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

Journal Article


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 of α-smooth muscle actin (α-SMA), features associated with CAF phenotype and increased cell migratory/invasive behavior. In three-dimensional (3D)-organotypic assays, WI-38 or human primary fibroblasts, preactivated with either CM from MCF10A-MycER cells or IGFs, resulted in a permissive TME that enabled nontransformed MCF10A matrix invasion. This effect was abolished by inhibiting IGF-1R activity. Thus, breast epithelial cell oncogenic activation and stromal fibroblast transition to CAFs are linked through the IGFs/IGF-1R axis, which directly promotes TME remodeling and increases tumor invasion.

Authors


  •   De Vincenzo, Anna (external author)
  •   Belli, Stefania (external author)
  •   Franco, Paola (external author)
  •   Telesca, Marialucia (external author)
  •   Iaccarino, Ingram (external author)
  •   Botti, Gerardo (external author)
  •   Carriero, Maria (external author)
  •   Ranson, Marie
  •   Stoppelli, Maria (external author)

Publication Date


  • 2019

Citation


  • De Vincenzo, A., Belli, S., Franco, P., Telesca, M., Iaccarino, I., Botti, G., Carriero, M. V., Ranson, M. & Stoppelli, M. Patrizia. (2019). Paracrine recruitment and activation of fibroblasts by c-Myc expressing breast epithelial cells through the IGFs/IGF-1R axis. International Journal of Cancer, Online First 1-13.

Scopus Eid


  • 2-s2.0-85071275770

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/880

Number Of Pages


  • 12

Start Page


  • 1

End Page


  • 13

Volume


  • Online First

Place Of Publication


  • United States

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 of α-smooth muscle actin (α-SMA), features associated with CAF phenotype and increased cell migratory/invasive behavior. In three-dimensional (3D)-organotypic assays, WI-38 or human primary fibroblasts, preactivated with either CM from MCF10A-MycER cells or IGFs, resulted in a permissive TME that enabled nontransformed MCF10A matrix invasion. This effect was abolished by inhibiting IGF-1R activity. Thus, breast epithelial cell oncogenic activation and stromal fibroblast transition to CAFs are linked through the IGFs/IGF-1R axis, which directly promotes TME remodeling and increases tumor invasion.

Authors


  •   De Vincenzo, Anna (external author)
  •   Belli, Stefania (external author)
  •   Franco, Paola (external author)
  •   Telesca, Marialucia (external author)
  •   Iaccarino, Ingram (external author)
  •   Botti, Gerardo (external author)
  •   Carriero, Maria (external author)
  •   Ranson, Marie
  •   Stoppelli, Maria (external author)

Publication Date


  • 2019

Citation


  • De Vincenzo, A., Belli, S., Franco, P., Telesca, M., Iaccarino, I., Botti, G., Carriero, M. V., Ranson, M. & Stoppelli, M. Patrizia. (2019). Paracrine recruitment and activation of fibroblasts by c-Myc expressing breast epithelial cells through the IGFs/IGF-1R axis. International Journal of Cancer, Online First 1-13.

Scopus Eid


  • 2-s2.0-85071275770

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/880

Number Of Pages


  • 12

Start Page


  • 1

End Page


  • 13

Volume


  • Online First

Place Of Publication


  • United States