Molecular Pathways: The Role of Primary Cilia in Cancer … · Molecular Pathways Molecular Pathways: The Role of Primary Cilia in Cancer Progression and Therapeutics with a Focus

Molecular Pathways

Molecular Pathways: The Role of Primary Cilia in CancerProgression and Therapeutics with a Focus on HedgehogSignaling

Nadia B. Hassounah1, Thomas A. Bunch2, and Kimberly M. McDermott1,2,3

AbstractAbnormal Hedgehog (Hh) pathway activity has been reported in many cancers, including basal cell

carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, and breast and prostate cancers. For

this reason, the Hh pathway is a flourishing area for development of anticancer drugs such as Hh ligand

antagonists (e.g., 5E1 and robotnikinin), Smo inhibitors (e.g., GDC-0449 and IPI-926), and Gli transcrip-

tional activity inhibitors (e.g., GANT58 and GANT61). It is now clear that primary cilia are required for

activation of the Hh pathway in normal vertebrate cells. It is in the primary cilium that both positive and

negative effectors of the Hh pathway are processed by posttranslational modifications. In many cancers,

preliminary results suggest that primary cilia are lost. As drugs that inhibit different steps of the Hh pathway

are developed, itwill be important to consider how these drugswill function in the context of primary cilia in

the tumor environment. Here, we 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 improving their efficacy. Further work is needed in this area tomaximize

the potential of these exciting therapeutic targets. Clin Cancer Res; 18(9); 2429–35. �2012 AACR.

BackgroundPrimary cilia: form and functionThe primary cilium is a microtubule-based organelle that

protrudes from the plasmamembrane and actsmuch like anantenna to sense extracellular signals. Recent studies havetaken this once forgotten organelle from obscurity to theforefront of cutting-edge research, showing its importance indevelopmental biology and human diseases such as cancer.Here we discuss the importance of understanding the role ofcilia in cancers when choosing targeted cancer therapeutics,specifically Hedgehog (Hh) pathway inhibitors.Cilia canbedivided into 2 categories: primary andmotile.

Epithelial cells that are the cancer-initiating cells generallyhave primary cilia rather thanmotile cilia; therefore, wewillfocus this discussion on primary cilia. Cells that haveprimary cilia have only a single cilium. Primary cilia areusually immotile but can sense physical and chemicalsignals. At the base of the primary cilium is the basal body(also known as the mother centriole), which is anchored in

the plasma membrane. The basal body acts to nucleate themicrotubule bundles that extend up the cilium (Fig. 1).

Hundreds of proteins that make up the primary ciliumhave been identified (1–9). Many of these proteins areinvolved in ciliogenesis, the formation of a new cilium.Other proteins localized to the cilium are involved in thesensory or signaling functions of the primary cilium.Cilia actlike antennae by sensing extracellular signals such as devel-opmental morphogens; for example, the Hh ligand receptorlocalizes to the cilium. At the core of both ciliogenesis andciliary sensory function is a highly regulated and activeprocess known as intraflagellar transport (IFT), as describedby Rosenbaum andWhitman (10) and by Scholey (11). TheKinesin-2 motor complex transports the IFT complex as wellas other protein cargo in an anterograde direction (towardthe plus end of the microtubules) to the tip of the cilium(Fig. 1). The cytoplasmicDynein2motor complex transportsthe IFT complex as well as other protein cargo in a retrogradedirection(toward theminusendof themicrotubules) towardthe cell body (Fig. 1). The IFT complex is made up of severalproteins, and mutations in IFT genes cause loss of ciliaryassembly and consequently result in lossof sensory functions(12). Manymutations in genes required for ciliogenesis havebeen identified and are now known to be causal for a largenumber of genetic disorders that are classified as ciliopathies,including Joubert syndrome, polycystic kidney disease,Bardet-Biedl syndrome, and nephronophthisis (13). Loss ofcilia or ciliary function in these ciliopathies results in thederegulation of developmental signaling pathways.

Authors' Affiliations: 1University of Arizona Cancer Center, 2Departmentof Cellular and Molecular Medicine, and 3BIO5 Institute, University ofArizona, Tucson, Arizona

Corresponding Author: Kimberly M. McDermott, 1515 N. Campbell Ave-nue, Tucson, AZ 85724. Phone: 520-626-8295; Fax: 520-626-3764; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-11-0755

�2012 American Association for Cancer Research.

