Signalling: Fuzzy logic

signaling update home

SOURCE:

Philip Beachy and colleagues report that inhibitors of the Hedgehog signaling pathway induce regression of established tumors in preclinical models of medulloblastoma, revealing a new therapeutic approach for this aggressive cancer.

Medulloblastomas are childhood tumours of cerebellar origin that are, in some cases, associated with inappropriate activation of the Hedgehog (Hh) signalling pathway. Philip Beachy and colleagues now report that inhibitors of this pathway induce regression of established tumours in preclinical models of medulloblastoma, revealing a new therapeutic approach for this aggressive cancer.

Hh encompases a family of secreted proteins that are essential for developmental patterning events, as well as for the maintenance of somatic stem cells and specification of organ size. Hh binds to the transmembrane receptor Patched (Ptch), allowing activation of another transmembrane protein named Smoothened (Smo). This leads to the activation of target genes by the Cubitus interruptus/Gli (CI/GLI) family of transcription factors.

Ligand-independent activation of this pathway has been shown to occur in medulloblastoma, caused either by mutations that render Smo insensitive to regulation by Ptch, or by mutational inactivation of Ptch. The absence of Ptch activity can promote tumour initiation, and subsequent loss of p53 function seems to promote tumour-cell growth in a mouse model of medulloblastoma.

Beachy and colleagues therefore decided to test the ability of cyclopamine, a plant-derived product that inhibits Hh signalling at the level of Smo, to slow medulloblastoma growth. They found that treatment of meduloblastoma-derived cell lines with cyclopamine inhibited proliferation and induced differentiation in culture. Furthermore, subcutaneous injection of cyclopamine into a mouse model of medulloblastoma — created by disruption of one Ptch allele and mutation of Trp53 (which encodes p53 in mice) — reduced the growth of established tumours.

Cells from freshly resected human medulloblastomas, which were found to have elevated Hh signalling activity, were also susceptible to a derivative of cyclopamine. Treatment with this drug reduced the viability of medulloblastoma cells by almost 50%, and downregulated the Hh-pathway signalling. Cyclopamine, however, had no effect on glioblastoma, ependymoma or fibroblast cells, indicating that it is not a general cytotoxin. Nor was the drug observed to have toxic effects on rodents or other mammals.

So why is Hh-pathway activation a characteristic of medulloblastomas, in particular? The authors suggest that as Hh is a known stem-cell factor and a mitogen in the developing cerebellum, this pathway might allow cancerous stem cells to continuously undergo self-renewal. The high expression levels of the neuronal stem-cell marker nestin in mouse and human tumours supports this theory. If they can be used in humans, Hh antagonists might be developed as a useful therapy for this cancer.

Kristine Novak

References

Berman, D. M. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559–1561 (2002) | Article | PubMed |
Ruiz i Altaba, A. et al. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. Cancer 2, 361–372 (2002) | Article | PubMed |

Links

WEB SITE

Nature's Alliance for Cell Signalling (AfCS) update: Hedgehog signalling models: taking the rough with the Smoothened

Philip Beachy's lab: