Paracrine recruitment and activation of fibroblasts by c-Myc expressing breast epithelial cells through the IGFs/IGF-1R axis

International Journal of Cancer. Journal International Du Cancer
Anna De VincenzoMaria Patrizia Stoppelli

Abstract

Fibroblasts are among the most abundant stromal cells in the tumor microenvironment (TME), progressively differentiating into activated, motile, myofibroblast-like, protumorigenic cells referred to as Cancer-Associated Fibroblasts (CAFs). To investigate the mechanisms by which epithelial cells direct this transition, the early stages of tumorigenesis were exemplified by indirect cocultures of WI-38 or human primary breast cancer fibroblasts with human mammary epithelial cells expressing an inducible c-Myc oncogene (MCF10A-MycER). After c-Myc activation, the conditioned medium (CM) of MCF10A-MycER cells significantly enhanced fibroblast activation and mobilization. As this was accompanied by decreased insulin-like growth factor binding protein-6 (IGFBP-6) and increased insulin-like growth factor-1 and IGF-II (IGF-I, IGF-II) in the CM, IGFs were investigated as key chemotactic factors. Silencing IGFBP-6 or IGF-I or IGF-II expression in epithelial cells or blocking Insulin-like growth factor 1 receptor (IGF-1R) activity on fibroblasts significantly altered fibroblast mobilization. Exposure of WI-38 fibroblasts to CM from induced MCF10A-MycER cells or to IGF-II upregulated FAK phosphorylation on Tyr397 , as well as the expression o...Continue Reading

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Citations

Jan 5, 2020·The Journal of Clinical Endocrinology and Metabolism·Nina Dabrosin, Charlotta Dabrosin
Apr 7, 2020·Expert Opinion on Therapeutic Targets·Rosamaria LappanoErnestina Marianna De Francesco
Dec 18, 2020·Frontiers in Cell and Developmental Biology·Zheng ZhouMeng Bian
Feb 20, 2021·Molecular and Cellular Endocrinology·Michael W Lero, Leslie M Shaw
Mar 27, 2021·Frontiers in Cell and Developmental Biology·Soudeh Ghafouri-FardMohammad Taheri

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