ClinicalCancer

Research

www.aacrjournals.org 2429

on December 19, 2020. © 2012 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst March 13, 2012; DOI: 10.1158/1078-0432.CCR-11-0755

http://clincancerres.aacrjournals.org/

Hh signaling and primary ciliaAlthough cilia have been implicated in numerous signal-

ing pathways that are important for development anddisease, such as the Hh, Wnt, and platelet-derived growthfactor (PDGF) pathways (14–19), themechanism by whichcilia regulate the Hh signaling pathway is the best charac-terized. Therefore, Hh signaling is the focus here. Due tospace limitations, we only provide an overview of cilia andHh signaling; for a recent and thorough review, please referto Goetz and Anderson (20). In vertebrate cells, Hh signal-ing requires primary cilia. Hedgehogs are a family of secret-ed proteins that include Sonic Hh (Shh), Indian Hh (Ihh),and Desert Hh (Dhh). These Hh ligands activate the down-stream Gli family of transcription factors that translocateinto the nucleus to activateHh target genes. The cilium itselfis a subcellular compartment in which key Hh pathwaycomponents, including Gli proteins, are brought together

differentially depending on the absence or presence of Hh.Proteins are actively transported into and out of the cilium.At the base of the cilium, the transition zone containstransition fibers (Fig. 1) and other protein complexes, suchas the septin ring complex, that are thought to restrictpassive diffusion (21, 22). A likely mechanistic function ofthe cilium is to regulate the Hh pathway by increasing thelocal concentration and bringing pathway componentstogether for key protein–protein interactions required forHh pathway regulation.

Details about the dynamic regulation of the entry and exitofHhpathway proteins into and out of the cilia are just nowbeing unraveled. Three Gli proteins (Gli1, Gli2, and Gli3)are encoded by distinct genes. These Gli proteins are post-translationally processed (with the exception of Gli1) intorepressor and activator forms in the absence and presence ofHh, respectively. Loss of ciliamutations results in abnormal

Figure 1. Regulation of the Hhpathway by primary cilia innormal cells. Structure ofprimary cilium: The primarycilium contains microtubulebundles (9 doublets arrayed as acylindrical structure) that arenucleated from the basal body.The microtubule bundles areenclosed in a ciliary membranethat is continuous but distinctfrom the plasma membrane. Atthe base of the cilium aretransition fibers localized in thetransition zone. This transitionzone is known to restrict passivediffusion of proteins in and out ofthe cilium. Kinesin 2 moves theIFT complex and its cargo (e.g.,Gli, Ptch, and Smo) toward theplus end of microtubules (ciliarytip). Dynein 2 moves the IFTcomplex and its cargo towardthe minus end of microtubules(cell body). Hh regulation: In theabsence ofHh (left), Gli protein isconverted to its repressor form(GliR). Also in the absence of Hh,Ptch1 is localized to the ciliarymembrane and Smo is kept outof the cilium. In the presence ofHh (right), Gli protein levelsincrease in the cilium and Gli isprocessed into the activatorform (GliA) for transport out of thecilium and into the nucleus,where it activates Hh targetgenes. In the presence of Hh,Ptch1 moves out of the ciliumand Smo moves into the cilium,where it promotes formation ofthe activator form of Gli (GliA).

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Clin Cancer Res; 18(9) May 1, 2012 Clinical Cancer Research2430




