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Mouse induced pluripotent stem cell microenvironment generates epithelial-mesenchymal transition in mouse Lewis lung cancer cells.

ABSTRACT: Induced pluripotent stem (iPS) cells may be a powerful tool in regenerative medicine, but their potential tumorigenicity is a significant challenge for the clinical use of iPS cells. Previously, we succeeded in converting miPS cells into cancer stem cells (CSCs) under the conditions of tumor microenvironment. Both stem cells and tumor cells are profoundly influenced by bi-directional communication with their respective microenvironment, which dictates cell fate determination and behavior. The microenvironment derived from iPS cells has not been well studied. In this paper, we have investigated the effects of secreted factors from Nanog-mouse iPS (miPS) cells on mouse Lewis lung cancer (LLC) cells that are found in the conditioned media. The results demonstrated that miPS cells secrete factors that can convert the epithelia phenotype of LLC cells to a mesenchymal phenotype, and that can promote tumorigenisity, migration and invasion. Furthermore, LLC cells that have been exposed to miPS conditioned medium became resistant to apoptosis. These various biological effects suggest that the miPS microenvironment contain factors that can promote an epithelial-mesenchymal transition (EMT) through an active Snail-MMP axis or by suppressing differentiation in LLC cells.

SUBMITTER: Chen L

PROVIDER: S-EPMC3902235 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Mouse induced pluripotent stem cell microenvironment generates epithelial-mesenchymal transition in mouse Lewis lung cancer cells.

Chen Ling L Mizutani Akifumi A Kasai Tomonari T Yan Ting T Jin Guoliang G Vaidyanath Arun A El-Aarag Bishoy Ya BY Liu Yixin Y Kudoh Takayuki T Salomon David S DS Fu Li L Seno Masaharu M

American journal of cancer research 20140115 1

Induced pluripotent stem (iPS) cells may be a powerful tool in regenerative medicine, but their potential tumorigenicity is a significant challenge for the clinical use of iPS cells. Previously, we succeeded in converting miPS cells into cancer stem cells (CSCs) under the conditions of tumor microenvironment. Both stem cells and tumor cells are profoundly influenced by bi-directional communication with their respective microenvironment, which dictates cell fate determination and behavior. The mi ...[more]

PMID: 24482741

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Project description:Trophectoderm cells of the blastocyst are the precursor of the placenta that is comprised of trophoblast, endothelial and smooth muscle cells. Since trophoectoderm cells are epithelial in nature, epithelial mesenchymal transition (EMT) of trophoblast stem (TS) cells might play pivotal role in placental morphogenesis. However, the molecular regulation of EMT during placental development and trophoblast differentiation still remained elusive. In this report, we sought to identify the molecular signature that regulates EMT during placental development and TS cell differentiation in mice. On E7.5 onwards the TS cells, located in the ectoplacental cone (EPC), rapidly divide and differentiate leading to formation of placenta proper. Using a real time PCR based array of functional EMT transcriptome with RNA from mouse implantation sites (IS) on E7.5 and E9.5, it was observed that there was an overall reduction of EMT gene expression in the IS as gestation progressed from E7.5 to E9.5 albeit the levels of EMT gene expression were substantial on both days. Further validation of array results using real time PCR and western blot analysis showed significant decrease in EMT-associated genes that included (a) transcription factors (Snai2, Zeb1, Stat3 and Foxc2), (b) extracellular matrix and cell adhesion related genes (Bmp1, Itga5, Vcan and Col3A1), (c) migration and motility- associated genes (Vim, Msn and FN1) and (d) differentiation and development related genes (Wnt5b, Jag1 and Cleaved Notch-1) on E9.5. To understand whether EMT is an ongoing process during placentation, the EMT-associated signatures genes, prevalent on E 7.5 and 9.5, were analysed on E12.5, E14.5 and E17.5 of mouse placenta. Interestingly, expression of these EMT-signature proteins were significantly higher at E12.5 though substantial expressions was observed in placenta with progression of gestation from mid- to late. To evaluate whether TS cells have the potential to undergo EMT ex vivo, TS cells were subjected to EMT induction, which was confirmed using morphological analysis and marker gene expression. Induction of EMT in TS cells showed similar gene expression profile of placental EMT. These results have broad biological implications, as inadequate mesenchymal transition leading to improper trophoblast-vasculogenic mimicry leads to placental pathophysiology and pregnancy failure.

Dataset Information

Mouse induced pluripotent stem cell microenvironment generates epithelial-mesenchymal transition in mouse Lewis lung cancer cells.

Publications

Mouse induced pluripotent stem cell microenvironment generates epithelial-mesenchymal transition in mouse Lewis lung cancer cells.

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