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Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer


Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer1,2. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development3,4, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway.

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Figure 1: Hedgehog signalling in airway repair and development.
Figure 2: Hh signalling in lung cancer.
Figure 3: Hh pathway activation is essential for the growth of SCLC.
Figure 4: Cyclopamine inhibits SCLC tumorigenicity.


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We acknowledge M. Scott for the donation of the Ptch-LacZ mice; A. Joyner for the Flag-Gli1 expression vectors; J. Chen for the gift of KAAD cyclopamine; J. Taipale, S. Karhadkar, B. Nelkin and K. Schuebel for discussions; and E. Gabrielson for help in obtaining lung cancer tissue. We also thank K. Young and L. Meszler and the Sidney Kimmel Comprehensive Cancer Center Cell Imaging Facility for technical assistance. This work is supported by the Flight Attendant Medical Research Institute and the NCI/SPORE. P.A.B. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to D. Neil Watkins.

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Watkins, D., Berman, D., Burkholder, S. et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003).

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