processing of both the repressor and activator forms of Gliproteins, suggesting that both are dependent on cilia. In theabsence of Hh, the Hh pathway stays in an "off" state viaprocessing of Gli transcription factors to the repressor form,which blocks transcriptional activation ofHh genes (Fig. 1).This appears to be cilia dependent through localization ofPatched (Ptch1 or Ptc1), a negative regulator of the path-way, to the ciliary membrane. In contrast, the Hh pathwayactivator protein Smoothened (Smo), as shown in Fig. 1, iskept out of the cilium in the absence ofHh (14, 23). Anothermechanism by which Gli proteins are regulated in a cilia-dependent manner is through the protein Suppressor ofFused (SuFu). SuFu is involved in the formation of both therepressor and activator forms of Gli proteins (24). In theabsence of Hh, SuFu sequesters Gli protein to the cytoplasmand keeps it in the repressor form. In the presence of Hh,the Hh pathway is kept in an "on" state via processingof Gli transcription factors into their activator forms, alsoin a cilia-dependent manner (Fig. 1). In the presence ofHh, its receptor, Ptch1, moves out of the cilium, as shownin Fig. 1, and Smo is phosphorylated and translocated intothe cilium, where it functions to promote Gli activation(14, 25, 26). Additionally, in the presence of Hh, SuFuaccumulates in the cilium but dissociates from Gli, pro-moting Gli’s conversion to the activator form and allowingit to enter the nucleus to activate Hh target genes (24, 27).

Primary cilia, Hh signaling, and cancerThe Hh pathway is an important regulator of cell growth

and differentiation during development. Abnormal activa-tion of the Hh pathway is critical for the development ofmany cancers, including glioblastoma, basal cell carcino-ma, medulloblastoma, and breast, prostate, melanoma,lung, and pancreatic cancers (28). In human cancers, theHh pathway is upregulated either through mutations ofpathwayproteins, such as Ptch1, Smo, and SuFu, or throughoverexpression of Hh. Experiments in mouse models ofcancer showed that cilia can play a dual role in promotingand preventing tumorigenesis through regulation of the Hhpathway (29, 30). This paradox is due to the primarycilium’s role in turning theHhpathway "on" in the presenceof Hh (by processing Gli proteins into the activator form)and keeping the Hh pathway "off" in the absence of Hh (byprocessing Gli proteins into the repressor form).In these mouse models of basal cell carcinoma and

medulloblastoma, an active form of Smo was ectopicallyexpressed in wild-type mice and mice genetically modifiedto havemutant primary cilia (29, 30). As expected, themicewith active Smo and wild-type cilia developed basal cellcarcinomas and medulloblastomas, and those with activeSmo but mutant cilia did not develop tumors. As describedabove, 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 Hhpathway and tumors were unable to form (Fig. 2C). Whenthe Hh pathway was activated downstream of cilia, byectopically expressing an activator form of one of the Gliproteins in the absence of cilia, the absence of cilia resulted

in a significant increase in tumorigenesis. Follow-up studiesshowed that the presence of cilia allowed for the formationof the repressor form of Gli protein (Fig. 2B). The cilia-generated repressor form of Gli protein is predicted tobalance out the exogenously expressed activator form ofGli protein to slow tumor growth. In the absence of cilia, therepressor form of the Gli transcription factor was reducedand unable to counteract the activator Gli protein, resultingin increased tumorigenesis (Fig. 2D).

Clinical–Translational AdvancesPrimary cilia expression in human cancers

Given that cilia are important for regulating the Hhpathway in normal cells and can play a dual role duringtumorigenesis, it is critical to learn more about whichhuman cancers make functional primary cilia and whichcancers have ciliary dysfunction. Moreover, depending onwhich step of the Hh pathway is functioning to sustaintumorigenesis, the presence or absence of cilia may have asignificant impact on the effectiveness of targeting differentsteps of the Hh pathway (upstream or downstream of cilia).

Only a limited number of studies have examined theexpression of primary cilia on human cancer cells fromprimary patient samples. A reduction in cilia frequencyrelative to adjacent normal tissue was observed in clear cellrenal cell carcinoma (31), breast cancers (32), melanoma(27), basal cell carcinoma (22),medulloblastoma (23), andpancreatic cancer (33). Pancreatic intraepithelial neoplasticlesions were also devoid of cilia, suggesting that loss of ciliamay occur early in tumorigenesis (25). In a study of medul-loblastoma (23), the presence of cilia correlated with des-moplastic medulloblastoma (better prognosis), and theabsence of cilia was associated with anaplastic medullo-blastoma (poor prognosis).

Cellular proliferation rates can influence the presence ofcilia. Therefore, it was an important finding in the studies ofmelanoma (27), renal cell carcinoma (31), and pancreaticcancer (33) that primary cilia loss was independent of Ki67staining (a cell proliferationmarker). This suggests that lossof cilia is not a result of altered cellular proliferation ratesand that primary cilia dysfunction in cancers may be due toanother mechanism, such as loss of a gene required forciliogenesis, potentially resulting from mutagenesis orgenomic instability (31, 33, 34).

