Download Title Molecular Pathways: The Role of Primary Cilia in Cancer

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Title
Molecular Pathways: The Role of Primary Cilia in Cancer Progression
and Therapeutics with a Focus on Hedgehog Signaling
Running Title
Primary Cilia in Cancer: Impact on HedgehogTargeted Therapy
Nadia B. Hassounah1, Thomas A. Bunch2 and Kimberly M. McDermott1, 2, ͵ǡȗ
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ABSTRACT
Abnormal Hedgehog (Hh) pathway activity has been reported in many cancers including
basal cell carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, breast
and prostate cancers. For this reason the Hh pathway is a flourishing area for
development of anti-cancer drugs such as Hh ligand antagonists (e.g. 5E1, robotnikinin),
Smo inhibitors (e.g. GDC-0449, IPI-926) and Gli transcriptional activity inhibitors (e.g.
GANT58, GANT61). In vertebrate cells it is now clear that primary cilia are required for
activation of the Hh pathway in normal cells. It is in the primary cilium that both positive
and negative effectors of the Hh pathway are processed by post-translational
modifications. In many cancers, preliminary results suggest that primary cilia are lost.
As drugs are developed that inhibit different steps of the Hh pathway, it is important to
consider how these drugs will function in the context of primary cilia in the tumor
environment. We will discuss why some of the Hh inhibitors may be ineffective if primary
cilia are lost on cancer cells. Understanding the relationships between clinical inhibitors
of the Hh pathway and the presence or absence of primary cilia may turn out to be
critical for targeting these therapeutics to the correct population of patients and for
improving their efficacy. Future work is needed in this area to maximize the potential of
these exciting therapeutic targets.
BACKGROUND
Primary Cilia: Form and Function. The primary cilium is a microtubule-based
organelle that protrudes from the plasma membrane and acts much like an ‘antenna’ to
sense extracellular signals. Recent studies have taken this once forgotten organelle
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from obscurity to the forefront of cutting-edge research, demonstrating its importance in
developmental biology and human diseases including cancer. Here we discuss the
importance of understanding cilia in cancers when choosing targeted cancer
therapeutics, specifically Hedgehog (Hh) pathway inhibitors.
There are two categories of cilia, primary and motile cilia. Epithelial cells that are the
‘cancer-initiating cell’ generally have primary cilia rather than motile cilia; therefore, we
will focus this discussion on primary cilia. Cells that have primary cilia only have a single
cilium. Primary cilia are usually immotile but can sense physical and chemical signals.
At the base of the primary cilium is the basal body (also known as the mother centriole),
which is anchored into the plasma membrane. The basal body acts to nucleate the
microtubule bundles that extend up the cilium (Fig. 1).
Hundreds of proteins have been identified that make up the primary cilium (1-9). Many
of these proteins are involved in ciliogenesis, the formation of a new cilium. Other
proteins localized to the cilium are involved in the sensory or signaling functions of the
primary cilium. Cilia act like antennae through sensing extracellular signals including
developmental morphogens; for example, the Hh ligand receptor localizes to the cilium.
At the core of both ciliogenesis as well as ciliary sensory function is a highly regulated
and active process known as intraflagellar transport (IFT) (10, 11). The Kinesin-2 motor
complex transports the IFT complex as well as other protein ‘cargo’ for anterograde
movement of proteins to the tip of the cilium (towards the plus end of microtubules) (Fig.
1). The cytoplasmic Dynein 2 motor complex transports the IFT complex plus ‘cargo’ for
retrograde movement from the tip of the cilium towards the cell body (towards the minus
end of microtubules) (Fig.1). The IFT complex is made up of several proteins and
mutations in IFT genes cause loss of ciliary assembly and consequently result in loss of
sensory functions (12). Many mutations in genes required for ciliogenesis have been
identified and are now known to be causal for a large number of genetic disorders
classified as ciliopathies. Ciliopathies include Joubert syndrome (JBTS), polycystic
kidney disease (PKD), Bardet-Biedl syndrome (BBS), and nephronophthisis (NPHP)
(13). Loss of cilia or ciliary function in these ciliopathies results in deregulation of
developmental signaling pathways.
