Fig. 3.

Citrate in tumour invasion and metastasis: the role of CAFs and senescence. The cartoon summaries the role of fibroblast activation and senescence in the modulation of carcinoma behaviour during tumour progression. Senescence can occur following proliferative exhaustion or more acutely following cellular stress and the latter also induces fibroblast activation and the formation of CAFs which secrete (purple arrowheads) extracellular citrate (green diamonds). Developing cancer cells induce both of these phenotypes by secreting ROS and TGF-β and in turn CAFs (yellow) and senescent fibroblasts (purple) deliver citrate and other factors to induce EMT (green spindle-shaped cells) and angiogenesis to promote invasion into the adjacent mesenchyme. This is achieved in part by the upregulation of pmCiC (blue) on the developing cancer cell surface (green shaded cells with black nuclei). Many favoured metastatic sites are citrate-rich and long-term exposure to citrate enhances MET and may aid the growth of metastatic deposits at these sites (arrows). The pmCiC inhibitor gluconate (red lines) mutes both tumour proliferation [1, 141] and metastatic spread [3] to support this hypothesis