The architecture of fibroblast monolayers of different origin differentially influences tumor cell growth

Authors

  • Emilie Flaberg,

    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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    • Emilie Flaberg, Hayrettin Guven, Laszlo Szekely, and George Klein are equally contributed to the article.

  • Hayrettin Guven,

    Corresponding author
    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
    • Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Nobels väg 16, Box 280, 171 77, Stockholm, Sweden
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    • Emilie Flaberg, Hayrettin Guven, Laszlo Szekely, and George Klein are equally contributed to the article.

    • Tel.: +46 8 524 86761, Fax: +46 8 330 498

  • Andrii Savchenko,

    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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  • Tatiana Pavlova,

    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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  • Vladimir Kashuba,

    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
    2. Institute of Molecular Biology and Genetics, UNAS, Kiev, Ukraine
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  • Laszlo Szekely,

    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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    • Emilie Flaberg, Hayrettin Guven, Laszlo Szekely, and George Klein are equally contributed to the article.

  • George Klein

    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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    • Emilie Flaberg, Hayrettin Guven, Laszlo Szekely, and George Klein are equally contributed to the article.


Abstract

Normal human and murine fibroblasts can inhibit proliferation of tumor cells when co-cultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. It requires direct cell-to-cell contact and is not transferable with supernatant. Here, we show that effective inhibition also requires the formation of a morphologically intact fibroblast monolayer before the seeding of the tumor cells. Interference with the formation of the monolayer impairs the inhibition. Subclones of TERT-immortalized fibroblasts were selected on the basis of differences in the growth pattern and related inhibitory activity. Whereas the well-organized “whirly” (WH) growth pattern was associated with strong inhibition, the disorganized “crossy” (CR) growth pattern was linked to reduced inhibition. Time lapse imaging of tumor-fibroblast co-cultures using extended field live cell microscopy revealed that fibroblast monolayers with growth inhibitory capacity also reduced the motility of the tumor cells whereas noninhibitory monolayers had no effect on tumor cell motility. Gene expression pattern of two isogenic pairs of fibroblasts, WH and CR subclones of the TERT immortalized line (inhibitory, and less inhibitory subsequently) and freshly explanted skin (inhibitory) and hernia (noninhibitory) fibroblasts derived from the same patient, identified a set of genes that co-segregated with the inhibitory phenotype. This suggests that our model system may reveal molecular mechanisms involved in contact-mediated microenvironmental surveillance that may protect the organism from the outgrowth of disseminated tumor cells.

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