Abstract
The interactions of cancer stem cells (CSCs) within the tumor microenvironment (TME), contribute to the overall phenomenon of intratumoral heterogeneity, which also involve CSC interactions with noncancer stromal cells. Comprehensive understanding of the tumorigenesis process requires elucidating the coordinated gene expression between cancer and tumor stromal cells for each tumor. We show that human gastric cancer cells (GSC1) subvert gene expression and cytokine production by mesenchymal stem cells (GSC-MSC), thus promoting tumor progression. Using mixed composition of human tumor xenografts, organotypic culture, and in vitro assays, we demonstrate GSC1-mediated specific reprogramming of “naïve” MSC into specialized tumor associated MSC equipped with a tumor-promoting phenotype. Although paracrine effect of GSC-MSC or primed-MSC is sufficient to enable 2D growth of GSC1, cell–cell interaction with GSC-MSC is necessary for 3D growth and in vivo tumor formation. At both the transcriptional and at the protein level, RNA-Seq and proteome analyses, respectively, revealed increased R-spondin expression in primed-MSC, and paracrine and juxtacrine mediated elevation of Lgr5 expression in GSC1, suggesting GSC-MSC-mediated support of cancer stemness in GSC1. CSC properties are sustained in vivo through the interplay between GSC1 and GSC-MSC, activating the R-spondin/Lgr5 axis and WNT/β-catenin signaling pathway. β-Catenin+ cell clusters show β-catenin nuclear localization, indicating the activation of the WNT/β-catenin signaling pathway in these cells. The β-catenin+ cluster of cells overlap the Lgr5+ cells, however, not all Lgr5+ cells express β-catenin. A predominant means to sustain the CSC contribution to tumor progression appears to be subversion of MSC in the TME by cancer cells. Stem Cells 2018 Stem Cells 2019;37:176–189.
Original language | English |
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Pages (from-to) | 176-189 |
Number of pages | 14 |
Journal | Stem Cells |
Volume | 37 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2019 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 The Authors. Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2018
Funding
GSC1 Cancer Cell Growth Is Supported by RP MSC In Vitro We thank Gal Akiri for helpful discussions. We thank Sara Selig and Ayala Ofir for critical reading of the manuscript, and Irena Reiter and Nisreen Hassan for excellent technical assistance. We thank Liat Linde, Ronit Modai-Hod, and Nili Avidan for excellent bioinformatics assistance. We also thank Maya Holdengreber Edith Suss-Toby and Melia Gurewitz for excellent bioimaging assistance. This research was supported by grants from the Daniel M. Soref Charitable Trust, the Skirball Foundation, and the ATS-Stem Cell Research Foundation.
Funders | Funder number |
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ATS-Stem Cell Research Foundation | |
Daniel M. Soref Charitable Trust | |
RP MSC In Vitro |
Keywords
- Cancer stem cells
- Gastric cancer
- Organotypic culture
- Reprogramming of MSC
- Tumor associated MSC
- Tumor microenvironment
- Tumor-stromal cell interactions