Mesenchymal-transitioned cancer cells instigate the invasion of epithelial cancer cells through secretion of WNT3 and WNT5B.
Bottom Line: In this study, we show that the mesenchymal-transitioned cancer cells instigate the invasive ability and metastatic potential of the neighboring epithelial cancer cells in vitro and in vivo.We identify WNT3 and WNT5B as critical factors secreted from Transforming growth factor-induced mesenchymal cancer cells for instigating the epithelial cancer cell invasion along with the induction of secondary EMT phenotype.These results shed light on the significance of cancer heterogeneity and the interaction between epithelial and mesenchymal-transitioned cancer cells within the tumor microenvironment in promoting metastatic disease through the WNT-dependent mechanism.
Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.Show MeSH
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Mentions: To determine whether the direct cell–cell interaction is required for promoting the metastatic potential of E-cells by neighboring with M-cells, we first examined the expression of EMT-related proteins in A549 or Panc-1 cells under the co-culture of E-cells with M-cells in the presence or absence of direct cell–cell contact (Fig.2a,b). Given that the upregulation of the mesenchymal marker (Snail and Vimentin) and the downregulation of the epithelial marker (E-cadherin) were markedly induced by both direct and separated co-culture of E-cells and M-cells, the soluble factor(s) derived from M-cells was at least sufficient for the induction of the secondary EMT phenotype of E-cells upon co-culture with M-cells. We further confirmed that the invasion of E-A549 cells was remarkably enhanced after the culture with M-A549-derived conditioned medium (M-A549-CM) compared with E-A549-CM (Fig.2c and Fig. S3). In concert with the enhanced invasive ability of E-A549 cells after the cultivation with M-A549-CM, the secondary EMT phenotype in E-A549 cells was also induced after the culture with M-A549-CM. Similar results were obtained in the invasion of E-Panc cells after the cultivation with M-Panc-CM (data not shown).
Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.