Sci. Signal., 15 September 2009
Cancer The Cilium as a Moving Target for Cancer Therapy
L. Bryan Ray
Science, Science Signaling, AAAS, Washington, DC 20005, USA
The primary cilium, an immotile single cilium found on most cells, has been implicated as a critical site for regulation of signaling by members of the Hedgehog family of ligands. Hedgehog proteins have major roles in control of development, but inappropriate signaling through the hedgehog pathway is essential to the formation of certain cancers. Wong et al. and Han et al. explored the role of primary cilia in two cancers, human basal cell carcinomas and medulloblastomas—the latter a common cause of brain tumors in children. In keeping with earlier indications that events at the primary cilium can have both positive and negative effects on hedgehog signaling, they found that loss of cilia (induced genetically by removal of the gene encoding the kinesin-II motor protein that is required for construction of the cilium) could either prevent or promote growth of cancer cells, depending on how the hedgehog pathway was activated in the particular cells. If the cells expressed a constitutively active form of smoothened, the hedgehog co-receptor that is activated when hedgehog ligands bind to the receptor protein patched, ablation of the cilium inhibited tumor cell growth in mice. However, if the downstream protein Gli2—a transcription factor that mediates gene regulation in response to the hedgehog pathway signaling—was constitutively active, loss of cilia promoted tumor growth. The mechanisms at work are not precisely understood, but the authors and Toftgård (in commentary) discuss possible mechanisms and the implications for screening cancer patients for the presence of cilia or for targeted therapies to inhibit hedgehog signaling, where the risk is now evident that inhibition of ciliogenesis could exacerbate cancer growth rather than curb it.
S. Y. Wong, A. D. Seol, P.-L. So, A. N. Ermilov, C. K. Bichakjian, E. H. Epstein Jr., A. A. Dlugosz, J. F. Reiter, Primary cilia can both mediate and suppress Hedgehog pathway–dependent tumorigenesis. Nat. Med. 15, 1055–1061 (2009). [PubMed]
Y.-G. Han, H. J. Kim, A. A. Dlugosz, D. W. Ellison, R. J. Gilbertson, A. Alvarez-Buylla, Dual and opposing roles of primary cilia in medulloblastoma development. Nat. Med. 15, 1062–1065 (2009). [PubMed]
R. Toftgård, Two sides to cilia in cancer. Nat. Med. 15, 994–996 (2009). [PubMed]
Citation: L. B. Ray, The Cilium as a Moving Target for Cancer Therapy. Sci. Signal. 2, ec308 (2009).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882