Details of a Researcher - Tamura, Ryota

Papers - Tamura, Ryota

Division display 1 - 20 of about 67 ／ All the affair displays >>

Suboccipital trans-horizontal fissure approach for cerebellar hemorrhage with rupture into the upper 4th and 3rd ventricles: the first clinical experience

Tamura R, Katayama M, Kuranari Y, Horiguchi T. Suboccipital trans-horizontal fissure approach for cerebellar hemorrhage with rupture into the upper 4th and 3rd ventricles: the first clinical experience

J Neurosurg; Case Lessons 3 CASE21647 2022

Research paper (scientific journal), Accepted

Schwannoma:Update on Molecular Profiling and Therapeutic Advances

Tamura R, Toda M

No Shinkei Geka 50 162 - 170 2022

Thesis (other), Accepted

Bilaterally Asymmetric Helical Myofibrils in Ascidian Tadpole Larvae

Matsuo K., Tamura R., Hotta K., Okada M., Takeuchi A., Wu Y., Hashimoto K., Takano H., Momose A., Nishino A.

Frontiers in Cell and Developmental Biology (Frontiers in Cell and Developmental Biology) 9 2021.12

The locomotor system is highly bilateral at the macroscopic level. Homochirality of biological molecules is fully compatible with the bilateral body. However, whether and how single-handed cells contribute to the bilateral locomotor system is obscure. Here, exploiting the small number of cells in the swimming tadpole larva of the ascidian Ciona, we analyzed morphology of the tail at cellular and subcellular scales. Quantitative phase-contrast X-ray tomographic microscopy revealed a high-density midline structure ventral to the notochord in the tail. Muscle cell nuclei on each side of the notochord were roughly bilaterally aligned. However, fluorescence microscopy detected left-right asymmetry of myofibril inclination relative to the longitudinal axis of the tail. Zernike phase-contrast X-ray tomographic microscopy revealed the presence of left-handed helices of myofibrils in muscle cells on both sides. Therefore, the locomotor system of ascidian larvae harbors symmetry-breaking left-handed helical cells, while maintaining bilaterally symmetrical cell alignment. These results suggest that bilateral animals can override cellular homochirality to generate the bilateral locomotor systems at the supracellular scale.

Access to Document (DOI)

Histopathological investigation of dura-like membrane in vestibular schwannomas

Oishi Y., Tamura R., Yoshida K., Toda M.

Brain Sciences (Brain Sciences) 11 ( 12 ) 2021.12

The dura-like membrane (DLM) is an outermost membranous structure arising from the dura mater adjacent to the internal auditory meatus (IAM) that envelops some vestibular schwannomas (VSs). Its recognition is important for the preservation of the facial and cochlear nerves during tumor resection. This study analyzes the histopathological characteristics of the DLM. The expression of CD34 and αSMA was histopathologically analyzed in tumor and DLM tissue of 10 primary VSs with and without a DLM. Tumor volume, resection volume percentage, microvessel density (MVD), and vessel diameter were analyzed. Volumetric analysis revealed that the presence of a DLM was significantly associated with lower tumor resection volume (p < 0.05). Intratumoral vessel diameter was significantly larger in the DLM group than the non-DLM group (p < 0.01). Larger VSs showed a higher intratumoral MVD in the DLM group (p < 0.05). Multilayered αSMA-positive vessels were identified in the DLM, tumor, and border; there tended to be more of these vessels within the tumor in the DLM group compared to the non-DLM group (p = 0.08). These arteriogenic characteristics suggest that the DLM is formed as the tumor induces feeding vessels from the dura mater around the IAM.

Access to Document (DOI)

History and current progress of chronic subdural hematoma

Tamura R., Sato M., Yoshida K., Toda M.

