Hedgehog signalling pathway: carcinogenesis and targeted therapy

Abstract

Hedgehog signalling pathway has not only a critical role in cell proliferation,differentiation and tissue polarity at embryonic period but also has a vital role in stem cell proliferation, tissue healing and carcinogenesis. Recent research has increased our understanding of this pathway and its relation to other signalling pathways. In addition, a large number of studies confirmed the alteration of Hh signalling pathway in various types of human malignancies including basal cell carcinomas, medulloblastomas, lung, gastrointestinal, ovarian, breast, prostate cancers and leukemia. More than 50 small biomolecules have been introduced which have inhibitory effects on Hh signalling pathway. Although, in many tumors some acceptable results have been showed in phase I clinical trial, closer studies are required to improve drug bioavailability, to decrease the side effects and to find the right small molecules for specific types of cancers, considering patients overall benefits as well.

Keywords: Hedgehog; Molecular targeted therapy; Neoplasm.

Figure 1

Hh signalling and cancer: Growth factors can increase the concentration of ligand which prevents the inhibitory effect of PTCH. Active Smo upregulates the GLI in cooperation with Fu. Finally GLI affects target genes. P53 and GLI antagonize one another, SUFU blocks the GLI, GLI2 and GLI3 could have activating or inhibitory effects whereas GLI1 is an activator of transcription. SmoC is actived Smo and inhibits GSK3β, PKA, and CKI. KIF7 is activator of GLI. Wnt and Hh signalling work together in a feedback loop manner.