Role of EphA2-PI3K signaling in vasculogenic mimicry induced by cancer-associated fibroblasts in gastric cancer cells

被引：31
作者：
Kim, Hee Sung [1 ]
Won, You Jin [2 ]
Shim, Ju Hee [2 ]
Kim, Hyun Ji [2 ]
Kim, Byung Sik [1 ]
Hong, Hea Nam [2 ]
机构：
[1] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Gastr Surg, Seoul 05505, South Korea
[2] Univ Ulsan, Coll Med, Dept Anat, 88 Olymp Rd 43 Gil, Seoul 05505, South Korea
来源：
ONCOLOGY LETTERS | 2019年 / 18卷 / 03期
关键词：
vasculogenic mimicry; erythropoietin-producing human hepatocellular receptor tyrosine kinase; cancer-associated fibroblasts; tumor microenvironment; gastric cancer; HEPATOCELLULAR-CARCINOMA; TUMOR-METASTASIS; EPHA RECEPTOR; GROWTH-FACTOR; EXPRESSION; VEGF; MICROENVIRONMENT; ANGIOGENESIS; INHIBITION; RECURRENCE;
D O I：
10.3892/ol.2019.10677
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Although erythropoietin-producing human hepatocellular receptor A2 (EphA2) signaling serves an important role in the tumor microenvironment, its contribution to vasculogenic mimicry (VM) formation in gastric cancer cells remains unclear. The aim of the present study was to investigate the role of EphA2 in VM formation induced by cancer-associated fibroblasts (CAFs). The conditioned medium of CAFs (CAF-CM) was prepared from 12 patients with gastric adenocarcinoma. VM was evaluated by the number of tubules and intersections in gastric cancer cells following CAF-CM treatment. The role of EphA2-phosphoinositide 3-kinase (PI3K) in VM was investigated using EphA2-targeted small interfering (si)RNAs (siEphA2), EphA2 inhibitors and PI3K-inhibitors. CAF-CM-induced VM formation was significantly associated with high protein expression levels of EphA2. EphA2 inhibitor and siEphA2 manipulation significantly decreased VM formation by CAF-CM. In siEphA2 cells, decreased expression levels of VM-associated proteins were observed. CAF-CM-induced VM formation was blocked by the PI3K-inhibitor. In conclusion, CAFs facilitate VM formation via EphA2-PI3K signaling in gastric cancer cells. Thus, EphA2-PI3K signaling may be required for CAF-promoted VM formation during gastric tumorigenesis.
引用
收藏
页码：3031 / 3038
页数：8
相关论文
共 39 条
[11]  
Japanese Gastric Cancer Association, 2011, GASTRIC CANCER, V14, P101, DOI [DOI 10.1007/S10120-011-0041-5, 10.1007/s10120-011-0041-5, DOI 10.1007/s10120-011-0041-5]
[12]   Morphological characteristics of vasculogenic mimicry and its correlation with EphA2 expression in gastric adenocarcinoma [J].
Kim, Hee Sung ;
Won, You Jin ;
Shim, Ju Hee ;
Kim, Hyun Ji ;
Kim, Jihun ;
Hong, Hea Nam ;
Kim, Byung Sik .
SCIENTIFIC REPORTS, 2019, 9 (1)
[13]   Evaluation of the 7th UICC TNM Staging System of Gastric Cancer [J].
Kwon, Sung Joon .
JOURNAL OF GASTRIC CANCER, 2011, 11 (02) :78-85
[14]   Recurrence of gastric cancer in patients who are disease-free for more than 5 years after primary resection [J].
Lee, Ju-Hee ;
Kim, Hyun-Il ;
Kim, Min Gyu ;
Ha, Tae Kyung ;
Jung, Min-Sung ;
Kwon, Sung Joon .
SURGERY, 2016, 159 (04) :1090-1098
[15]   Vasculogenic Mimicry: a New Prognostic Sign of Gastric Adenocarcinoma [J].
Li, Man ;
Gu, Yanjun ;
Zhang, Zhiguang ;
Zhang, Shiwu ;
Zhang, Danfang ;
Saleem, Ali F. ;
Zhao, Xiulan ;
Sun, Baocun .
PATHOLOGY & ONCOLOGY RESEARCH, 2010, 16 (02) :259-266
[16]   Hypoxia induced epithelial-mesenchymal transition and vasculogenic mimicry formation by promoting Bcl-2/Twist1 cooperation [J].
Liu, Kun ;
Sun, Baocun ;
Zhao, Xiulan ;
Wang, Xudong ;
Li, Yanlei ;
Qiu, Zhiqiang ;
Gu, Qiang ;
Dong, Xueyi ;
Zhang, Yanhui ;
Wang, Yong ;
Zhao, Nan .
EXPERIMENTAL AND MOLECULAR PATHOLOGY, 2015, 99 (02) :383-391
[17]   IGFBP2 promotes vasculogenic mimicry formation via regulating CD144 and MMP2 expression in glioma [J].
Liu, Y. ;
Li, F. ;
Yang, Y. T. ;
Xu, X. D. ;
Chen, J. S. ;
Chen, T. L. ;
Chen, H. J. ;
Zhu, Y. B. ;
Lin, J. Y. ;
Li, Y. ;
Xie, X. M. ;
Sun, X. L. ;
Ke, Y. Q. .
ONCOGENE, 2019, 38 (11) :1815-1831
[18]   Contribution of the PI3K/MMPs/Ln-5γ2 and EphA2/FAK/Paxillin signaling pathways to tumor growth and vasculogenic mimicry of gallbladder carcinomas [J].
Lu, Xin-Sui ;
Sun, Wei ;
Ge, Chun-Yan ;
Zhang, Wen-Zhong ;
Fan, Yue-Zu .
INTERNATIONAL JOURNAL OF ONCOLOGY, 2013, 42 (06) :2103-2115
[19]   Vascular channel formation by human melanoma cells in vivo and in vitro:: Vasculogenic mimicry [J].
Maniotis, AJ ;
Folberg, R ;
Hess, A ;
Seftor, EA ;
Gardner, LMG ;
Pe'er, J ;
Trent, JM ;
Meltzer, PS ;
Hendrix, MJC .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 155 (03) :739-752
[20]   VEGF Increases Paracellular Permeability in Brain Endothelial Cells via Upregulation of EphA2 [J].
Miao, Ziwei ;
Dong, Yanbin ;
Fang, Wengang ;
Shang, Deshu ;
Liu, Dongxin ;
Zhang, Ke ;
Li, Bo ;
Chen, Yu-Hua .
ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, 2014, 297 (05) :964-972
1234