TGF-beta receptors can also activate other downstream effectors like MAP kinase (MAPK), phosphatidyl-inositol-3 kinase (PI3K) and have a crosstalk with other signaling routes involved in CCA pathogenesis, such as WNT, HIPPO, NF-B, Notch, hedgehog, JAK/STAT, MAPK, and PI3K-AKT [73,74]. This evidence concerns the gene PIK3CA and cholangiocarcinoma.