HHIP and colorectal carcinoma: In mouse models, the overexpression of Shh ligands provided advantages in growth to tumor cells by activating HH signaling pathway in the surrounding stroma.196 Further studies have shown that Shh ligands are upregulated in CRC in order to activate the stromal HH signaling pathway, while stromal downstream genes, such as Gli1 and Hhip expression, are decreased.283 This could explain the negative results and Shh ligand overexpression that were evident in clinical trials involving vismodegib for CRC.