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[Cancer Research 63, 923-928, March 1, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Evidence for Lack of Enhanced Hedgehog Target Gene Expression in Common Extracutaneous Tumors1

Zhilan Hu, Jeannette M. Bonifas, Geraldine Aragon, Levy Kopelovich, Yu Liang, Shoichiro Ohta, Mark A. Israel, David R. Bickers, Michelle Aszterbaum and Ervin H. Epstein, Jr.2

The Cooperative Human Tissue Network, University of Alabama, Birmingham, AL 35294 [G. A.]; Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [L. K.]; Departments of Dermatology [Z. H., J. M. B., M. A., E. H. E.]; and Neurological Surgery [Y. L., S. O.]; San Francisco General Hospital and the University of California School of Medicine, San Francisco, California 94110; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756 [M. A. I.]; and Department of Dermatology, Columbia University, New York, New York 10032 [D. R. B.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Abnormal hedgehog signaling, most commonly caused by loss of PTCH1 inhibitor activity,drives tumorigenesis of basal cell carcinomas (BCCs). To assess whether other tumors also have abnormal hedgehog signaling, we have assayed RNA from common cancers at nine different sites for levels of expression of hedgehog target genes that are up-regulated uniformly in BCCs. We report here that such dysregulation appears not to be common in the types of non-BCC cancers studied, indicating that the molecular pathogenesis of BCCs, like their frequency and behavior, differs markedly from that of most other cancers.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Abnormalities of hedgehog signaling have been identified as the master switch controlling the abnormal behavior of BCCs,3 the commonest human cancer (1 , 2) . These abnormalities can arise by somatic mutations in genes encoding several of the molecules that mediate hedgehog signaling; heritable mutations in PTCH1, an inhibitor of hedgehog signaling, underlie the BCNS. The latter is a hereditary syndrome in which patients are at increased risk not only for BCCs but also for medulloblastomas, rhabdomyosarcomas, odontogenic and epidermal cysts, and perhaps for meningiomas (3) . Mutations of PTCH1 and other hedgehog pathway genes occur frequently in sporadic tumors of the types that are of higher than normal incidence in BCNS patients. These include BCCs (and the related tumor trichoepitheliomas), medulloblastomas (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) , and odontogenic cysts (19) .

By contrast, limited information is available regarding hedgehog signaling in other tumors (20) . Most of the available data have come from studies of two types. First, low-frequency amplifications of the region of chromosome 12q that contains GLI1 have been found in several tumor types [e.g., childhood nonrhabdomyosarcoma sarcomas (21 , 22) , gliomas (23, 24, 25) , and B-cell lymphomas (26 , 27) ]. The GLI1 gene encodes a transcription factor that mediates at least some of hedgehog target gene expression, and GLI1 expression is itself up-regulated in cells responding to hedgehog ligand. However, the amplicons typically include additional genes, such as CDK4, and amplification of these other genes, but not of GLI1, occurs in some tumors. This suggests that what is critical to the growth of tumor cells carrying the 12q amplification is overexpression of one or more of these other genes rather than overexpression of GLI1 (25) . Low-level up-regulation of GLI1 mRNA expression has been found in adult sarcomas without accompanying GLI1 gene amplification, and the amount of GLI1 mRNA in these tumors correlates with the degree of clinical malignancy (28) . However, the genesis of this up-regulation and its contribution to the activation of expression of other target genes, let alone to the behavior of the cells, are unknown.

Second, PTCH1 mutations have been identified, albeit at low frequency, in DNA from sporadic tumors or cell lines derived from various cancers: (a) breast; (b) colon; (c) esophagus; (d) bladder; and (e) brain (10 , 29, 30, 31, 32) . Because PTCH1 mutations cannot be detected in DNA of many BCNS patients (33) , despite uniform linkage to the site of the PTCH1 gene on chromosome 9q, or in sporadic BCCs, despite uniform dysregulation of hedgehog signaling in these tumors, it is likely that current screening detects only a fraction of PTCH1 gene mutations. Furthermore, mutations in genes encoding other participants in hedgehog signaling also may drive aberrant signaling and tumorigenesis (31 , 34 , 35) . Therefore, currently, it is impractical to survey extracutaneous tumors adequately for pathogenetic abnormalities of this pathway simply by screening for mutations in genes encoding pathway members. Further complicating our efforts to understand the pathogenetic significance of identified mutations is the recent finding that even medulloblastomas (36) , tumors in which evidence for hedgehog signaling abnormalities is excellent, may lose only one copy of the PTCH1 gene but retain apparently normal function of the other allele (37 , 38) .

