SHH and neoplasm: Based on existing evidence in the literature and our current data, we propose a model where epithelial tumor cells could be chronically exposed to TGF-β1 excreted by either stromal cells, immune cells or the tumor cells within the tumor microenvironment, resulting in the up-regulation of Shh both at the mRNA and at the protein levels and consequently causes activation of Hh signaling and the acquisition of EMT phenotype, which is responsible for tumor cell aggressiveness and metastasis (Fig. 9).