These studies suggest that cilia dysfunction is a commonevent in cancers and that it may occur early during thetumorigenic process. However, further work on these andadditional types of cancer is needed. The reported samplesizes are small (ranging from 8 to 38 patient samples), andthere is a general lack of quantitation and statistical analysis.Comparisons with normal tissue are also needed. Normaltissue adjacent to cancer has been used and may provideinteresting findings; however, field effects in tissue sur-rounding cancer have been documented (35). Also, cilialengths have not been examined in cancers or normal tissuefor comparison. Cilia may be present in cancers, but if theyhave abnormal lengths, this may affect signaling (20). Not

Primary Cilia in Cancer: Impact on Hedgehog-Targeted Therapy

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Figure 2. Role of cilia in Hh pathway activation in cancer cells. A, cancer-associated overexpression of Hh ligands or mutations in genes such asPtch1 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 arepresent, then inhibitors targeting Hh ligand, Smo, and Gli trafficking (red boxes) will be effective. Inhibitors that target Gli activity downstream of cilia(white box) will also be effective at reducing the Hh pathway in this context. B, cancer-associated overexpression of Gli1 (GliA) in the presence of ciliawill result in low levels of Hh pathway activation. In this context, cilia make the repressor form of Gli (GliR), counterbalancing GliA to reduceoveractivation of the Hh pathway. Mutations in REN(KCTD11) can also result in increased GliA activity. Because this activation is downstream of cilia,only the downstream Gli targeting inhibitors (gold box) are predicted to be effective. C, cancer-associated overexpression of Hh ligands or mutationsin 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 mutationsdownstream of cilia, such as overexpression of Gli1 (GliA) and mutations in Ren(KCTD11), have been found in cancers and will turn on the Hhpathway in the absence of cilia due to high GliA and low GliR. Therefore, only downstream Gli targeting inhibitors (gold box) are predicted to beeffective in this scenario.

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surprisingly, there is a range in the percentage of patientsamples with cilia and a range in the percentage of cells withcilia in independent tumors. It is important to explore theseranges further by asking whether specific levels of ciliafrequency correlate with specific cancer subtypes and withclinical data such as survival, recurrence, and response totreatment. It is also critical to correlate cilia frequency withmarkers of relevant pathways, such as Hh target genes, tobegin to understand whether there is a causal associationbetween cilia and human cancers.

Primary cilia and clinical inhibitors of the Hh pathwayHh-targeted drugs are expected to be effective as antican-

cer drugs by killing cancer cells as well as by targetingstromal cells associated with tumorigenesis (e.g., inhibitingangiogenesis). In this section, our focus is on the role ciliaplay in the efficacy of Hh-targeted drugs, specifically withregard to cancer cells; however, the same concepts are likelyto apply to inhibition of Hh pathway signaling in stromalcells. Although all of theHh-targeted drugsmentioned haveshown preclinical efficacy in cell lines and, in some cases,mouse models, efficacy in clinical trials is mixed, rangingfrom full or partial response to no efficacy [for a detailedreview, please see Ng and colleagues (36)]. We predict thatthe efficacy of Hh-targeted anticancer drugs will rely onwhether activation of the Hh pathway is upstream (depen-dent) or downstream (independent) of cilia, as well aswhether the cancer cells are positive or negative for primarycilia. Hh pathway activation in cancer can be divided into 2groups: Hh ligand driven and mutation driven. As wedescribe below, Hh ligand–driven cancer can only be ciliadependent, whereas mutation-driven cancers can be ciliadependent or independent.Ligand-driven Hh pathway activation (cilia dependent).