Hedgehog Signaling and Primary Cilia. While cilia have been implicated in numerous
signaling pathways important in development and disease, including the Hh, Wnt and
PDGF pathways (14-19). The mechanism by which cilia regulate the Hh signaling
pathway is the best characterized. Therefore Hh signaling will be the focus here. Due to
space limitations we only provide an overview of cilia and Hh signaling; for a recent and
thorough review please refer to Goetz et. al. (20). In vertebrate cells, Hh signaling
requires primary cilia. Hedgehogs are a family of secreted proteins that include Sonic
Hh (Shh), Indian Hh (Ihh), and Desert Hh (Dhh). These Hh ligands activate the
downstream Gli family of transcription factors that translocate into the nucleus to
activate Hh target genes. The cilium itself is a subcellular compartment in which key Hh
pathway components including Gli proteins are brought together differentially depending
on the absence or presence of Hh. Transport of proteins into and out of the cilium is via
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active transport. At the base of the cilium the transition zone contains transition fibers
and other protein complexes such as the septin ring complex that are thought to restrict
passive diffusion (Fig. 1) (21, 22). A likely mechanistic function of the cilium is to
regulate the Hh pathway by increasing the local concentration and bringing pathway
components together for key protein-protein interactions required for Hh pathway
regulation.
The details of the dynamic regulation of entry and exit of Hh pathway proteins into and
out of the cilia are just now being unraveled. There are three Gli proteins (Gli1, Gli2 and
Gli3) encoded by distinct genes. These Gli proteins are post-translationally processed
into repressor (with the exception of Gli1) and activator forms in the absence and
presence of Hh, respectively. Loss of cilia mutations results in abnormal processing of
both the repressor and activator forms of Gli proteins suggesting that both are
dependent on cilia. In the absence of Hh, the Hh pathway stays in an ‘off’ state via
processing of Gli transcription factors to the repressor form which blocks transcriptional
activation of Hh genes (Fig. 1). This appears to be cilia-dependent through localization
of Patched (Ptch1 or Ptc1), a negative regulator of the pathway, to the ciliary membrane.
In contrast, the Hh pathway activator protein Smoothened (Smo) is kept out of the cilium
in the absence of Hh (Fig. 1) (14, 23). Another mechanism by which Gli proteins are
regulated in a cilia-dependent manner is through the protein Suppressor of Fused
(SuFu). SuFu is involved in the formation of both the repressor and activator forms of
Gli proteins (24). In the absence of Hh, SuFu sequesters Gli protein to the cytoplasm
and keeps it in the repressor form. In the presence of Hh, the Hh pathway is in an ‘on’
state via processing of Gli transcription factors into their activator forms, also in a ciliadependent manner (Fig. 1). In the presence of Hh, its receptor, Ptch1, moves out of the
cilium and Smo is phosphorylated and translocated into the cilium where it functions to
promote Gli activation (Fig. 1) (14, 25, 26). Additionally, SuFu, in the presence of Hh,
accumulates in the cilium but dissociates from Gli, promoting Gli’s conversion to the
activator form and allowing it to enter the nucleus to activate Hh target genes (24, 27).
Primary Cilia, Hedgehog Signaling and Cancer. The Hh pathway is an important
regulator of cell growth and differentiation during development. Abnormal activation of
the Hh pathway is critical in the development of many cancers including glioblastoma,
basal cell carcinoma, medulloblastoma, as well as, breast, prostate, melanoma, lung
and pancreatic cancers (28). In human cancers, the Hh pathway is upregulated either
through mutations of pathway proteins such as Ptch1, Smo and SuFu or through
overexpression of Hh. Experiments in mouse models of cancer demonstrate that cilia
can play a dual role in promoting and preventing tumorigenesis through regulation of the
Hh pathway (29, 30). This paradox is due to the primary cilium’s role in turning the Hh
pathway ‘on’ in the presence of Hh (by processing Gli proteins into the activator form)
and keeping the Hh pathway ‘off’ in the absence of Hh (by processing Gli proteins into
the repressor form).
