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Tumorspheres from transformed fibroblasts highlight the great plasticity of differentiated tumorigenic cells

ABSTRACT: Tumors are heterogeneous tissues. A subpopulation of cells with stemness features (cancer stem cells: CSCs) has been implicated in tumor maintenance and progression. There is evidence that CSCs can originate from tumor cell dedifferentiation. Here we used in vitro transformed human fibroblasts (cen3tel cells) and the tumorsphere assay to search for and possibly characterize CSCs from differentiated transformed cells. To obtain tumorspheres, cen3tel cells were grown in the absence of serum and in the presence of growth factors. Sphere cells were analysed for the expression of specific genes and their genome wide gene expression profiles relative to cells grown in adhesion were determined by microarray analysis. Cen3tel cells formed spheres showing self-renewal capacity and Sox2 overexpression, suggesting that they contained a subset of cells with CSC-like features. Sphere cells displayed the deregulation of a c-MYC-miR-34a circuitry, likely associated with cell protection from apoptosis. Gene expression profiles of sphere cells revealed an extensive transcriptional reprogramming. Genes upregulated in tumorspheres identified processes related to tumorigenesis and stemness, such as chromatin organization, cholesterol biosynthetic pathway, apoptosis suppression, immunity and defense, interferon mediated immunity and cytokine and chemokine mediated signalling pathway. However, sphere cells were only slightly more tumorigenic in vivo than adherent cells. Our results indicate that tumorigenic cells obtained from differentiated human fibroblasts are highly plastic and can acquire cancer stem cells properties. However, tumorsphere cells are not the main tumorigenic population, highlighting a further level of complexity in tumor heterogeneity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109787 | GEO | 2018/12/25

REPOSITORIES: GEO

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Project description:The recent identification of cancer stem cells (CSCs) in multiple human cancers provides a new inroad to understanding tumorigenesis at the cellular level. CSCs are defined by their characteristics of self-renewal, multipotentiality, and tumor initiation upon transplantation. By testing for these defining characteristics, we provide evidence for the existence of CSCs in a transgenic mouse model of glioma, S100Ã-verbB;Trp53. In this glioma model, CSCs are enriched in the side-population (SP) cells. These SP cells have enhanced tumor-initiating capacity, self-renewal, and multipotentiality compared to non-SP cells from the same tumors. Furthermore, gene expression analysis comparing FACS-sorted cancer SP cells to non-SP cancer cells and normal neural SP cells identified 45 candidate genes that are differentially expressed in glioma stem cells. We validated the expression of two genes from this list (S100a4 and S100a6) in primary mouse gliomas and human glioma samples. Analyses of xenografted human GBM (glioblatoma multiforme) cell lines and primary human glioma tissues show that S100A4 and S100A6 are expressed in a small subset of cancer cells and that their abundance is positively correlated to tumor grade. In conclusion, this study shows that CSCs exist in a mouse glioma model, suggesting that this model can be used to study the molecular and cellular characteristics of CSCs in vivo and to further test the cancer stem cell hypothesis. Experiment Overall Design: This study features two factors, injected cell origin (either tumorsphere or neurosphere) and FACS cell population (either side population or non-side population cells). There were two different tumorspheres, labeled 3447 and 4346 that were isolated from brain tumors in S100beta-verbB;p53-/- or S100beta-verbB;p53+/- mice. The tumorspheres were injected separately into the brains of NOD.Cg-Prkdc<scid>Il2rg<tm1Wjl>/SzJ mice to generate biological triplicates of each primary tumor. Tumorspheres were isolated and cultured before FACS sorting to obtain side population and non-side population cells. As a control, untransformed neurospheres from three independent S100beta-verbB;p53-/- or S100beta-verbB;p53+/- mice were isolated, cultured, and FACS sorted to obtain side population and non-side population cells. Side population and non-side population cells cultured from three mice injected with the 3447 cultured tumorspheres were assayed for gene expression (six samples). Side-population stem cells cultured from three mice injected with the 4346 cultured tumorspheres were assayed for gene expression (three samples). Side-population and non-side population cells cultured from three mice injected with the neurospheres were assayed for gene expression (six samples).

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Tumorspheres from transformed fibroblasts highlight the great plasticity of differentiated tumorigenic cells

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