Cancer-Associated Fibroblasts Produce Netrin-1 to Control Cancer Cell Plasticity

Cancer Res. 2019 Jul 15;79(14):3651-3661. doi: 10.1158/0008-5472.CAN-18-2952. Epub 2019 May 14.


Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature. Both colon and lung CAF secreted netrin-1 when cocultured with respective cancer cells, and netrin-1 upregulation in CAF was associated with increased cancer cell stemness. Pharmacologic inhibition of netrin-1 with a netrin-1-mAb (Net1-mAb) abrogated the CAF-mediated increase of cancer stemness both in coculture experiments and in mice. Net-1-mAb inhibited intercellular signaling between CAF and cancer cells by modulating CAF-mediated expression of cytokines such as IL6. Together these data demonstrate that netrin-1 is upregulated not only in cancer cells but also in cancer-associated stromal cells. In addition to its direct activity on cancer cells, inhibition of netrin-1 may reduce proneoplastic CAF-cancer cell cross-talk, thus inhibiting cancer plasticity. SIGNIFICANCE: Netrin-1, a navigation cue during embryonic development, is upregulated in cancer-associated fibroblasts and regulates cancer cell stemness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Plasticity / physiology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Female
  • HCT116 Cells
  • Heterografts
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Mice
  • Mice, SCID
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Netrin Receptors / biosynthesis
  • Netrin-1 / biosynthesis*
  • Up-Regulation


  • NTN1 protein, human
  • Netrin Receptors
  • UNC5B protein, human
  • Netrin-1