In these mouse models of basal cell carcinoma and medulloblastoma, an active form of
Smo was ectopically expressed in wild type mice and mice genetically modified to have
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mutant primary cilia (29, 30). As expected, the mice with active Smo and wild type cilia
developed basal cell carcinomas and medulloblastomas and those with active Smo but
mutant cilia did not develop tumors. As described above, the mammalian Hh pathway
requires cilia for Smo-dependent activation of Gli proteins (Fig. 2A). Therefore, without
cilia the active Smo could not activate the Hh pathway and tumors were unable to form
(Fig. 2C). When the Hh pathway was activated downstream of cilia, by ectopically
expressing an activator form of one of the Gli proteins in the absence of cilia, the
absence of cilia resulted in a significant increase in tumorigenesis. Follow-up studies
show that presence of cilia allows for the formation of the repressor form of Gli protein
(Fig. 2B). Cilia-generated repressor form of Gli protein is predicted to balance out the
exogenously expressed activator form of Gli protein to slow tumor growth. In the
absence of cilia the repressor form of the Gli transcription factor is reduced and unable
to counteract the activator Gli protein, resulting in increased tumorigenesis (Fig. 2D).
CLINICAL–TRANSLATIONAL ADVANCES
Primary Cilia Expression in Human Cancers. Given that cilia are important in
regulating the Hh pathway in normal cells and that they can play a dual role during
tumorigenesis, it is critical that we learn more about which human cancers make
functional primary cilia and which cancers have ciliary dysfunction. Moreover,
depending on which step of the Hh pathway is functioning to sustain tumorigenesis, the
presence or absence of cilia may have a significant impact on the effectiveness of
targeting different steps of the Hh pathway (upstream or downstream of cilia).
Only a limited number of papers have examined the expression of primary cilia on
human cancer cells from primary patient samples. A reduction in cilia frequency relative
to adjacent normal tissue has been observed in clear cell renal cell carcinoma (31),
breast cancers (32), melanoma (27), basal cell carcinoma (22), medulloblastoma (23)
and pancreatic cancer (33). Pancreatic intraepithelial neoplastic lesions were also
devoid of cilia, suggesting that loss of cilia may occur early in tumorigenesis (25). In the
medulloblastoma study (23), presence of cilia correlated with desmoplastic
medulloblastoma (better prognosis), and the absence of cilia was associated with
anaplastic medulloblastoma (poor prognosis).
Cellular proliferation rates can influence the presence of cilia. Therefore it was an
important finding in the renal, pancreatic and melanoma studies that primary cilia loss
was independent of Ki67 staining (a cell proliferation marker). This suggests that loss of
cilia is not a result of altered cellular proliferation rates and that primary cilia dysfunction
in cancers may be due to another mechanism such as loss of a gene required for
ciliogenesis, potentially resulting from mutagenesis or genomic instability (31, 33, 34).
These studies suggest that cilia dysfunction is a common event in cancers and that it
may occur early during the tumorigenic process. However, further work on these and
additional cancer types are needed. Reported sample sizes are small (ranging from 8 to
38 patient samples) and there is a general lack of quantitation and statistical analysis.
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Comparison to normal tissue is also needed. Normal tissue adjacent to cancer has been
used and may provide interesting findings, however, field effects in tissue surrounding
cancer have been documented (35). Also, cilia lengths have not been examined in
cancers or normal tissue for comparison. Cilia may be present in cancers, but if they
have abnormal lengths this may affect signaling (20). Not surprisingly, there is a range
in the percentage of patient samples with cilia and a range in the percentage of cells
with cilia in independent tumors. It is important to further explore these ranges by asking
if specific levels of cilia frequency correlate with specific cancer subtypes and with
clinical data such as survival, recurrence and response to treatment.It is also critical
that cilia frequency be correlated with markers of relevant pathways such as Hh target
genes to begin to understand if there is a causal association between cilia and human
cancers.
Primary Cilia and Clinical Inhibitors of the Hedgehog Pathway. Hh-targeted drugs
are expected to be effective as anti-cancer drugs through killing cancer cells as well as
through targeting stromal cells associated with tumorigenesis (e.g. inhibition of
angiogenesis). In this section, our focus is on the role cilia play in the efficacy of Hhtargeted drugs specifically on cancer cells; however, the same concepts are likely to
apply to inhibition of Hh pathway signaling in stromal cells. While all of the Hh-targeted
drugs mentioned show pre-clinical efficacy in cell lines and in some cases mouse
models, efficacy in clinical trials is mixed ranging from full or partial response to no
efficacy (for a detailed review please see Ng et. al. (36)). We predict that the efficacy of
Hh-targeted anti-cancer drugs will rely on whether activation of the Hh pathway is
upstream (cilia-dependent) or downstream (cilia-independent) of cilia, as well as if the
cancer cells are positive or negative for primary cilia. Hh pathway activation in cancer
can be divided into two groups: 1. Hh ligand-driven and 2. mutation-driven. As we will
describe below, Hh ligand-driven cancer can only be cilia-dependent, while mutationdriven cancers can be cilia-dependent or cilia-independent.
Ligand-Driven Hh pathway Activation (Cilia-Dependent): Overexpression of Hh ligands
have been documented in many cancers (37, 38). Hh-induced signaling in cancer can
occur through autocrine (cancer-cancer) and paracrine (stroma-cancer) expression of
Hh (39). Hh pathway activation from elevated ligand is upstream of cilia (ciliadependent). As described, cilia are required to respond to ligand and activate the Hh
pathway via Smo and Gli proteins (Fig. 2A). Therefore, therapeutically treating patients
who have Hh pathway upregulation driven by elevated Hh ligand through administering
a ligand antagonist (e.g. 5E1 or robotnikinin), Smo antagonist (e.g. GDC-0449, IPI-926),
or Gli-processing inhibitor (e.g. HPI-2,3) would be predicted to be effective only if the
tumor cells have cilia (Fig. 2A). For example, HPI-2,3 have both been shown to reduce
Hh pathway signaling in response to Hh ligand in vitro using cell lines. Pre-clinical
reports showing reduced Hh pathway signaling for HPI-2,3 were all tested on NIH-3T3
cells that are known to be ciliated (40). Clinical trial data is not currently available for
HPI-2,3.
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Mutation-Driven Hh Pathway Activation (Cilia-Independent): Overexpression of Hh
ligand does not mean that the cancer cells rely on ligand for Hh pathway activation. As
cancers evolve through multiple stages of activation, the elevated Hh ligand levels
observed may have been important in stimulating tumor growth at an earlier stage when
cilia were present. If the tumor cells no longer have cilia then the high Hh ligand levels
are no longer relevant to activation in the tumor cells. Instead, continued activation of
the Hh pathway would require a secondary mutation downstream of cilia (ciliaindependent), which would relieve reliance on Hh ligand (Fig. 2D). Emerging data
suggests that many cancers have lost cilia. Therefore, in cancer cells without cilia, any
observed Hh pathway activation must be driven by mutations that are downstream of
cilia. Mutations in the pathway that are downstream of cilia allow the Hh pathway to be
turned on even in the absence of cilia. There are several examples of Hh pathway
mutations that have been documented that are downstream of cilia and would therefore
allow the Hh pathway to be turned on even in the absence of cilia. SuFu is a protein
known to sequester the Gli proteins in the cytoplasm and thereby exerts a negative
effect on Hh pathway activation (41). Mutations in SuFu have been documented in
medulloblastomas (36, 37), and loss of SuFu protein has been observed in prostate
cancers. Additionally, loss-of-heterozygosity mutations in SuFu have been reported in
rhabdomyosarcoma (36, 37, 42, 43). Medulloblastomas also have been shown to have
loss of REN(KCTD11), a protein that antagonizes Gli-mediated transactivation of the Hh
target genes, ultimately resulting in activation of the Hh pathway downstream of cilia
(Fig. 2D) (44). Glioblastomas have been found to have amplification of Gli1 (36).
