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Targeting Hedgehog:
A novel approach to inhibiting cancer growth

The Hedgehog (Hh) signaling pathway plays a crucial role in human embryogenesis, but is largely inactive in adult tissues under normal conditions.^1,2 The Hh signal is relayed by a number of key proteins, including Patched (PTCH) and Smoothened (SMO) at the cell surface. In the absence of Hh ligand, PTCH acts as a suppressor of SMO.^1,3 Upon ligand binding to PTCH, SMO is translocated to the primary cilium, where the transcription factor GLI is activated, translocates to the nucleus, and leads to the expression of Hh target genes.^1,3 GLI mediates the expression of genes involved in cell growth and differentiation.¹

Ligand-dependent Hedgehog signaling

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Accumulating evidence shows overactive Hh signaling in certain cancers. While this is caused by mutations in components of the Hh pathway, activation of the Hh pathway in tumors such as colon, pancreatic, and ovarian carcinoma is due to overexpression of Hh ligands.^4,5

Hh ligand-expressing cancerous epithelial cells may abnormally activate the Hh signaling pathway in adjacent stromal cells, which may then provide a growth-promoting microenvironment for the tumor.⁴

Ligand-independent Hedgehog signaling

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Ligand-independent Hedgehog signaling mainly occurs as a result of loss-of-function mutations in PTCH or gain-of-function mutations in SMO.^1,3 Such mutations lead to constitutive activation of the Hh pathway, even in the absence of Hh ligand binding to PTCH.¹ Mutations in Hh pathway components were first identified in familial basal cell carcinomas (BCCs). Mutations leading to activation of the Hh pathway are also responsible for the majority of sporadically occurring BCCs.^1,6

References:

1.

Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov. 2006;5:1026-1033.

2.

Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15:3059-3087.

3.

Evangelista M, Tian H, de Sauvage FJ. The Hedgehog signaling pathway in cancer. Clin Cancer Res. 2006;12:5924-5928.

4.

Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455:406-410.

5.

Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30:303-312.

6.

Theunissen J-W, de Sauvage FJ. Paracrine Hedgehog signaling in cancer. Cancer Res. 2009;69:6007-6010.