Human Marrow Stromal Cells Downsize the Stem Cell Fraction of Lung Cancers by Fibroblast Growth Factor 10

Abstract

The functional interplay between cancer cells and marrow stromal cells (MSCs) has attracted a great deal of interest due to the MSC tropism for tumors but remains to be fully elucidated. In this study, we investigated human MSC-secreted paracrine factors that appear to have critical functions in cancer stem cell subpopulations. We show that MSC-conditioned medium reduced the cancer stem cell-enriched subpopulation, which was detected as a side population and quiescent (G₀) cell cycle fraction in human lung cancer cells by virtue of fibroblast growth factor 10 (FGF10). This reduction of the stem cell-enriched fraction was also observed in lung cancer cells supplemented with recombinant human FGF10 protein. Moreover, supplementary FGF10 attenuated the expression of stemness genes encoding transcription factors, such as OCT3/4 and SOX2, and crippled the self-renewal capacity of lung cancer cells, as evidenced by the impaired formation of floating spheres in the suspension culture. We finally confirmed the therapeutic potential of the FGF10 treatment, which rendered lung cancer cells prone to a chemotherapeutic agent, probably due to the reduced cancer stem cell subpopulation. Collectively, these results add further clarification to the molecular mechanisms underlying MSC-mediated cancer cell kinetics, facilitating the development of future therapies.

ACKNOWLEDGMENTS

We thank Mitsu Takahashi for technical assistance and Brent Bell for reading the manuscript.

These studies were supported, in part, by Grants-in-Aid for Scientific Research and the Project for Development of Innovative Research on Cancer Therapeutics from the Ministry of Education, Culture, Sports, Science and Technology (Tokyo, Japan), the Core Research for Evolutional Science and Technology Program, the Adaptable and Seamless Technology Transfer Program from the Japan Science and Technology Agency (Tokyo, Japan), and the Urgent Research Grant Program from the Astellas Foundation for Research on Metabolic Disorders (Tokyo, Japan).