Overexpression of Hh ligands has been shown in manycancers (37, 38). Hh-induced signaling in cancer can occurthrough autocrine (cancer-cancer) and paracrine (stroma-cancer) expression of Hh (39). Hh pathway activation fromelevated ligand is upstream of cilia (cilia dependent). Asdescribed above, cilia are required to respond to ligand andactivate the Hh pathway via Smo and Gli proteins (Fig. 2A).Therefore, therapeutically treating patients who have Hhpathway upregulation driven by elevated Hh ligand byadministering a ligand antagonist (e.g., 5E1 and robot-nikinin), Smo antagonist (e.g., GDC-0449 and IPI-926),or Gli-processing inhibitor (e.g., HPI-2 and HPI-3) wouldbe predicted to be effective only if the tumor cells have cilia(Fig. 2A). For example, HPI-2 and HPI-3 have both beenshown to reduce Hh pathway signaling in response to Hhligand in vitro in studies using cell lines. Preclinical reportsshowing reducedHh pathway signaling forHPI-2,3 were alltested on NIH-3T3 cells that are known to be ciliated (40).Clinical trial data are not currently available for HPI-2,3.Mutation-driven Hh pathway activation (cilia indepen-

dent). Overexpression of Hh ligand does not mean thatthe cancer cells rely on ligand for Hh pathway activation. Ascancers evolve through multiple stages of activation, theelevated Hh ligand levels observed may have been impor-

tant for stimulating tumor growth at an earlier stage whencilia were present. If the tumor cells no longer have cilia, thehigh Hh ligand levels are no longer relevant to activation inthe tumor cells. Instead, continued activation of the Hhpathway would require a secondary mutation downstreamof cilia (cilia independent), whichwould relieve reliance onthe Hh ligand (Fig. 2D). Emerging data suggest that manycancers have lost cilia. Therefore, in cancer cells withoutcilia, any observedHhpathway activationmust be drivenbymutations that are downstream of cilia. Mutations in thepathway that are downstream of cilia allow theHh pathwayto be turned on even in the absence of cilia. There are severalexamples of Hh pathway mutations that have been shownto be downstreamof cilia andwould therefore allow theHhpathway to be turned on even in the absence of cilia. SuFu isa protein that is known to sequester the Gli proteins in thecytoplasm and thereby exert a negative effect on Hh path-way activation (41). Mutations in SuFu have been found inmedulloblastomas (36, 37), and loss of SuFu protein hasbeen observed in prostate cancers. Additionally, loss-of-heterozygosity mutations in SuFu have been reported inrhabdomyosarcoma (36, 37, 42, 43). Medulloblastomasalso have been shown to have loss of REN(KCTD11), aprotein that antagonizes Gli-mediated transactivation ofthe Hh target genes, ultimately resulting in activation ofthe Hh pathway downstream of cilia (Fig. 2D; ref. 44).Glioblastomas have been found to have amplification ofGli1 (36). Mutations in Gli1 and Gli3 have been found inpancreatic adenocarcinoma (39). Murine studies suggestthat activation of a downstream component of the Hhpathway will activate the Hh pathway, leading to enhancedtumorigenesis when cilia are absent (Fig. 2D; refs. 29,30, 45). When cilia are present, the repressor form of Gliprotein can still bemade,which can counteract downstreamactivation of the pathway (Fig. 2B). Therefore, we predictthat if the cancer cells lack cilia, it will be necessary to targetinhibition of the Hh pathway downstream of cilia with adrug such as GANT58 or GANT61 (Fig. 1F). Emerging dataindicate that many patients have a low frequency of ciliatedtumor cells. This tumor heterogeneity suggests that combi-natorial treatment with Hh-targeted drugs that are ciliadependent and independent may be an effective treatmentfor some patients.

GANT61 inhibits Hh signaling downstream of cilia byinhibiting Gli transcriptional activity and has been showntobe effective at inhibiting theHh signaling pathway in cellscontaining or lacking cilia. For example,GANT61 effectivelyinhibited Hh signaling in HEK293 and NIH-3T3 cells,which are both known to have cilia (46). In a prostatexenograft model with the 22RV1 prostate cancer cell linethat was shown to lack cilia, GANT61 treatment resulted intumor regression (46). These preclinical data support ourhypothesis that GANT61 is a cilia-independent inhibitor.

