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Hedgehog signalling in cancer formation and maintenance

Nature Reviews Cancer volume 3, pages 903–911 (2003)Cite this article

Key Points

  • Hedgehog (HH) signalling is required for cell differentiation and organ formation during embryogenesis. In the adult, HH signalling remains active in some organs where it has been implicated in the regulation of stem-cell maintenance and proliferation.

  • HH signalling targets include genes that are important for cell proliferation — proto-oncogenes — as well as growth factors.

  • Misregulation of HH signalling has been shown to cause formation of basal-cell carcinoma and medulloblastoma, and mutations of HH pathway components have been found both in familial and sporadic cases. More recently, small-cell lung cancer (SCLC) and pancreatic adenocarcinoma have been linked to HH signalling, providing a molecular mechanism for these aggressive diseases.

  • Importantly, HH signalling seems to be required not only for cancer initiation but also for tumour growth and survival of medulloblastomas, SCLC and pancreatic adenocarcinoma.

  • HH inhibitors could provide novel therapeutic approaches for treatment of otherwise hard to cure cancer types. Synthetic compounds have been identified that act as HH inhibitors in a very specific manner.

Abstract

The Hedgehog signalling pathway is essential for numerous processes during embryonic development. Members of this family of secreted proteins control cell proliferation, differentiation and tissue patterning in a dose-dependent manner. Although the overall activity of the pathway is diminished after embryogenesis, recent reports show that the pathway remains active in some adult tissues, including adult stem cells in the brain and skin. There is also evidence that uncontrolled activation of the pathway results in specific types of cancer.

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Figure 1: Hedgehog signalling pathway.
Figure 2: Hedgehog pathway and cancer.

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Acknowledgements

We would like to dedicate this manuscript to the memory of Ira Herskowitz, who inspired us to contemplate about the connection between embryonic signalling pathways and cancer. We would like to thank all members of the Hebrok laboratory for stimulating discussions. In particular, we would like to thank P. Heiser and J. Lau as well as H. Kawahira, D. Cano and M. Tzanakakis for critical reading of the manuscript. Work in M. H.'s laboratory was supported by grants from the Juvenile Diabetes Research Foundation, the Hillblom Foundation and the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine, Diabetes Center, University of California, San Francisco, 94143, California, USA

    Marina Pasca di Magliano & Matthias Hebrok

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  1. Marina Pasca di Magliano
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  2. Matthias Hebrok
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Databases

Cancer.gov

pancreatic adenocarcinomas

SCLC

LocusLink

Ci

Dhh

Fu

Gli1

Gli2

Gli3

hh

Hip1

Ihh

Ptch1

Ptch2

Shh

Smo

SuFu

OMIM

BCNS

Glossary

HEPTAHELICAL BUNDLE

A transmembrane domain of the Smoothened protein that is composed of seven α-helical stretches.

EXOCRINE ACIN

Alveolar structures that are formed by the cells that produce and release pancreatic digestive enzymes in the lumen of collecting pancreatic ducts.

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di Magliano, M., Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 3, 903–911 (2003). https://doi.org/10.1038/nrc1229

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