Molecular Pathways: The Role Of Primary Cilia In Cancer Progression And Therapeutics With A Focus On Hedgehog Signaling.
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research
Abnormal Hedgehog (Hh) pathway activity has been reported in many cancers, including basal cell carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, and breast and prostate cancers. For this reason, the Hh pathway is a flourishing area for development of anticancer drugs such as Hh ligand antagonists (e.g., 5E1 and robotnikinin), Smo inhibitors (e.g., GDC-0449 and IPI-926), and Gli transcriptional activity inhibitors (e.g., GANT58 and GANT61). It is now clear that primary cilia are required for activation of the Hh pathway in normal vertebrate cells. It is in the primary cilium that both positive and negative effectors of the Hh pathway are processed by posttranslational modifications. In many cancers, preliminary results suggest that primary cilia are lost. As drugs that inhibit different steps of the Hh pathway are developed, it will be important to consider how these drugs will function in the context of primary cilia in the tumor environment. Here, we 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 improving their efficacy. Further work is needed in this area to maximize the potential of these exciting therapeutic targets.<br /><br />
Primary Cilia Regulate Branching Morphogenesis During Mammary Gland Development.
Source: Current Biology : Cb
During mammary gland development, an epithelial bud undergoes branching morphogenesis to expand into a continuous tree-like network of branched ducts . The process involves multiple cell types that are coordinated by hormones and growth factors coupled with signaling events including Wnt and Hedgehog [2-5]. Primary cilia play key roles in the development of many organs by coordinating extracellular signaling (of Wnt and Hedgehog) with cellular physiology [6-8]. During mammary development, we find cilia on luminal epithelial, myoepithelial, and stromal cells during early branching morphogenesis when epithelial ducts extend into the fat pad and undergo branching morphogenesis. When branching is complete, cilia disappear from luminal epithelial cells but remain on myoepithelial and stromal cells. Ciliary dysfunction caused by intraflagellar transport defects results in branching defects. These include decreased ductal extension and decreased secondary and tertiary branching, along with reduced lobular-alveolar development during pregnancy and lactation. We find increased canonical Wnt and decreased Hedgehog signaling in the mutant glands, which is consistent with the role of cilia in regulating these pathways [6-11]. In mammary gland and other organs, increased canonical Wnt [12-14] and decreased Hedgehog [15, 16] signaling decrease branching morphogenesis, suggesting that Wnt and Hedgehog signaling connect ciliary dysfunction to branching defects.<br /><br />