Hedgehog signaling: Small-cell lung cancer shows its spikes

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The hedgehog (Hh) signaling pathway is activated during the repair of acute airway injury and lung development. A subset of small-cell lung cancers (SCLC) also exhibits Hh pathway activation, which is required for the maintenance of the malignant phenotype. Thus, SCLC may recapitulate a Hh regulated stage of airway epithelial differentiation and may respond to pharmacological blockade of the Hh pathway.

Small-cell lung cancer (SCLC) is a particularly difficult form of cancer to treat. Now, by investigating the role of hedgehog (Hh) signaling in regeneration and carcinogenesis of airway epithelium, Stephen Baylin and colleagues may have opened up a new avenue for the future treatment of SCLC.

The Hh receptor ligand sonic hedgehog (Shh) mediates epithelial-mesenchymal interactions in lung development by signaling to adjacent lung mesenchyme. Deletion of Shh function leads to severe lung defects due to loss of branching morphogenesis. The Hh pathway has been implicated in multiple cancers and the differentiation of regenerating epithelia, so the authors hypothesized that Hh signals might be of importance in epithelial repair.

Baylin and colleagues tested this hypothesis by studying mouse models in which specific epithelial cells were depleted due to systemic administration of naphthalene. The regenerating airways exhibited expression of both Shh and Gli1, a transcriptional target of Hh signaling. The authors also observed that airway epithelial regeneration results in wide-spread activation of airway intraepithelial Hh signaling, immediately preceding the differentiation of neuroendocrine cells. Normally rare, these cells are implicated in the regulation of airway epithelial development and growth. The group's data imply that during normal development, neuroendocrine precursors within the airway epithelial compartment respond to a Shh signal amplified by adjacent epithelial cells.

To examine the role Shh may play in cancer growth, Baylin's group analysed SCLC tissue. Five out of ten of these tumors expressed both Shh and Gli1, but of non-SCLC (NSCLC) tumors, nine out of 40 expressed Shh. Of these, only four expressed Gli1. This result was backed up by the finding that in human lung-cancer cell lines, all seven SCLC and seven NSCLC cell lines expressed Shh protein. Five out of seven SCLC but none of the NSCLC cell lines expressed Gli1 proteins. The growth of SCLC cells in vitro turned out to be dependent on ligand-mediated activation of the Hh pathway. Using the Veratrum alkaloid cyclopamine, which inhibits the Hh pathway, Baylin's group showed that the toxin induces growth inhibition in SCLC cells that express both Shh and Gli1 by specific inhibition of the Hh pathway. Indeed, systemic administration of cyclopamine to mice bearing SCLC xenografts saw growth inhibition of the Shh- and Gli1-expressing SCLC cells, suggesting a potential new therapeutic approach in treating this form of cancer.

The Signaling Gateway Team

References

Watkins, D. Neil Berman, David M. Burkholder, Scott G. Wang, Baolin Beachy, Philip A. Baylin, Stephen B. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature, 422, 313–317 (2003)10.1038/nature01493