The Hedgehog Signaling Pathway in Cancer
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Molecular Pathways
The Hedgehog Signaling Pathway in Cancer
Marie Evangelista, Hua Tian, and Frederic J. de Sauvage
Abstract The Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is
crucial for proper development. At the molecular level, Hh ligands drive cell proliferation in some
cell types while causing others to undergo differentiation. Hh signaling is most active during
embryogenesis, and aberrant reactivation of the pathway in adult tissue can lead to the develop-
ment of cancer. A comprehensive understanding of Hh signaling during development will un-
doubtedly shed light into the mechanism of Hh in cancer progression and identify potential
targets for therapeutic intervention.
Pathway Overview repressor (15). For the purposes of this review, the three
proteins will be referred to as Gli proteins. In the absence of Hh
Hedgehog (Hh) is a morphogen that acts in a short- or long- signaling, protein kinases, such as protein kinase A, glycogen
range fashion on various tissue types (refer to refs. 1 – 3 for a synthase kinase 3h, and casein kinase 1a, phosphorylate Gli,
comprehensive review of Hh signaling). In mammals, there are leading to proteosome-mediated cleavage of Gli into an NH2-
three Hh proteins: Sonic Hh, Indian Hh, and Desert Hh. In terminal truncated form, which acts as a repressor of Hh target
cells that make Hh, newly made protein enters the secretory gene expression (Fig. 1A; refs. 16 – 19). Suppressor of fused
pathway and undergoes autoprocessing and lipid modifica- (Sufu) acts as another negative regulator of the pathway by
tions, resulting in the addition of a palmitoyl group to its NH2 binding to Gli, both in the cytoplasm and in the nucleus, to
terminus and cholesterol to its COOH terminus (4). Subse- prevent it from activating Hh target genes (20 – 23).
quent release of Hh depends on Dispatched (Disp), a multi- In the presence of Hh ligand, the precise mechanism by
transmembrane protein, whereas diffusion of Hh requires which the Hh signal is transmitted from Smo to Gli is not well
Tout-velu-dependent synthesis of heparan sulfate proteogly- understood in vertebrates. In flies, Hh binding to Ptc leads to
cans (5, 6). the surface localization of Smo along with a complex
In cells receiving the Hh signal, pathway transmission is involving the kinase Fused (Fu) and the kinesin-like molecule
regulated at multiple levels. In the absence of Hh, Patched1 Costal 2 (Cos2; refs. 24 – 27). Thus, Fu and Cos2 relay the
(Ptch1), a 12-transmembrane receptor, acts catalytically to sup- signal from Smo to cubitus interruptus (Ci), the fly homo-
press the activity of Smoothened (Smo), a seven-transmembrane logue of Gli. However, in vertebrates, this mechanism does not
protein, by preventing its localization to the cell surface seem to be conserved, as a Cos2 orthologue has not been
(Fig. 1A; refs. 7, 8). Hh pathway activation is initiated when identified and Fu is not required for transducing the Hh signal
Hh ligand binds to Ptch1, relieving its inhibition on Smo (28, 29). In contrast, recent studies have shown that Hh
(Fig. 1B; refs. 1, 2, 9). The amount of Hh available to bind signaling in vertebrates requires the presence of a nonmotile
Ptch1 is tightly regulated by Hh-binding proteins, such as Hh- cilium (Fig. 1B; refs. 30 – 32). Genetic studies in mice revealed
interacting protein (Hip; ref. 10) and growth arrest-specific that disruption of several components of anterograde or
gene (Gas1; ref. 11), which sequester Hh. In contrast, two retrograde intraflagellar transport leads to neural tube pattern-
newly identified single-transmembrane proteins, cell adhesion ing and limb development defects caused by impaired Hh
molecule-related/down-regulated by oncogenes (Cdon/Cdo) signaling between Smo and Gli (30 – 32). How Smo signals to
and brother of Cdo (Boc), may facilitate Hh ligand binding to the Gli proteins is currently an active area of research in the
Ptch1 (12 – 14). Hh field today.
Surface localization of Smo is thought to initiate a signaling
cascade, leading to the activation of the glioma-associated (Gli)
Hh Signaling in Cancer
family of zinc finger transcription factors. In vertebrates, there
are three Gli proteins, with Gli1 and Gli2 thought to activate Aberrant activation of the Hh pathway in cancers is caused
Hh target genes whereas Gli3 is thought to act mainly as a either by mutations in the pathway (ligand independent) or
through Hh overexpression (ligand dependent). Connections
between the former and cancer were established from observa-
Authors’ Affiliation: Department of Molecular Biology, Genentech, Inc., South tions that mutations in the negative regulator, PTCH1, led to
San Francisco, California Gorlin syndrome (33, 34), a condition where patients develop
Received 7/14/06; revised 8/15/06; accepted 8/23/06. numerous basal cell carcinomas (BCC) and are predisposed to
Requests for reprints: Frederic J. de Sauvage, Department of Molecular Biology, medulloblastoma (a rare tumor of cerebellar granule neuron
Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA 94080.
Phone: 650-225-5841; Fax: 650-225-6497; E-mail: sauvage@ gene.com.
progenitor cells) and rhabdomyosarcoma (a muscle tumor).
F 2006 American Association for Cancer Research. Inactivating mutations in PTCH1 have been detected in the
doi:10.1158/1078-0432.CCR-06-1736 majority of sporadic BCC, although a small number (f10%) are
Clin Cancer Res 2006;12(20) October 15, 2006 5924 www.aacrjournals.org
Hh Signaling Pathway in Cancer Fig. 1. Model of Hh signaling in vertebrates. A, in the absence of Hh ligand, Ptch1inhibits surface localization of Smo and protein kinases phosphorylate Gli proteins, leading to an NH2-terminal truncated form, which acts as a repressor of Hh target gene expression. Gli3 is the predominant repressor. Sufu also regulates the pathway by binding to Gli, both in the cytoplasm and in the nucleus, to prevent it from activating Hh target genes. Table, summary of genes implicated in cancer and potential treatment using Hh antagonists or Hh antibodies. B, Hh-mediated (Sonic, Indian, or Desert) inactivation of Ptch1 allows relocation of Smo to the tip of cilia, leading to downstream signaling events and the activation of the Gli proteins. Mutations in the pathway (*) or overexpression of the Hh ligand are highlighted (**) in (A) and (B) along with possible avenues of treatment using antibodies or small molecules (red arrows). caused by a specific SMO mutation that make tumors less Although mutations in components of the Hh pathway have sensitive to PTCH1 repression (35, 36). In almost all BCC cases, not yet been identified in tumors other than those mentioned the Hh pathway is hyperactivated as indicated by up-regulation above, activation of the Hh pathway via ligand overexpression of Hh target genes (37). Mutations in PTCH1, SMO, or SUFU is being documented in a growing number of cancers. Several have also been identified in sporadic medulloblastoma, where reports have shown that Hh overexpression, sometimes one third of the tumors show increased Hh signaling (38, 39). accompanied by increased expression of Hh target genes, is www.aacrjournals.org 5925 Clin Cancer Res 2006;12(20) October 15, 2006
Molecular Pathways
detected in a broad spectrum of human tumor biopsies and cell platelet-derived growth factor (53), fibroblast growth factor
lines, including small cell lung cancer (40), gastric and upper (54), bone morphogenic protein (55), Notch (56), and Wnt
gastrointestinal track cancer (41), pancreatic cancer (42), and (57, 58), which have been identified as Hh target genes in
prostate cancer (43, 44). various models. However, to date, few universal target
genes have been identified across different systems and much
work still needs to be done to determine how Hh over-
Role of the Hh Pathway in Ligand-Overexpressing
expression contributes to tumorigenesis. Undoubtedly, to
Tumors successfully target Hh-overexpressing cancers, it will be
The mechanism by which Hh acts in ligand-overexpressing important to understand the precise mechanism of how Hh
cancers is still unclear. One model suggests that these tumors exerts its effects.
rely on autocrine signaling, where Hh ligand produced by However, results derived from cell lines grown in vitro
tumor cells acts on neighboring tumor cells to stimulate should be interpreted with caution. In some of these experi-
their growth or survival. This model is supported by in vitro ments, high concentrations of Hh antagonist, 100- to 1,000-
data showing that proliferation of tumor cell lines is fold higher than what is needed to block Hh signaling, were
accelerated by addition of Hh ligand (41) and inhibited by necessary to cause growth inhibition. Interestingly, cell lines
a Hh neutralizing antibody (40) or by addition of cyclop- established from the Ptch1 +/ P53 / medulloblastoma model
amine, a Hh pathway antagonist. In this model, Hh ligand also become insensitive to Hh antagonists, whereas tumors
may directly affect the survival or proliferation of the entire directly passaged s.c. in mice (i.e., direct allografts) main-
tumor cell (40 – 44). However, in prostate, Hh pathway tained their molecular signature and were reproducibly
activity seems to correlate with higher-grade tumors, and responsive to Hh antagonists (59). This suggests that cell
treatment of an aggressive prostate xenograft model with lines grown in vitro may lose their dependence on the Hh
cyclopamine, a pathway antagonist (see below), prevents pathway for survival and that the high concentrations of Hh
metastasis to the lung. Furthermore, constitutive activation of antagonist required to inhibit their growth may be due to
the Hh pathway by overexpressing Gli1 in a rarely metasta- nonspecific effects.
sizing clone, AT2.1, drove tumors to metastasize to the
lung through induction of genes involved in epithelial- Clinical-Translational Advances
mesenchymal transition (43). Thus, it has been suggested
that overexpression of Hh ligand leading to pathway The clear link between Hh pathway and human cancers, such
activation may be important for tumor proliferation, survival, as BCC and medulloblastoma, drove the effort to identify small-
and/or metastasis (40 – 44). molecule Hh antagonists to block the pathway. In addition to
Alternatively, Hh may be acting on a small fraction of cancer cyclopamine, a natural Hh antagonist isolated from corn lilies
stem cells that are capable of self-renewal and differentiation that targets Smo (60), different classes of small-molecule Hh
among multiple lineages. Hh signaling is required for the antagonists have been identified through cell-based screens using
normal growth and regeneration of organs, such as lung, Hh reporter assays (61, 62). Using cyclopamine or small-
gastrointestinal track, prostate, from stem cells, and inappro- molecule Hh antagonists as tools, experiments have shown the
priate and constitutive activation of Hh pathway during tissue potential use of targeting this pathway both in tumors where the
repair and regeneration could promote tumorigenesis. Hh pathway is mutated and in tumors where Hh ligand is
signaling has been indicated in proliferation of tissue stem cells overexpressed. Elegantly illustrating the former, small-molecule
from central nervous system (45 – 47), mammary gland (48), Hh antagonists have been used to treat endogenous medullo-
and hematopoietic stem cell (49). Genetic inhibition of Sonic blastoma in the Ptch1 +/ P53 / mouse model where tumors
Hh signaling results in the loss of neural stem cell forming develop with 100% incidence (63). In addition, studies have
potential from embryonic cortex (50), and activation of Hh shown that cyclopamine can inhibit growth of medulloblastoma
signaling was shown to increase the number of mammary stem tumors in vivo and in vitro (64, 65). Surprisingly, most human
cell in vitro (51). In addition, pharmacologic inhibition of Hh medulloblastoma tumors tested seemed to be responsive,
signaling with cyclopamine in adult mice leads to reduced suggesting potential broad application of Hh antagonist in
proliferation of stem cell in the subventricular zone (45) treating this particular brain tumor, of which only f25% harbor
Expression of Hh pathway components has also been detected mutations in the Hh pathway.
in mammary gland stem cells and in human breast "cancer Hh antagonists have also shown promises for treatment of
stem cells" characterized as CD44+CD24 /lowLin (51). In vitro, BCC. In ex vivo models of BCC, CUR-61414, an aminoproline
cyclopamine was able to decrease mammary gland stem cells as Hh antagonist, eliminated BCC-like lesions in various mouse
measured by their capacity to form mammospheres (48, 51). models where tumor formation was driven by exposure of
Therefore, inhibition of the Hh pathway may provide a way to skin explant cultures to recombinant Hh or by PTCH1
directly target cell populations that ultimately cause tumors. mutations. This compound effectively down-regulates Hh
Finally, Hh may act through a paracrine mechanism in reporter gene expression and induces apoptosis specifically
ligand-dependent tumors. This model is more reminiscent of its within BCC-like lesions while leaving normal adjacent cell
role in development and organogenesis, where Hh ligand is intact (66).
secreted from the epithelium and signals to the underlying In xenograft models of Hh-overexpressing tumors, including
myofibroblast/mesenchyme/stroma compartment. The stromal small cell lung cancer, gastric and upper gastrointestinal track
compartment then signals back to the epithelium to regulate cancer, pancreatic cancer, and prostate cancer, tumor growth
epithelial proliferation and differentiation through the pro- inhibition on treatment with cyclopamine has also been shown
duction of factors, such as insulin-like growth factor (52), (40 – 44). However, the activity of other pharmacologic agents
Clin Cancer Res 2006;12(20) October 15, 2006 5926 www.aacrjournals.orgHh Signaling Pathway in Cancer
has yet to be reported in these models, and the exact role of the inhibition of downstream effector molecules, such as Smo,
Hh pathway in these types of tumors still needs to be fully with small-molecule antagonists. The latter has broader appli-
investigated to better assess the potential use of Hh pathway cations in treating both ligand-dependent and mutation-driven
antagonist in the clinic. cancers.
An important issue that remains to be addressed is the
Conclusion and Outlook potential toxicity of blocking a critical developmental pathway,
such as Hh. Thus far, treatment with Hh antagonists, such as
Aberrant Hh pathway activation, driven by either mutation cyclopamine, seems to be well tolerated in animals. However,
or ligand overexpression, is often associated with human because the pathway is reactivated during tissue repair and
cancers. Inhibition of the Hh pathway may provide a thera- regeneration through stimulation of endogenous stem cell
peutic opportunity for treatment of tumors, such as pancreatic populations, the effect of systemic administration of Hh
cancer, where few options are available. Effective intervention antagonists on stem cell populations within the bone marrow,
of the Hh pathway can be achieved at the level of ligand gut, muscle, liver, skin, brain, and others will have to be
binding to its receptor using anti-Hh antibodies or through carefully monitored.
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