Tumor endothelial cells promote metastasis and cancer stem cell-like phenotype through elevated Epiregulin in esophageal cancer.
Tumor endothelial cells have been found to be associated with metastasis and cancer progression. In this study, we reported that human esophageal cancer endothelial cells (HECEC), unlike corresponding human esophageal normal endothelial cells (HENEC) displayed several distinct feature couple with unique gene expression profile. Further studies showed that HECEC can enhance migration, invasion and self-renewal properties of esophageal carcinoma cell in vitro by a direct cell-cell interaction. In vivo assay demonstrated that HECEC could significantly enhance the invasion and lung metastasis of esophageal cancer cells. To elucidate the molecular mechanisms of HECEC in esophageal carcinoma progression, we employed the microarray to analyze the gene expression profiles before and after treating with HECEC, HENEC or conditioned meium from HECEC. Among the highly expressed HECEC-regulated genes, we focused on Epiregulin (EREG). Further studies demonstrated that overexpression of EREG in EC9706 or Kyse30 cells can induce actin reorganization, sphere formation ability and a significantly enrichment of CD44+cancer stem-like cells. Moreover, up-regulation of EREG in esophageal cancer cells could enhance lung metastasis and decrease the survival time in vivo. Further study indicated that EREG could induce activation of the Src and FAK. In addition, all these effects could also be inhibited by the function-blocking anti-EREG antibody in a dose dependent manner. Immunohistochemical analysis revealed that high level of EREG was significantly correlated with lymph node metastases and poor prognosis. In summary, HECEC play key roles in enhancing the invasion, migration, cancer stem cell phenotype and metastatic potential of esophageal cancer cells through Epiregulin.
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China.
Lichao
L
Sun
Department of Hematology and Oncology, Children's Hospital of Soochow University Suzhou, Jiangsu, People's Republic of China.
Jian
J
Pan
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China.
Long
L
Yu
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China.
Huiqi
H
Liu
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China.
Xiong
X
Shu
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China.
Lixin
L
Sun
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital Beijing, People's Republic of China.
Jinning
J
Lou
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China.
Zhihua
Z
Yang
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China.
Yuliang
Y
Ran
CD44; EREG; Esophageal cancer; cancer stem cell; metastasis; tumor endothelial cells