Molecular Pathways: The Role of Primary Cilia in Cancer Progression and Therapeutics with a Focus on Hedgehog Signaling
Cet article passe en revue les travaux récents sur le rôle des cils cellulaires primaires dans la progression d'un cancer et la réponse à un inhibiteur de la voie Hedgehog
Abnormal Hedgehog (Hh) pathway activity has been reported in many cancers including basal cell carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, breast and prostate cancers. For this reason the Hh pathway is a flourishing area for development of anti-cancer drugs such as Hh ligand antagonists (e.g. 5E1, robotnikinin), Smo inhibitors (e.g. GDC-0449, IPI-926) and Gli transcriptional activity inhibitors (e.g. GANT58, GANT61). In vertebrate cells it is now clear that primary cilia are required for activation of the Hh pathway in normal cells. It is in the primary cilium that both positive and negative effectors of the Hh pathway are processed by post-translational modifications. In many cancers, preliminary results suggest that primary cilia are lost. As drugs are developed that inhibit different steps of the Hh pathway, it is important to consider how these drugs will function in the context of primary cilia in the tumor environment. We will discuss why some of the Hh inhibitors may be ineffective if primary cilia are lost on cancer cells. Understanding the relationships between clinical inhibitors of the Hh pathway and the presence or absence of primary cilia may turn out to be critical for targeting these therapeutics to the correct population of patients and for improving their efficacy. Future work is needed in this area to maximize the potential of these exciting therapeutic targets.