LGR5 was shown to be capable of association with TGF-β receptors and its activation by R-spondin ligands determines the activation of LGR5 and the concomitant activation of TGF-βRII; furthermore, in colorectal cancer specimens, LGR5 expression correlates with SMAD2 expression [401]. This evidence concerns the gene RSPO1 and colorectal cancer.