Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome

Interferon-γ-inducible protein CXCL10 (IP-10) is a small (10 kDa) secretable protein in the CXC subfamily of cytokines. Consistent with known functions of CXC cytokines, CXCL10 mediates leukocyte trafficking, adaptive immunity, inflammation, haematopoiesis and angiogenesis (Groom and Luster, 2011; Liu et al, 2011; Zlotnik and Yoshie, 2012). The CXCL10 induces the chemotaxis of various subtypes of leukocytes including T and B lymphocytes, NK cells, dendritic cells and macrophages (Luster and Ravetch, 1987; Loetscher et al, 1998; Qin et al, 1998; Lo et al, 2010). The CXCL10 signals through the G-protein-coupled seven-transmembrane receptor CXCR3 (Clark-Lewis et al, 2003; Billottet et al, 2013). In human cells, CXCR3 exists in three major isoforms – CXCR3-A, CXCR3-B and CXCR3-alt – that are associated with alternative splicing and potentially different functions (Clark-Lewis et al, 2003; Liu et al, 2011). Signalling occurs through the recruitment of GTP-binding proteins with downstream activation of multiple pathways involved in the regulation of cell survival, proliferation and motility. The CXCR3-A has been associated with pro-survival functions, whereas CXCR3-B is thought to mediate suppressive effects on cell growth and migration; however, these effects are cell and stimuli specific (Liu et al, 2011; Wu et al, 2012; Utsumi et al, 2014).