Journal of the Neurological Sciences (Journal of the Neurological Sciences) 429 2021.10

ISSN 0022510X

Chronic subdural hematoma (CSDH) is characterized by an encapsulated collection of old blood. Although CSDH has become the most frequent pathologic entity in daily neurosurgical practice, there are some unresolved research questions. In particular, the causes and recurrent risk factors of CSDH remain as an object of debate. The split of the dural border layer forms a few tiers of dural border cells over the arachnoid layer. Tissue plasminogen activator plays an important role as a key factor of defective coagulation. Historically, CSDH has often been treated via burr hole craniostomy using a closed drainage system. Several different operative strategies and peri-operative strategies such as the addition of burr holes, addition of cavity irrigation, position of drain, or postural position, have been described previously. Although the direction of the drainage tube, residual air, low intensity of T1-weighted images on MRI, and niveau formation have been reported as risk factors for recurrence, antiplatelet or anticoagulant drug use has not yet been verified as a risk factor. Recently, pharmaceutical strategies, including atorvastatin, significantly improved the neurological function in CSDH patients. Many case series, without randomization, have been reported; and given its promising result, several randomized clinical trials using pharmaceutical as well as operative and perioperative strategies were initiated to obtain sufficient data. In contrast, relatively fewer basic studies have achieved clinical applications in CSDH, although it is one of the most common clinical entities. Further scientific basic research may be essential for achieving a novel treatment strategy for CSDH.

Access to Document (DOI)

Current understanding of neurofibromatosis type 1, 2, and schwannomatosis

Tamura R.

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 22 ( 11 ) 2021.06

ISSN 16616596

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.

Access to Document (DOI)

Novel histopathological classification of meningiomas based on dural invasion

Murase M., Tamura R., Kuranari Y., Sato M., Ohara K., Morimoto Y., Yoshida K., Toda M.

Journal of Clinical Pathology (Journal of Clinical Pathology) 74 ( 4 ) 238 - 243 2021.04

ISSN 00219746

Aims Histological invasion into the adjacent brain parenchyma is frequently investigated in meningioma because it is an important morphological criterion for grade II meningioma according to the 2016 WHO classification. However, few studies have focused on dural invasion of meningiomas. Herein, we propose a novel histopathological classification based on dural invasion of meningiomas. Methods Forty-nine cases with WHO grade I meningiomas who underwent Simpson grade I removal were collected. After the meningeal layer (ML) and periosteal layer (PL) of dura mater were visualised by Masson's trichrome stain, we evaluated the depth (to the ML and PL) and the patterns (1, expanding; 2, infiltrating) of dural invasion of meningiomas using serial paraffin sections. Invasion-associated markers, including Ki-67, matrix metalloproteinase (MMP)-1, MMP-9 and MMP-13, aquaporin 1 and Na-K-2Cl cotransporter, were quantitatively analysed by immunohistochemistry. Results Thirty-five cases (71.4%) showed the dural invasion. In 27 of these 35 cases (77.1%), dural invasion was localised in ML. Type 1 (expanding type) and type 2 (infiltrating type) invasions were observed in 23 and 12 cases, respectively. The recurrence rate in cases with type 2 invasion was significantly higher than that in cases with type 1 invasion. The percentage of MMP-1-positive tumour cells was also significantly higher in cases with dural invasion than those without, suggesting involvement of MMP-1 in dural invasion. Conclusions We quantitatively evaluated the depth and patterns of dural invasion in meningiomas. The patterns of dural invasion were associated with meningioma recurrence.

Access to Document (DOI)

Quiescent and Activated Fibroblasts in Lateral Ventricular Meningioma With a Dura-like Membrane

Sato M., Tamura R., Morimoto Y., Oishi Y., Yoshida K., Toda M.

