Overall, the results presented here clearly suggest two main aspects regarding IL-8 evaluation in CRC biology: (i) an activated IL-8 network in the TME of CRC tissues profoundly modifies cancer and non-cancer cell behavior; thus, identifying the source of IL-8 production is necessary to define TSI, which in turn may impact on tumor progression and, eventually, may inform the development of specific IL-8 axis-directed therapeutic strategies. This evidence concerns the gene CXCL8 and cancer.