Review
Feature Review
Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer

https://doi.org/10.1016/j.molmed.2010.05.003Get rights and content

The Hedgehog (Hh) cascade controls cell proliferation, differentiation and patterning of tissues during embryogenesis but is largely suppressed in the adult. The Hh pathway can become reactivated in cancer. Here, we assimilate data from recent studies to understand how and when the Hh pathway is turned on to aid the neoplastic process. Hh signaling is now known to have a role in established tumors, enabling categorization of tumors based on the role Hh signaling plays in their growth. This categorization has relevance for prognosis and targeted therapeutics. In the first category, abnormal Hh signaling initiates the tumor. In the second category, Hh signaling helps maintain the tumor. In the third category, Hh signaling is implicated but its role is not yet defined.

Section snippets

Hedgehog (Hh) signaling in cancer

The orderly process of development depends upon well-orchestrated signals. These signals transform a single cell into a complex multicellular organism. Incredibly, in spite of the complex end result, the transformation employs relatively few types of signals, including Wnt, Notch, transforming growth factor-β, fibroblast growth factor and Hedgehog (Hh). These secreted protein signals direct cell proliferation, cell fate determination, epithelial-to-mesenchymal transitions and the rearrangement

Category 1 cancers: Hh signaling is important for tumor initiation and maintenance

Gorlin syndrome is caused by the loss of one functional copy of PTCH[7], which activates the Hh signaling pathway. Several mouse models of Hh pathway activation were engineered and studies in these mice have revealed that constitutive Hh signaling alone is sufficient to form BCC, RMS and MB. Activating the Hh pathway at any of several levels of the signal transduction cascade including SMOH, SUFU and GLI or in conjunction with inactivation of additional tumor-suppressor genes leads to the

Category 2 cancers: Hh signaling is important for maintenance but not initiation of the tumor

In category 2 cancers, Hh signaling does not play a role in tumor initiation but instead is important for tumor maintenance and growth. Examples of category 2 tumors include colon cancer and pancreatic cancer. In both, Hh signals derived from the stroma are important for maintaining proliferation of tumor cells.

Category 3 “unclassified” cancers: Hh signaling is implicated in tumorigenesis but its role is not defined

Category 3 cancers include those where the Hh pathway is active but its role in the initiation and growth of the tumor is not well defined. Many cancers fall into this category and include lymphoma, breast cancer, ovarian cancer, esophageal cancer, liver cancer and lung cancer. We include prostate cancer in this category owing to residual controversy in the field; however, data from Wade Bushman's laboratory as well as multiple mouse models presented in abstract form and at meetings demonstrate

Concluding remarks

In the same way that developmental biology has been unified by near-universal molecules, genes and signaling pathways, cancer biology has been refined by the recognition of changes in signaling pathways including Hh that give tumor cells the properties they require to grow. Hh signaling is sufficient to trigger cancer in cells where Hh signaling is normally necessary for growth and development. Presumably cells that comprise mature tissues, which relied upon Hh signaling for development,

Declaration regarding conflict of interest

No research in the authors’ laboratory or authors’ consulting work is supported by companies that are developing Hh pathway drugs. In the past M.P.S. has served as an expert witness for Genentech on non-Hh pathway topics and E.W.H. has a family member who works at Genentech on projects unrelated to Hh signaling.

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