World Neurosurgery (World Neurosurgery) 147 e215 - e224 2021.03

ISSN 18788750

Background: Lateral ventricular meningioma (LVM) is a rare entity, accounting for 0.5%–5% of all intracranial meningiomas. This type of meningioma arises from meningothelial inclusion bodies in the tela choroidea and/or mesenchymal stroma of the choroid plexus. Although not yet fully characterized, a membranous structure is frequently observed around LVMs. This study analyzed quiescent and activated fibroblast phenotypes in LVMs with focus on the relationship between tumor growth and development of the membranous structure. Methods: This retrospective study analyzed 9 LVM cases for which gross total removal was achieved. Expression of the ependymal cell marker (Forkhead Box J1 [FoxJ1]) was histopathologically evaluated. The distribution of quiescent and activated fibroblasts was also analyzed using anti-fibroblast-specific protein-1 (FSP1)/S100A4 antibody and anti-α-smooth muscle actin (αSMA) antibody, respectively. The control group was 5 cases with primary convexity meningioma for which Simpson grade I removal was achieved. Results: Small LVMs (≤30 mm) were covered by a FoxJ1-positive(+) ependymal cell monolayer; no αSMA(+) cells were detected in the tumor; and a thick membrane capsule was not observed. None of the convexity meningiomas showed FoxJ1(+) cells. Large LVMs (>30 mm) had thick membrane capsules without an ependymal cell monolayer, which resembled dura mater. The FSP1/S100A4(+) and αSM(+) cells were clearly concentrated in the peripheral area just below the thick dura mater-like membrane capsules. Conclusions: This study found an association between activated fibroblasts and dura mater–like membrane capsules in LVMs. The characteristics of membranous structure in LVMs may differ depending on tumor size.

Access to Document (DOI)

Recent progress in the research of suicide gene therapy for malignant glioma

Tamura R., Miyoshi H., Yoshida K., Okano H., Toda M.

Neurosurgical Review (Neurosurgical Review) 44 ( 1 ) 29 - 49 2021.02

ISSN 03445607

Malignant glioma, which is characterized by diffuse infiltration into the normal brain parenchyma, is the most aggressive primary brain tumor with dismal prognosis. Over the past 40 years, the median survival has only slightly improved. Therefore, new therapeutic modalities must be developed. In the 1990s, suicide gene therapy began attracting attention for the treatment of malignant glioma. Some clinical trials used a viral vector for suicide gene transduction; however, it was found that viral vectors cannot cover the large invaded area of glioma cells. Interest in this therapy was recently revived because some types of stem cells possess a tumor-tropic migratory capacity, which can be used as cellular delivery vehicles. Immortalized, clonal neural stem cell (NSC) line has been used for patients with recurrent high-grade glioma, which showed safety and efficacy. Embryonic and induced pluripotent stem cells may be considered as sources of NSC because NSC is difficult to harvest, and ethical issues have been raised. Mesenchymal stem cells are alternative candidates for cellular vehicle and are easily harvested from the bone marrow. In addition, a new type of nonlytic, amphotropic retroviral replicating vector encoding suicide gene has shown efficacy in patients with recurrent high-grade glioma in a clinical trial. This replicating viral capacity is another possible candidate as delivery vehicle to tackle gliomas. Herein, we review the concept of suicide gene therapy, as well as recent progress in preclinical and clinical studies in this field.

Access to Document (DOI)

Suboccipital Trans-horizontal Fissure Approach for Posterior Cranial Fossa Lesions: A Cadaveric Study and First Clinical Experience. Oper Neurosurg (Hagerstown)

Tamura R, Katayama M, Yamamoto K, Horiguchi T

Oper Neurosurg (Hagerstown) 21 E479 - E487 2021

Research paper (scientific journal), Accepted

A Multilayered Dural Repair Technique Using Duragen For Early Cranioplasty Following Decompressive Craniotomy

Tamura R, Kuranari Y, Mishima M, Katayama M

Surgeries 2 371 - 377 2021

Research paper (scientific journal), Accepted

Anterior transpetrosal approach: experiences in 274 cases over 33 years. Technical variations, operated patients, and approach-related complications

Tomio R, Horiguchi T, Borghei-Razavi H, Tamura R, Yoshida K, Kawase T

J Neurosurg 13 1 - 9 2021

Research paper (scientific journal), Accepted

Prognostic Significance of Preoperative Neutrophil-to-Lymphocyte Ratio in Patients With Meningiomas

Kuranari Y., Tamura R., Tsuda N., Kosugi K., Morimoto Y., Yoshida K., Toda M.

