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| 1.
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Naito, Hisamichi ; Takara, Kazuhiro ; Wakabayashi, Taku ; Kawahara, Hiroki ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />It is widely accepted that blood vessels in the tumor microenvironment are immature because mural ce
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ll (MC) adhesion to endothelial cells (ECs) is broadly lacking. Hyperpermeability of the tumor vasculature then results in interstitial hypertension that mitigates against penetration of anticancer drugs into the depths of the tumor. It has been suggested that treatment with angiogenesis inhibitors normalizes blood vessels, resulting in restoration of normal permeability and improved drug delivery. However, recent reports suggest that cancer cell invasion is induced from the edge of the tumor into peripheral areas after treatment with angiogenesis inhibitors. Therefore, it is important to assess the status of blood vessels in the fibrous cap at the tumor rim after antiangiogenesis therapy. In the present study, we found that mature blood vessels in which ECs are covered with MCs are present in the fibrous cap. After treatment with angiogenesis inhibitors, immature blood vessels were destroyed and vascular function was significantly improved, but maturing blood vessels in which ECs were covered with MCs remained visible. These maturing blood vessels showed a less dilated character after treatment with the angiogenesis inhibitors. It is widely accepted that well-matured blood vessels are sheathed in extracellular matrix (ECM) and that cancer cells migrate along tracks made of ECM collagen fibers. Therefore, our data indicate the importance of destroying maturing blood vessels outside the tumor parenchyma to prevent cancer cell invasion. © 2011 Japanese Cancer Association.
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Wakabayashi, Taku ; Naito, Hisamichi ; Takara, Kazuhiro ; Kidoya, Hiroyasu ; Sakimoto, Susumu ; Oshima, Yusuke ; Nishida , Kohji ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
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Purpose. The neovascular form of age-related macular degeneration (AMD) is characterized by the growth of abnormal new b
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lood vessels from the choroid, termed choroidal neovascularization (CNV). The origin of the new vessels in CNV, however, has not been elucidated fully to our knowledge. The purpose of this study is to identify vascular endothelial side population (SP) cells in the preexisting choroidal vessels, and investigate their potential role in AMD. Methods. We made single cell suspensions of freshly isolated mouse choroidal, retinal, and brain tissue by enzymatic digestion. Vascular endothelial SP cells were isolated using flow cytometry based on the ability to efflux the DNA-binding dye, Hoechst 33342, via ATP-binding cassette (ABC) transporters. Results. In the choroid, 2.8% of CD31+CD45- vascular endothelial cells (ECs) showed a typical SP staining pattern. They were not bone marrow-derived and possessed high colony-forming capacity in vitro. They proliferated during laser-induced CNV in vivo. In contrast, stereotypic SP staining pattern was not observed in retinal and brain ECs. Retinal and brain EC-SP cells included increased SP populations with less colony-forming capacity within the SP compartment, because they contained cells with and without proliferative potential. The latter still could efflux the dye due to high levels of ABC transporters, such as ABCB1a, ABCC4, and ABCC6. Conclusions. The EC-SP cells in the choroid may represent vessel-residing endothelial stem/progenitor cells contributing mainly to angiogenesis, and may be useful for augmenting vascular regeneration or for developing new antiangiogenic therapy in AMD. © 2013 The Association for Research in Vision and Ophthalmology, Inc.
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| 3.
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Kawahara, Hiroki ; Naito, Hisamichi ; Takara, Kazuhiro ; Wakabayashi, Taku ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Background:A drug delivery system specifically targeting endothelial cells (ECs) in tumors is requir
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ed to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors.Methods and Results:Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs.Conclusions:ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors. © 2013 Kawahara et al.
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| 4.
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Ryu Kanzaki, ; Naito, Hisamichi ; Kise, Kazuyoshi ; Takara, Kazuhiro ; Eino, Daisuke ; Minami, Masato ; Shintani, Yasushi ; Funaki, Soichiro ; Kawamura, Tomohiro ; Kimura, Toru ; Okumura, Meinoshin ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Alterations to the tumor stromal microenvironment induced by chemotherapy could influence the behavi
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or of cancer cells. In the tumor stromal microenvironment, cancer-associated fibroblasts (CAFs) play an important role. Because the receptor tyrosine kinase Axl and its ligand Gas6 could be involved in promoting non-small cell lung cancer (NSCLC), we investigated the role of Gas6 secreted by CAFs during chemotherapy in NSCLC. In a murine model, we found that Gas6 expression by CAFs was upregulated following cisplatin treatment. Gas6 expression might be influenced by intratumoral hypoperfusion during chemotherapy, and it increased after serum starvation in a human lung CAF line, LCAFhTERT. Gas6 is associated with LCAFhTERT cell growth. Recombinant Gas6 promoted H1299 migration, and conditioned medium (CM) from LCAFhTERT cells activated Axl in H1299 cells and promoted migration. Silencing Gas6 in LCAFhTERT reduced the Axl activation and H1299 cell migration induced by CM from LCAFhTERT. In clinical samples, stromal Gas6 expression increased after chemotherapy. Five-year disease-free survival rates for patients with tumor Axl- and stromal Gas6-positive tumors (n = 37) was significantly worse than for the double negative group (n = 12) (21.9% vs 51.3%, p = 0.04). Based on these findings, it is presumed that Gas6 derived from CAFs promotes migration of Axl-expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome. © 2017 The Author(s).
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Matsushita, Jun ; Inagaki, Shigenori ; Nishie, Tomomi ; Sakasai, Tomoki ; Tanaka, Junko ; Watanabe, Chisato ; Mizutani, Ken-ichi ; Miwa, Yoshihiro ; Matsumoto, Ken ; Takara, Kazuhiro ; Naito, Hisamichi ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; Nagai, Takeharu ; Takahashi, Satoru ; Ema, Masatsugu ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Angiogenesis is important from normal development as well as from tumour growth. However, the molecu
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lar and cellular mechanisms underlying angiogenesis are not fully understood, partly because of the lack of a good animal model from imaging. Here, we report the generation of a novel transgenic (Tg) mouse that expresses a bioluminescent reporter protein, Nano-lantern, under the control of Fetal liver kinase 1 (Flk1). Flk1-Nano-lantern BAC Tg mice recapitulated endogenous Flk1 expression in endothelial cells and lymphatic endothelial cells during development and tumour growth. Importantly, bioluminescence imaging of endothelial cells from the aortic rings of Flk1-Nano-lantern BAC Tg mice enabled us to observe endothelial sprouting from 18 hr without any detectable phototoxicity. Furthermore, Flk1-Nano-lantern BAC Tg mice achieved time-lapse luminescence imaging of tumour angiogenesis in freely moving mice with implanted tumours. Thus, this transgenic mouse line contributes a unique model to study angiogenesis within both physiological and pathological contexts.
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