Role of Primary Cilia in BCC
The primary cilia are small, cylindrical microtubule-based organelles that project from the membrane of most vertebrate cell types. It has gradually become clear that they represent highly specialized cellular sites that contain higher than average densities of selected signaling molecules and coordinate signal transduction to control a variety of cellular processes (reviewed in Christensen et al.). Primary cilia have emerged as key organelles in Hh signal transduction in mammalian systems. As mentioned before, multiple components of the Hh pathway concentrate in the primary cilium or its basal body, including Shh, Ptch1 and Smo. Sufu and Gli transcription factors also localize to cilia[52–54] and require intraflagellar transport (Ift) proteins for processing and function. Not surprisingly, primary cilia are present on cells in murine skin and hair follicles throughout morphogenesis and during hair follicle cycling in postnatal life, and play an essential role in hair follicle development. In the mouse skin, disruption of laminin-511, an extracellular protein that plays an important role in promoting primary cilia formation and function, disrupted primary cilia formation in the dermal papilla as well as hair development.[55,56] Mice with disrupted dermal cilia owing to genetic inactivation of Ift88 in dermal cells have severe hypotrichosis in affected areas, resembling the skin of mice lacking Shh or Gli2.[58,59] BCCs are hair-follicle-derived tumors, and primary cilia have indeed been described in BCC cells through electron microscopy since 1963, which suggested their possible involvement in BCC development. Wong and colleagues have recently tested the hypothesis that primary cilia play a role in BCC tumorigenesis. In this study, ciliary ablation by conditional deletion of Kif3A (encoding kinesin family member 3A) or Ift88, both required for ciliogenesis, inhibited BCC-like tumors induced by an activated SmoM2 allele, but accelerated tumors induced by activated Gli2, demonstrating that the cilia function can either mediate or suppress BCC tumorigenesis depending on the nature of the oncogenic initiating event. Thus, while primary cilia inhibitors might be therapeutic in a subset of BCCs, they might also accelerate tumor growth in others, suggesting caution in the consideration of their possible use as therapeutic targets in the treatment of BCC.
Future Oncol. 2010;6(6):1003-1014. © 2010 Future Medicine Ltd.
Cite this: Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling - Medscape - Jun 01, 2010.