A number of developmental signalling pathways have been shown to be reactivated during tumour formation — the Hedgehog (HH) pathway seems to be the latest member of this growing list. HH signalling mediates pattern formation during embryogenesis, and has recently been shown to regulate epithelial–mesenchymal interactions during lung development. In Nature, Watkins et al. report that Hh signalling also promotes lung tumour development.

Sonic Hedgehog (SHH) — a secreted ligand for the HH receptor patched (PTCH) — is a signalling switch expressed by a variety of differentiation subpopulations of cells throughout the embryo. Loss of Shh function results in severe lung defects in mice. Unlike skin and colon, the adult airway epithelium only proliferates in response to injury. In a search for factors that activate airway epithelial-cell proliferation after injury, Watkins et al. observed increased expression of both Shh and its transcriptional effector Gli1 in an adult mouse model of acute airway repair. This was surprising, as this pathway had been previously only associated with embryonic lung epithelial cells, where it signals adjacent lung mesenchyme to regulate branching morphogenesis.

Watkins et al. next looked to see if SHH was upregulated in lung tumours. They examined different tumour types, and found that 5 of 10 human small-cell lung carcinoma (SCLC) samples expressed SHH and GLI1. Only 9 of 40 non-SCLC (NSCLC) tumour samples expressed SHH, however, and only 4 of these also expressed GLI1. These findings indicate that the HH signalling pathway is reactivated in lung cancer cells — predominantly in SCLC.

But is ligand-driven HH pathway activation required for SCLC formation? Antibody inhibition of SHH prevented the growth of cultured SCLC cells. Furthermore, treatment of nine SCLC cell lines that expressed both SHH and GLI1 with cyclopamine — an alkaloid inhibitor of the HH pathway — induced both growth arrest and apoptosis. Cyclopamine had no effect on growth of NSCLC cells, and a closely related compound that does not inhibit HH signalling had no effect on SCLC cells. Cyclopamine also inhibited growth of three different SHH- and GLI1-expressing SCLC xenografts in nude mice, but not of NSLC or colon cancer xenografts.

Activation of HH signalling has been previously associated with medulloblastoma. The HH pathway regulates cerebellar progenitor differentiation, and in this brain tumour it is believed to allow malignant cells to maintain progenitor-like fates. Similarly, SCLC might represent a malignancy that arises from an airway epithelial progenitor and has maintained its HH signalling capabilities, as these cells continue to express SHH and lack PTCH mutations. Drugs designed to inhibit HH signalling could therefore have therapeutic effects in patients with SCLC.