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腫瘍細胞由来のVEGFを慢性的に阻害すると大腸がん細胞の悪性形質化を増強する
著者
山岸, 直子 徳島大学大学院医科学教育部(プロテオミクス医科学専攻)
Dang, Duyen T University of Michigan
Dang, Long H University of Florida
資料タイプ
学位論文
抄録
Background: Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells.
Methods: To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system.
Results: Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function (s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines.
Conclusions: Our findings suggest that chronic inhibition of tumor cell-derived VEGF accelerates tumor cell malignant phenotypes.
掲載誌名
BMC cancer
ISSN
14712407
cat書誌ID
AA12034763
出版者
BioMed Central
13
開始ページ
229
発行日
2013-05-07
備考
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨 : LID201310041003.pdf
論文本文 : k2624_fulltext.pdf
本論文は,著者Naoko Yamagishiの学位論文として提出され,学位審査・授与の対象となっている。
著者の申請により要約(2014-07-18公開)に替えて論文全文を公開(2019-12-19)
権利情報
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第2624号
学位記番号
甲医第1169号
学位授与年月日
2013-07-25
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系