Mutations in Gli1 and Gli3 have been documented in pancreatic adenocarcinoma (39).
Murine studies suggest that activation of a downstream component of the Hh pathway
will activate the Hh pathway leading to enhanced tumorigenesis when cilia are absent
(29, 30, 45) (Fig. 2D). When cilia are present, the repressor form of Gli protein can still
be made which can counteract downstream activation of the pathway (Fig. 2B).
Therefore, we predict that if the cancer cells lack cilia it will be necessary to target
inhibition of the Hh pathway downstream of cilia with a drug such as GANT58 or
GANT61 (Fig. 1F). Emerging data indicates that many patients have a low frequency of
ciliated tumor cells. This tumor heterogeneity suggests that combinatorial treatment with
Hh-targeted drugs that are cilia-dependent and cilia-independent may be an effective
treatment for some patients.
GANT61 inhibits Hh signaling downstream of cilia by inhibiting Gli transcriptional activity
and has indeed been demonstrated to be effective at inhibiting the Hh signaling
pathway in cells containing or lacking cilia. For example, GANT61 effectively inhibited
Hh signaling in HEK293 and NIH-3T3 cells, which are both known to have cilia (46). In a
prostate xenograft model using the 22RV1 prostate cancer cell line that was shown to
lack cilia, GANT61 treatment resulted in tumor regression (46). This pre-clinical data
supports our hypothesis that GANT61 is a cilia-independent inhibitor.
Mutation-Driven Hh Pathway Activation (Cilia-Dependent): Another mechanism by
which the Hh pathway can be activated upstream of cilia involves mutations in Hh
pathway proteins that require cilia for their regulation. Deactivation of Ptch1 (negative
regulator) and constitutive activation of Smo (positive regulator) are upstream of cilia
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(cilia-dependent) (Fig. 2A). While these mutations require the presence of cilia for
activation, the cancer cells no longer rely on Hh ligand for pathway activation.
Inactivation or loss of heterozygosity mutations in the Ptch1 receptor or activating Smo
mutations are common in basal cell carcinoma with 90% of basal cell carcinomas
having loss of function of Ptch1 and 10% having activation of Smo (36, 37). Ptch1
receptor mutations and loss of heterozygosity are also seen in medulloblastomas and
rhabdomyosarcomas (36, 37).
As described above, murine studies have shown that activation of a Hh pathway
component upstream of cilia, such as mutations in the Smo protein, requires primary
cilia for Hh pathway activation (29, 30). If a patient is found to have a mutation in the Hh
pathway upstream of cilia (e.g. Ptch1 or Smo), and the tumor has cilia then inhibiting the
Hh pathway with Smo inhibitors such as GDC-0449 is predicted to be effective (Fig. 2A).
If the tumor carries Ptch1 or Smo mutations, but does not have primary cilia, we predict
that the Hh pathway activation is no longer dependent on the Ptch1 or Smo mutations
but may now have Hh pathway activation due to a Hh pathway mutation at a later ciliaindependent step (Fig. 2D). The Ptch1 or Smo mutations may have been important in
an earlier stage in cancer progression similar to elevated Hh ligand levels discussed in
the previous paragraph. If the cancer cells do not have cilia, the tumor would not be
responsive to Smo or Gli-processing inhibitors and instead would need to be treated
with downstream inhibitors such as the Gli antagonists GANT58 or GANT61 (Fig. 1F).