Frontiers in Oncology (Frontiers in Oncology) 10 2020.11

Background: Meningiomas are the most common benign intracranial tumors. However, even WHO grade I meningiomas occasionally show local tumor recurrence. Prognostic factors for meningiomas have not been fully established. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor for several solid tumors. The prognostic value of NLR in meningiomas has been analyzed in few studies. Materials and Methods: This retrospective study included 160 patients who underwent surgery for meningiomas between October 2010 and September 2017. We analyzed the associations between patients’ clinical data (sex, age, primary/recurrent, WHO grade, extent of removal, tumor location, peritumoral brain edema, and preoperative laboratory data) and clinical outcomes, including recurrence and progression-free survival (PFS). Results: Forty-four meningiomas recurred within the follow-up period of 3.8 years. WHO grade II, III, subtotal removal, history of recurrence, Ki-67 labeling index ≥3.0, and preoperative NLR value ≥2.6 were significantly associated with shorter PFS (P < 0.001, < 0.001, 0.002, < 0.001, and 0.015, respectively). Furthermore, NLR ≥ 2.6 was also significantly associated with shorter PFS in a subgroup analysis of WHO grade I meningiomas (P = 0.003). In univariate and multivariate analyses, NLR ≥2.6 remained as a significant predictive factor for shorter PFS in patients with meningioma (P = 0.014). Conclusions: NLR may be a cost-effective and novel preoperatively usable biomarker in patients with meningiomas.

Access to Document (DOI)

Historic overview of genetic engineering technologies for human gene therapy

Tamura R., Toda M.

Neurologia Medico-Chirurgica (Neurologia Medico-Chirurgica) 60 ( 10 ) 483 - 491 2020.10

ISSN 04708105

The concepts of gene therapy were initially introduced during the 1960s. Since the early 1990s, more than 1900 clinical trials have been conducted for the treatment of genetic diseases and cancers mainly using viral vectors. Although a variety of methods have also been performed for the treatment of malignant gliomas, it has been difficult to target invasive glioma cells. To overcome this problem, immortalized neural stem cell (NSC) and a nonlytic, amphotropic retroviral replicating vector (RRV) have attracted attention for gene delivery to invasive glioma. Recently, genome editing technology targeting insertions at site-specific locations has advanced; in particular, the clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/ Cas9) has been developed. Since 2015, more than 30 clinical trials have been conducted using genome editing technologies, and the results have shown the potential to achieve positive patient outcomes. Gene therapy using CRISPR technologies for the treatment of a wide range of diseases is expected to continuously advance well into the future.

Access to Document (DOI)

A pilot study of the adverse events caused by the combined use of bevacizumab and vascular endothelial growth factor receptor-targeted vaccination for patients with a malignant glioma

Tamura R., Morimoto Y., Sato M., Hikichi T., Yoshida K., Toda M.

Vaccines (Vaccines) 8 ( 3 ) 1 - 10 2020.09

Anti-angiogenic therapy, targeting vascular endothelial growth factor (VEGF)-A/VEGF receptors (VEGFRs), is beneficial for tumor growth prevention in a malignant glioma. A simultaneous blockade using both bevacizumab (Bev), which targets circulating VEGF-A, and a multi-kinase inhibitor on VEGFRs was more effective for advanced solid cancers, including melanoma and renal cell carcinoma. However, previous clinical trials demonstrated a high adverse event rate. Additionally, no studies previously assessed treatment efficacy and safety using both VEGF-A and VEGFR-targeted agents for malignant gliomas. We had conducted clinical trials investigating VEGFRs peptide vaccination in patients with malignant gliomas, in which the treatment exhibited safety and yielded therapeutic effects in some patients. The combined use of Bev and VEGFRs vaccination may enhance the anti-tumor effect in malignant gliomas. In this pilot study, the adverse event profile in patients treated with Bev after the vaccination was investigated to establish this treatment strategy, in comparison to those treated with Bev collected from the published data or treated with the vaccination alone. In our previous clinical studies on patients with malignant gliomas, Bev was administered to 13 patients after VEGFRs vaccinations. One patient had a Grade 4 pulmonary embolism. Two patients had Grade 2 cerebral infarctions. There were no significant differences in the adverse event rates among patients treated with Bev, with the vaccination, or with Bev after the vaccination. Although careful observation is imperative for patients after this combination treatment strategy, VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.

