Abstract & Authors:展开
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 co-cultured 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 monoclonal antibody (Net1-mAb) abrogated the CAF-mediated increase of cancer stemness both in co-culture experiments and in mice. Netrin-1 mAb inhibited intercellular signaling between CAF and cancer cells by modulating CAF-mediated expression of cytokines such as interleukin-6 (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 pro-neoplastic CAF-cancer cell crosstalk, thus inhibiting cancer plasticity.
Pei-Ju Sung,Nicolas Rama,Jeromine Imbach,Stephany Fiore,Benjamin Ducarouge,David Neves,Huei-Wen Chen,David Bernard,Pan-Chyr Yang,Agnès Bernet,Stephane Depil,Patrick Mehlen