Based on this rationale, we predict that only ciliated cancer cells could be responsive to
GDC-0449. Of patients with basal cell carcinoma containing Ptch1 or Smo mutations,
66% responded to the GDC-0449 Smo inhibitor in a phase I clinical trial (47). We
hypothesize that the 66% that were responsive to GDC-0449 have cancer cells that
express cilia. The non-responsive tumors may lack ciliated cancer cells. This is
consistent with the finding that ~63% of the primary human basal cell carcinoma patient
samples that were tested had cilia (29). Further studies are needed to determine if this
correlation holds true and if presence of cilia on basal cell carcinoma is predictive of
responsiveness to GDC-0449 treatment. It is also possible that many of the nonresponsive patients are no longer dependent on the Hh pathway for survival.
FUTURE DIRECTIONS AND SUMMARY
Further work is needed to determine if the predicted relationships between the presence
of cilia and responsiveness to specific Hh pathway inhibitors are clinically relevant. If
they are, then the presence or absence of cilia is another tool available to clinicians to
use in choosing Hh-targeted drugs to treat individual cancers. On a more general note,
if the trend continues that cancer cells lose cilia, then Hh inhibitors that are upstream of
cilia may prove generally ineffective and the focus will need to be on developing
additional inhibitors that are downstream of cilia (cilia- and ligand-independent). These
therapeutics are currently underrepresented amongst Hh clinical inhibitors and would be
predicted to target a much broader range of tumor cells.
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FIGURE LEGEND
Figure 1. Regulation of the Hedgehog Pathway by Primary Cilia in Normal Cells.
Structure of Primary Cilium: The primary cilium contains microtubule bundles (9
doublets arrayed as a cylindrical structure) that are nucleated from the basal body. The
microtubule bundles are enclosed in a ciliary membrane that is continuous, but distinct,
from the plasma membrane. At the base of the cilium are transition fibers localized in
the transition zone. This transition zone is known to restrict passive diffusion of proteins
in and out of the cilium. Kinesin 2 moves the IFT complex and its ‘cargo’ (e.g. Gli, Ptch
and Smo) towards the plus-end of microtubules (ciliary tip). Dynein 2 moves the IFT
complex and its ‘cargo’ towards the minus-end of microtubules (cell body).
Hh Regulation: In the absence of Hh (left side) Gli protein is converted to its repressor
form (GliR). Also in the absence of Hh, Ptch1 is localized to the ciliary membrane and
Smo is kept out of the cilium. In the presence of Hh (right side) Gli protein levels
increase in the cilium and Gli is processed into the activator form (GliA) for transport out
of the cilium and into the nucleus where it activates Hh target genes. In the presence of
Hh, Ptch1 moves out of the cilium and Smo moves into the cilium where it promotes
formation of the activator form of Gli (GliA).
Figure 2. The Role of Cilia in Hedgehog Pathway Activation in Cancer Cells.
A. Cancer-Associated overexpression of Hh ligands or mutations in genes such as
Ptch1 or Smo, which lie upstream of cilia, will only result in activation of the Hh pathway
by increasing GliA levels if cilia are present. If cilia are present, then inhibitors targeting
Hh ligand, Smo, and Gli trafficking (grey boxes) will be effective. Inhibitors that target Gli
activity downstream of cilia (white box) will also be effective in reducing the Hh pathway
in this context. B. Cancer-associated overexpression of Gli1 (GliA) in the presence of
cilia will result in low levels of Hh pathway activation. In this context, cilia make the
repressor form of Gli (GliR) counterbalancing GliA to reduce over activation of the Hh
pathway. Mutations in REN(KCTD11) can also result in increased GliA activity. As this
activation is downstream of cilia only the downstream Gli targeting inhibitors (white box)
are predicted to be effective. C. Cancer-associated overexpression of Hh ligands or
mutations in genes such as Ptch or Smo, which lie upstream of cilia, will not activate the
Hh pathway in the absence of cilia. D. Cancer-associated mutations downstream of cilia
such as overexpression of Gli1 (GliA) or mutations in Ren(KCTD11) have been
documented in cancers and will turn on the Hh pathway in the absence of cilia due to
high GliA and low GliR. Therefore, only downstream Gli targeting inhibitors (white box)
are predicted to be effective in this scenario.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
No potential conflicts of interest were disclosed.
