Beyond osteopontin, another multifunctional cytokine released by CAFs is transforming growth factor beta (TGFB) that can act synergistically with hypoxia-induced tumor cell-expressed HIF1A to sustain 5-FU/oxaliplatin resistance via activation of the hedgehog pathway, as demonstrated by in vitro and in vivo experiments using patient-derived cells[70]. This evidence concerns the gene SPP1 and neoplasm.