Access to Document (DOI)

Current understanding of lymphatic vessels in the central nervous system

Tamura R., Yoshida K., Toda M.

Neurosurgical Review (Neurosurgical Review) 43 ( 4 ) 1055 - 1064 2020.08

ISSN 03445607

Lymphangiogenesis is associated with some pathological conditions such as inflammation, tissue repair, and tumor growth. Recently, a paradigm shift occurred following the discovery of meningeal lymphatic structures in the human central nervous system (CNS); these structures may be a key drainage route for cerebrospinal fluid (CSF) into the peripheral blood and may also contribute to inflammatory reaction and immune surveillance of the CNS. Lymphatic vessels located along the dural sinuses absorb CSF from the adjacent subarachnoid space and brain interstitial fluid via the glymphatic system, which is composed of aquaporin-4 water channels expressed on perivascular astrocytic end-feet membranes. Magnetic resonance imaging (MRI) clearly visualized these lymphatic vessels in the human dura mater. The conception of some neurological disorders, such as multiple sclerosis and Alzheimer’s disease, has been changed by this paradigm shift. Meningeal lymphatic vessels could be a promising therapeutic target for the prevention of neurological disorders. However, the involvement of meningeal lymphatic vessels in the pathophysiology has not been fully elucidated and is the subject of future investigations. In this article, to understand the involvement of meningeal lymphatic vessels in neurological disorders, we review the differences between lymphangiogenesis in the CNS and in other tissues during both developmental and adulthood stages, and pathological conditions that may be associated with meningeal lymphatic vessels in the CNS.

Access to Document (DOI)

Surgical outcomes of anterior cerebellopontine angle meningiomas using the anterior transpetrosal approach compared with the lateral suboccipital approach

Hassaan S.A., Tamura R., Morimoto Y., Kosugi K., Mahmoud M., Abokerasha A., Moussa A., Toda M., Yoshida K.

Acta Neurochirurgica (Acta Neurochirurgica) 162 ( 6 ) 1243 - 1248 2020.06

ISSN 00016268

Background: Anterior transpetrosal approach (ATPA) and lateral suboccipital approach (LSO) are the major surgical approaches for cerebellopontine angle (CPA) meningiomas. Particularly, anterior CPA meningiomas are challenging lesions to be treated surgically. To date, only a few studies have directly compared the outcomes of both approaches focusing on the anterior CPA meningiomas. Methods: For the comparative analysis, anterior CPA meningiomas that were eligible for both APTA and LSO were collected in our hospital from April 2005 to March 2017. Anterior CPA meningiomas targeted for this study were defined as follows: (1) without cavernous sinus, clivus, and middle cranial fossa extension, (2) the posterior edge is 1 cm behind the posterior wall of the internal auditory canal, and (3) the inferior edge is above the jugular tuberculum. Based on these criteria, the operative outcomes of 17 patients and 13 patients who were operated via ATPA and LSO were evaluated. Results: The complication rate of the LSO group was significantly higher than that of the ATPA group (30.7% vs. 0%, p = 0.033). The removal rate did not differ between the ATPA and LSO groups (97.35% vs. 99.23%, p = 0.12). The operative time was significantly shorter in the LSO group than in the ATPA group (304.3 min vs. 405.8 min, p = 0.036). Conclusions: Although the LSO is more widely used for CPA meningiomas, ATPA is also considered for these anterior CPA meningiomas.