ACKNOWLEDGMENTS AND GRANT SUPPORT
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The authors thank Brian Keady, Greg Pazour and Jeremy Reiter for editorial comments
on the manuscript. Funding was provided by the Cancer Center Support Grant, National
Cancer Institute, NIH, P30CA023074 (K.M. McDermott); Cancer Biology Training Grant,
National Cancer Institute, NIH, T32CA009213 (N.B. Hassounah); R00, National Institute
of Child Health and Human Development, NIH, R00HD056965 (K.M. McDermott).
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Hh Ligand
No Ligand
Gli
Gli
Smo
Kinesin
Dynein
GliA
GliR
IFT
complex
Gli
Gli
Cilium
Gli
Microtubule
doublet
bundles
Hh
Hh
Hh
Ptch1
Hh
Transition
fibers
Ciliary
membrane
GliA
GliR
Smo
Transition
zone
Basal
body
GliR
GliA
1
GliR
OFF
ch
GliR
GliA
Plasma
membrane
Pt
GliR
Hh
GliA
GliA
ON
Nucleus
Can
© 2012 American Association for Cancer
Research
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Author Manuscript Published OnlineFirst on March 13, 2012; DOI: 10.1158/1078-0432.CCR-11-0755
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A
Cancer:
Mutation-driven or
ligand-dependent
(Upstream of cilia)
GDC-0449
IPI-926
SANT1, 2, 3, 4
CUR-61414
HhAntag691
BMS-833923
PF-04449913
LDE-225
TAK-441
LEQ506
Gli
Smo
5E1
Robotnikinin
Hh
Hh
Hh
Hh
B
Ptch1
Smo
Basal
body
Basal
body
GliA
Gli
GliA
Ptch1
GliA
GliA
GliR
GliA
Overexpression
A
GliA Gli
GliA
GliA
Hh targets ON
GANT58, GANT61
HPI-1, physalin F, B
arsenic trioxide
D
Cancer:
Mutation-driven or
ligand-dependent
(Upstream of cilia)
REN(KCTD11)
Hh targets Low
GliA
Cancer:
Mutation-driven,
ligand-independent
(Downstream of cilia)
Ciliary
dysfunction
Hh
Hh
Hh
Hh
Overexpression
Hh
Gli
GliR
GliR
Hh
C
Gli
HPI-2, 3, 4
arsenic trioxide
Overexpression
Hh Hh
Hh
Hh
GANT58, GANT61
HPI-1, physalin F, B
arsenic trioxide
Cancer:
Mutation-driven,
ligand-independent
(Downstream of cilia)
Hh
Hh
Ciliary
dysfunction
GliR
Smo
GliA
Basal
body
GliA
Overexpression
Hh
Basal
body
Hh targets OFF
Ptch1
GliA
GliA
GANT58, GANT61
HPI-1, physalin F, B
arsenic trioxide
REN(KCTD11)
GliA
GliA
GliA
Hh targets ON
© 2012 American Association for Cancer Research
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Molecular Pathways: The Role of Primary Cilia in Cancer
Progression and Therapeutics with a Focus on Hedgehog
Signaling
Nadia Bassam Hassounah, Thomas Allen Bunch and Kimberly Marie McDermott
Clin Cancer Res Published OnlineFirst March 13, 2012.
Updated version
Author
Manuscript
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