Given the importance of more broadly assessing hedgehog signaling in cancers and the above-described technical difficulties of mutation detection, we have investigated a selection of more common sporadic extracutaneous tumors for hedgehog signaling dysregulation not indirectly by searching for mutations or amplifications but rather directly by assaying for abnormal accumulation of species of mRNA known to be induced by hedgehog signaling and uniformly up-regulated in BCCs: (a) PTCH1; (b) GLI1; (c) HIP; and (d) PDGFR{alpha} (4 , 39, 40, 41, 42, 43, 44, 45, 46) . We have found essentially no enhanced accumulation of any of these mRNA species in the 68 tumor specimens studied, indicating that hedgehog signaling dysregulation is not crucial to the development of most common non-BCC cancers.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tumors and RNA Extraction.
Tumors and adjacent nontumorous tissues (both primary tumors and metastases), in excess of that needed for pathological evaluation, were collected fresh and stored initially on dry ice and then at -70°. For RNA isolation from tissues other than brain, tissues were homogenized on ice with a Polytron in guanidine isothiocyanate buffer, the homogenate was applied to a RNeasy spin column (RNeasy Midi kit; Qiagen), the column was washed, and the RNA was eluted in RNase-free water. For glioblastoma multiforme and gliotic tissues, RNA was extracted with TRIzol (Life Technologies, Inc.) and further purified to mRNA with a Fast Track oligo dT column (Invitrogen).

TaqMan mRNA Quantitation.
mRNA was quantitated using TaqMan real-time PCR amplification (PE Biosystems). All results were normalized to the amount of GAPDH mRNA in each sample. Primers and probes used were as follows: PTCH 1, Probe: 6FAM-AATTCCCGCTCTGCGGGCG-TAMRA, Primers: Forward: 5'-TCTTCATGGCCGCGTTAATC, Reverse: 5'-TTGCAGGAAAAATGAGCAGAAC; GLI1, Probe: 6FAM-TGCTGGTGGTTCACATGCGCAGA-TAMRA, Primers: Forward: 5'-TGAGGCCCTTCAAAGCCC, Reverse: 5'-ATGACTTCCGGCACCTTTC; HIP, Probe: 6FAM-TGTATGTGTCCTATACCACCAACCAAGAACGGTAMRA, Primers: Forward: 5'-TGCTAAGCCTCGCATTCCA, Reverse: 5'-ACAACCCTAAGAATGTGGTCATGA; PDGFR{alpha}, Probe: 6FAM-CCTCCAGCGAATTTCATACCTCGGTTTCT-TAMRA, Primers: Forward: 5'-CTCACTTATTGTCCTGGTTGTCATTT, Reverse: 5'-CTGCATCGGGTCCACAT; GAPDH, Probe: 6FAM-CAAGCTTCCCGTTCTCAGCC-TAMRA, Primers: Forward: 5'-GAAGGTGAAGGTCGGAGTC, Reverse: 5'-GAAGATGGTGATGGGATTTC.

Amplification was performed using 50°C for 2 min, 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. mRNA quantitation was assessed by the fluorescence intensity emitted after PCR amplification. The difference in the fluorescence (threshold) between tubes with GAPDH amplification and those with the specific mRNA amplification was compared for tumor and normal tissue extracts.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
We examined the following tumors and corresponding normal tissues: (a) bladder–2 and 1; (b) brain–16 and 2 (the latter were histologically normal samples from tissue taken from patients with epilepsy); (c) breast–15 and 6; (d) colorectal-15 and 16; (e) esophagus–2 and 2; (f) kidney–4 and 5; (g) lung–7 and 7; (h) ovary-2 and 0; (i) stomach–3 and 2; and (j) uterus–2 and 1. Matched normal tissue was obtained from all patients from whom the tumors were collected, and for most patients, both normal and tumor tissue results could be compared. The results from the normal samples at each site were quite consistent, and so we simply compared each tumor versus all available normal tissues at that site (Table 1)Citation .


View this table:
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  		Table 1 Tumor characteristics and Hedgehog target gene expression in cancersa

 
In all 68 tumors examined, the mRNA encoding genes that are targets of hedgehog signaling and up-regulated uniformly in BCCs (PTCH1, GLI1, HIP, and PDGFR{alpha}) was no greater and in most instances was less than that in adjacent normal tissue.

