, 中尾 和貴, 深山 正久, 黒田 雅彦, 永井 良三  日本病理学会会誌  102-  (1)  346  -346  2013/04  [Not refereed][Not invited]
  • KLF5は腸管腫瘍形成に必須である(KLF5 is essential for oncogenesis of intestinal tumors)
    仲矢 丈雄, 眞田 昌, 眞鍋 一郎, 深山 正久, 小川 誠司, 黒田 雅彦, 永井 良三  日本癌学会総会記事  71回-  443  -444  2012/08  [Not refereed][Not invited]

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