Reciprocal Reprogramming of Cancer Cells and Associated Mesenchymal Stem Cells in Gastric Cancer

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

Crosstalk Between Mesenchymal Stromal Cells and Tumor-Associated Macrophages in Gastric Cancer

“…Hitherto, the cellular and molecular mechanisms of MSC transition from BM-MSCs to tumor-derived MSCs have not been clearly elucidated. Accumulating evidences have indicated that cancer cells or their conditioned medium could induce the activation of MSCs to assume a tumor-promoting phenotype ( 65 , 66 ). Moreover, tumor-educated neutrophils were also reported to induce the transformation of MSCs into cancer-associated fibroblasts (CAFs), which in turn remarkably facilitated the growth and metastasis of gastric cancer ( 67 ).…”

Pre-clinical Models for Studying the Interaction Between Mesenchymal Stromal Cells and Cancer Cells and the Induction of Stemness

“…Despite recent data are therefore questioning the validity of the CSC model, the CSC-MSC interaction is well documented and is crucial for 3D growth and stemness of tumour cells (15), or for the generation of an hybrid MSC-CSC cell populations, occurring via entosis, i.e., a form of cell-to-cell internalization, or via fusion, as demonstrated in different tumours (16–20). Indeed, the selection processes of hybrid cells after MSC–tumour cell fusion contribute to CSC development (20, 21).…”

Mesenchymal stem/stromal cells: Developmental origin, tumorigenesis and translational cancer therapeutics

“…TA-MSCs with MSC-like properties have become apparent as contributory stromal cells in tumor initiation, progression and metastasis. TA-MSCs have the ability to promote CSC proliferation and to maintain tumor “stemness” in ovarian cancer [49 , 53] , glioma [51] , and gastric cancer [54] . Taken together, these data provide evidence that both MSCs and TA-MSCs play a more potent pro-tumorigenic role in maintaining cancer stemness through increasing CSCs population.…”