Mutation-driven Hh pathway activation (cilia depen-dent). Another mechanism by which the Hh pathway canbe activated upstream of cilia involves mutations in Hhpathway proteins that require cilia for their regulation.Deactivation of Ptch1 (negative regulator) and constitutive






activation of Smo (positive regulator) are upstream of cilia(cilia dependent; Fig. 2A). Although these mutationsrequire the presence of cilia for activation, the cancer cellsno longer rely on the Hh ligand for pathway activation.Inactivation or loss-of-heterozygosity mutations in thePtch1 receptor or activating Smo mutations are commonin basal cell carcinoma, with 90% of basal cell carcinomashaving loss of function of Ptch1 and 10% having activationof Smo (36, 37). Ptch1 receptor mutations and loss ofheterozygosity are also seen in medulloblastomas andrhabdomyosarcomas (36, 37).

As described above, murine studies have shown thatactivation of an Hh pathway component upstream of cilia,such asmutations in the Smoprotein, requires primary ciliafor Hh pathway activation (29, 30). If a patient is found tohave a mutation in the Hh pathway upstream of cilia (e.g.,Ptch1 or Smo) and the tumor has cilia, then inhibiting theHh pathway with a Smo inhibitor such as GDC-0449 ispredicted to be effective (Fig. 2A). If the tumor carries Ptch1or Smo mutations but does not have primary cilia, wepredict that the Hh pathway activation is no longer depen-dent on the Ptch1 or Smomutations but may now have Hhpathway activation due to a Hh pathway mutation at a latercilia-independent step (Fig. 2D). The Ptch1 or Smo muta-tions may have been important in an earlier stage in cancerprogression, similar to the elevated Hh ligand levels dis-cussed in the previous paragraph. If the cancer cells do nothave cilia, the tumor would not be responsive to Smo- orGli-processing inhibitors and instead would need to betreated with downstream inhibitors, such as the Gli antago-nists GANT58 or GANT61 (Fig. 1F). On the basis of thisrationale, we predict that only ciliated cancer cells could beresponsive to GDC-0449. In a phase I clinical trial, 66% ofpatients with basal cell carcinoma containing Ptch1 or Smomutations responded to theGDC-0449 Smo inhibitor (47).We hypothesize that these patients had cancer cells thatexpressed cilia. The nonresponsive tumors may have lackedciliated cancer cells. This is consistent with the finding inone study that �63% of tested samples from patients withprimary human basal cell carcinoma had cilia (29). Further

studies are needed to determine whether this correlationwill hold true andwhether the presence of cilia on basal cellcarcinoma is predictive of responsiveness to GDC-0449treatment. It is also possible thatmanyof the nonresponsivepatients are no longer dependent on the Hh pathway forsurvival.

Future Directions and ConclusionsFurtherwork is needed todeterminewhether the predicted

relationships between the presence of cilia and responsive-ness to specific Hh pathway inhibitors are clinically relevant.If they are, then the presence or absence of cilia will provideanother tool for clinicians to use in choosing Hh-targeteddrugs to treat individual cancers. On a more general note, ifthe trend continues that cancer cells lose cilia, then Hhinhibitors that are upstream of cilia may prove generallyineffective, and we will need to focus on developing addi-tional inhibitors that aredownstreamof cilia (cilia and ligandindependent). Such therapeutics are currently underrepre-sented among Hh clinical inhibitors and would be predictedto target a much broader range of tumor cells.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

Authors' ContributionsConception and design: N.B. Hassounah, K.M. McDermottWriting, review, and/or revisionof themanuscript:N.B.Hassounah, T.A.Bunch, K.M. McDermott

AcknowledgmentsThe authors thank Brian Keady, Greg Pazour, and Jeremy Reiter for

editorial comments on the manuscript.

Grant SupportThis publication was made possible by Grant Numbers P30CA023074

and T32CA009213 from the National Cancer Institute, National Insti-tutes of Health; and Grant Number R00HD056965 National Instituteof Child Health and Human Development, National Institutes ofHealth.

ReceivedDecember 19, 2011; revised January 27, 2012; accepted February8, 2012; published OnlineFirst March 13, 2012.

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2012;18:2429-2435. Published OnlineFirst March 13, 2012.Clin Cancer Res Nadia B. Hassounah, Thomas A. Bunch and Kimberly M. McDermott

SignalingProgression and Therapeutics with a Focus on Hedgehog Molecular Pathways: The Role of Primary Cilia in Cancer

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