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ID 111606
Title Alternative
大腸がん細胞においてVEGF経路を標的とした薬剤は、neuropilin-1/cMet複合体の活性化を介した悪性化適応応答を誘導する
DIRECT EFFECTS OF VEGF/VEGF-R TARGETING AGENTS ON COLON CANCER CELLS
Author
Tomida, Chisato University of Tokushima
Yamagishi, Naoko Wakayama Medical University
Nagano, Hikaru Osaka Prefecture University
Keywords
VEGF
neuropilin-1
cMet
sunitinib
bevacizumab
evasive adaptation
Content Type
Thesis or Dissertation
Description
Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) are important treatments for a number of human malignancies, including colorectal cancers. However, there is increasing evidence that VEGF/VEGF-R inhibitors promote the adaptive and evasive resistance of tumor cells to the therapies. The mechanism by which the cancer cells become resistant remains unclear. One potential mechanism is that VEGF/VEGF-R blockers directly act on tumor cells independently of anti-angiogenic effects. In this study, the direct effects of an anti-VEGF antibody (bevacizumab) and a VEGF-R tyrosine kinase inhibitor (sunitinib) on the evasive adaptation of colon cancer cells were compared. HCT116 and RKO human colon cancer cell lines were chronically exposed (3 months) to bevacizumab or sunitinib in vitro to establish bevacizumab- and sunitinib-adapted cells, respectively. Transwell migration and invasion assays, western blotting, reverse transcription-quantitative polymerase chain reaction, co-immunoprecipitation analysis, cell survival assays and ELISAs were conducted to analyze the adapted cells. Compared with the control vehicle-treated cells, the two cell models exhibited increased migration and invasion activities to different degrees and through different mechanisms. The bevacizumab-adapted cells, but not in the sunitinib-adapted cells, exhibited redundantly increased expression levels of VEGF/VEGF-R family members, including VEGF-A, placental growth factor, VEGF-C, VEGF-R1 and VEGF-R3. In addition, the phosphorylation levels of VEGF-R1 and VEGF-R3 were increased in the bevacizumab-adapted cells compared with the control cells. Thus, the inhibition of VEGF-R1 and VEGF-R3 decreased the evasive activities of the cells, suggesting that they remained dependent on redundant VEGF/VEGF-R signaling. By contrast, the sunitinib-adapted cells exhibited increased neuropilin-1 (NRP1) expression levels compared with the control cells. In the sunitinib-adapted cells, NRP1 interacted with phosphorylated cMet, and the cMet activation was dependent on NRP1. Thus, NRP1 or cMet blockade suppressed the evasive activation of the sunitinib-adapted cells. These results suggest that the sunitinib-adapted cells switched from a VEGF-R-dependent pathway to an alternative NRP1/cMet-dependent one. The findings of the present study indicate that VEGF/VEGF-R inhibitors directly act on colon cancer cells and activate their evasive adaptation via different mechanisms.
Journal Title
International Journal of Oncology
ISSN
10196439
17912423
NCID
AA10992511
Publisher
Spandidos Publications
Volume
52
Issue
4
Start Page
1350
End Page
1362
Published Date
2018-02-28
Remark
内容要旨・審査要旨・論文本文の公開
本論文は, 著者CHISATO TOMIDA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。
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3142号
Diploma Number
甲栄第251号
Granted Date
2018-03-23
Degree Name
Doctor of Nutritional Science
Grantor
Tokushima University
departments
Medical Sciences