徳島大学 教育・研究者情報データベース(EDB)

1. (英) Yamagishi Naoko

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2. 近藤 茂忠

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3. 増田 清士

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4. 西田 憲生([徳島大学.大学院医歯薬学研究部.医学域.先端医学教育研究プロジェクト]/[徳島大学.大学院医歯薬学研究部.医学域.医科学部門.社会医学系.医療教育学])

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5. 桑野 由紀([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.生理系.遺伝情報医学])

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6. (英) Dang T Duyen

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7. (英) Dang H Long

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8. 二川 健([徳島大学.大学院医歯薬学研究部.医学域.栄養科学部門.医科栄養学系.生体栄養学])

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9. 六反 一仁

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(英) Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells

(英) 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. 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. 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. Our findings suggest that chronic inhibition of tumor cell-derived VEGF accelerates tumor cell malignant phenotypes.

1. 分散分析(analysis of variance)
2. (英) Antibodies, Monoclonal
3. アポトーシス(apoptosis)
4. (英) Enzyme Inhibitors
5. (英) Gene Knockdown Techniques
6. (英) HCT116 Cells
7. (英) Humans
8. (英) Hypoxia-Inducible Factor 1
9. (英) Phenotype
10. (英) Pregnancy Proteins
11. (英) Spheroids, Cellular
12. (英) Vascular Endothelial Growth Factor A
13. (英) Vascular Endothelial Growth Factor Receptor-1
14. (英) Vascular Endothelial Growth Factor Receptor-2

1. (英) Article.ELocationID: 10.1186/1471-2407-13-229

2. (英) Article.PublicationTypeList.PublicationType: Journal Article

3. (英) Article.PublicationTypeList.PublicationType: Research Support, Non-U.S. Gov't

4. (英) OtherID: PMC3658959