Mesenchymal stem cells promote epithelial to mesenchymal transition and metastasis in gastric cancer though paracrine cues and close physical contact.
Mesenchymal stem cells (MSCs) have been shown to integrate into the tumor stroma; however, the precise mechanisms of this process are still elusive. In this study, the EMT phenotype and the enhanced metastatic ability of tumor cells were observed using transwell and trans-endothelial migration assays, respectively, as well as by using electron and laser confocal microscopy. Critical genes were screened and validated using gene arrays and clinical samples, and the changes at the protein level were examined both in vitro and in vivo. Cancer cells acquired an "activated" carcinoma-associated fibroblasts (CAFs) phenotype after being in close contact with MSCs and enhancing tumor metastasis and growth in vivo. Paracrine signals also induced EMT and promoted transwell and trans-endothelial migration, the changes were dependent on β-catenin, MMP-16, snail and twist. Notably, the higher expression levels of β-catenin and MMP-16 were correlated with tumor invasion and distant organ and lymph node metastases in intestinal type gastric cancer. MSCs within the tumor niche significantly facilitated tumor growth and metastasis by paracrine cues and close physical connection. This occurred partly through snail, twist and its downstream targets, specifically β-catenin/MMP-16.
State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, 710032, China; Department of Digestive Diseases, The First Affiliated Hospital of Xiamen University, 10 Shanggu Road, Xiamen, 361003, China.
Zengfu
Z
Xue
Xiumin
X
Wu
Xiong
X
Chen
Yali
Y
Liu
Xin
X
Wang
Kaichun
K
Wu
Yongzhan
Y
Nie
Daiming
D
Fan
D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019899:Paracrine Communication; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
EPITHELIAL-MESENCHYMAL TRANSITION; MESENCHYMAL STEM CELLS; MMP-16; β-CATENIN