Access to Document (DOI)

Quantitative assessment and clinical relevance of VEGFRs-positive tumor cells in refractory brain tumors

Tamura R., Sato M., Morimoto Y., Ohara K., Kosugi K., Oishi Y., Kuranari Y., Murase M., Yoshida K., Toda M.

Experimental and Molecular Pathology (Experimental and Molecular Pathology) 114 2020.06

ISSN 00144800

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-β and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.

Access to Document (DOI)

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - A case series

Tamura R., Morimoto Y., Kosugi K., Sato M., Oishi Y., Ueda R., Kikuchi R., Nagashima H., Noji S., Kawakami Y., Sasaki H., Yoshida K., Toda M.

BMC Cancer (BMC Cancer) 20 ( 1 ) 2020.03

Background: The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas. Recently, an exploratory clinical investigation of VEGFRs peptide vaccination was conducted in patients with progressive neurofibromatosis type 2. Those studies suggested that cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells expressing VEGFR1 and/or 2. In the present study, synergistic activity of the combination of VEGFRs peptide vaccination with chemotherapy was evaluated. Methods: We performed the first clinical trial to assess VEGFR1 and 2 vaccination along with temozolomide (TMZ) -based chemoradiotherapy for the patients with primary glioblastomas. Furthermore, histopathological changes after the vaccination were evaluated using paired pre- and post- vaccination specimens. Results: The disappearance of radiographically enhanced lesion was observed in 2 patients after the vaccination, including one in which the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not observed. The histopathological findings of pre- and post-vaccination specimens demonstrated that tumor vessels showed negative or slight VEGFRs expressions after the vaccination and most endothelial cells were covered with PDGFR-β-positive pericytes. Notably, CTLs induced by VEGFRs peptide vaccination attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. Conclusions: VEGFR1 and 2 vaccination may have a preliminary synergistic effect when administered with TMZ. The limitation of the present study was the paucity of the number of the samples. Further studies involving more patients are warranted to confirm the findings of this study. Trial registration: This study was registered as UMIN000013381 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 5 March, 2014 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs031180170 on 1 March, 2019.

Access to Document (DOI)

Gene Therapy Using Neural Stem/Progenitor Cells Derived from Human Induced Pluripotent Stem Cells: Visualization of Migration and Bystander Killing Effect

Tamura R., Miyoshi H., Morimoto Y., Oishi Y., Sampetrean O., Iwasawa C., Mine Y., Saya H., Yoshida K., Okano H., Toda M.

Human Gene Therapy (Human Gene Therapy) 31 ( 5-6 ) 352 - 366 2020.03

ISSN 10430342

Glioblastoma is the most aggressive brain tumor characterized by diffuse infiltration into the normal brain parenchyma. Neural stem cells are known to possess the tumor-tropic migratory capacity and thus can be used as cellular vehicles for targeted delivery of therapeutic agents. In the present study, we evaluated the efficacy of herpes simplex virus thymidine kinase (HSV-TK) suicide gene therapy for glioblastoma using neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs). Although transduction of hiPSCs is preferable for a safe and stable supply in the clinical setting, high-level and/or constitutive HSV-TK expression was highly cytotoxic to hiPSCs. To overcome this problem, we used the tetracycline-inducible system to control the expression of HSV-TK. hiPSC-derived NS/PCs expressing HSV-TK were transplanted in an orthotopic xenograft mouse model of human glioblastoma. Glioblastoma cell growth in mice was dramatically inhibited following ganciclovir (GCV) administration. Survival of the mice was significantly prolonged with administration of GCV compared with control groups. Time-lapse imaging of organotypic brain slice cultures first demonstrated the directional migration of NS/PCs toward glioblastoma cells and the bystander killing effect upon GCV treatment. hiPSC-derived NS/PCs with HSV-TK/GCV suicide gene system may have considerable therapeutic potential for the treatment of glioblastoma. Color images are available online.

Access to Document (DOI)

　 Previous page - Next page 　