We analyzed 15 glioblastoma multiforme tumors, one grade 3 anaplastic astrocytoma, five glioma cell lines, and one medulloblastoma cell line and found no up-regulation of hedgehog target genes. An exception to this general lack of up-regulation of hedgehog target genes in brain cancers was our finding that 6 of the 15 glioblastomas had 2–16-fold increases in PDGFR{alpha}. However, 5 of these 6 tumors had no increase in other hedgehog target genes, suggesting that the up-regulation of PDGFR{alpha} expression was driven by non-hedgehog mechanisms. The 6th brain tumor had an 8-fold increase in PTCH1 mRNA in addition to its 8-fold increase in PDGFR{alpha} mRNA but had no increase in mRNA encoding GLI1 or HIP. There were insufficient amounts of RNA available for further study of this tumor, and there were no distinguishing histological or other features of this tumor as compared with the other 14 glioblastomas.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
We found no increased expression of four genes uniformly up-regulated in BCCs in extracutaneous cancers, suggesting that activation of hedgehog signaling is unlikely to be of major importance in the more common non-BCC cancers. This conclusion must be considered tentative for several reasons.

First, we have no proof that these genes actually are targets of hedgehog signaling in these tumor types. Nonetheless, PTCH1 expression is a conserved target of hedgehog signaling in organisms as diverse as humans and flies and tissues as diverse as wings, eyes, skin, and lung (47, 48, 49) , making it likely that PTCH1 and/or at least one of these other well-described targets of hedgehog signaling in other cells would be a target of dysregulated hedgehog signaling in human non-BCC tumors as well. By contrast, human sporadic medulloblastomas, which occur in higher than normal incidence in BCNS patients, frequently do have PTCH1 or SMO mutations and increased PTCH1 mRNA (7, 8, 9, 10 , 16 , 31 , 36) , and at least in ptc1 +/- mice, these tumors have enhanced ptc1 promoter activity (50) . Furthermore, rhabdomyosarcomas in ptc1 +/- mice have increased gli1 mRNA (51) , as well as increased ptc1 promoter activity (50) .

Second, there is at least one situation in which hedgehog mutations appear to influence cell behavior without causing abnormal expression of these four genes. This is the ASZ001 cell line, which was established from a mouse BCC that (like all other BCCs in ptc1 +/- mice) had elevated ptc1 promoter activity, in this instance attributable to lost functioning of both ptc1 alleles (50) . This cell line also has mutations in both p53 alleles. These cells continue to proliferate at calcium concentrations sufficient to cause normal mouse epidermal keratinocytes grown from wild-type or p53-null mice to cease proliferation and undergo irreversible differentiation. Nonetheless, these cells in vitro have levels of mRNA encoding gli1, hip, and PDGFR{alpha} no higher than those of cultured normal mouse epidermal keratinocytes. Thus, it is possible that mutant ptc1 may influence cell behavior without up-regulating expression of (at least these) hedgehog target genes. The recent reports that: (a) the hedgehog pathway component smoothened is able to signal as a G protein-coupled receptor (52) and (b) PTCH1 loss may affect the cell cycle directly by releasing otherwise sequestered cyclin B (53) may be relevant to this finding.

Finally, we did not study an unlimited number of tumors, even of breast and colon/rectum, and also did not study some visceral tumors (e.g., prostate cancers and nonglioblastoma brain tumors). Hence, these, as well as less common cancers of other viscera and/or specific subtypes, may have hedgehog target gene transcriptional changes. Indeed, not only adult sarcomas (28) but also occasional nonmedulloblastoma brain cancers (54) have been reported by others to have some elevation of GLI1 message. Recently, Dahmane et al. (55) have reported the expression of GLI1 and PTCH1 in human brain cancers, not only in primitive neuroectodermal tumors but also in glial tumors. Our results are not inconsistent with theirs; we too found expression of all four tested genes in gliomas. However, we did not find expression levels to be elevated consistently; quite unlike the average 100-fold increase of expression levels in BCCs (45) , and the reverse transcription-PCR results they illustrate suggest that they found considerably lower expression levels of GLI1 and PTCH1 in gliomas than in primitive neuroectodermal tumors.

Of note, nonpregnant female ptc1 +/- mice have uniformly abnormal breast ductal epithelium, resembling ductal carcinoma in situ (56) . Nonetheless, none of the ductal human breast cancers that we studied had evidence of hedgehog target gene dysregulation.

It is unclear why dysregulation of this pathway appears to be limited to those tumors also found in increased incidence in BCNS patients because that is not the case for other tumor suppressor genes whose mutations underlie hereditary human cancer syndromes (e.g., p53/Li-Fraumeni syndrome). This discrepancy should be considered against the background of the extremely high incidence of BCCs, an incidence that is as high in some Caucasian populations as is their incidence of all other cancers combined. At least three possible explanations seem formally possible: (a) genes encoding proteins active in the hedgehog signaling pathway may be especially susceptible to UV radiation mutagenesis; against this possibility is the finding that BCCs induced in ptc1 +/- mice by ionizing radiation also have hedgehog dysregulation (50) as do BCCs arising on sun-protected parts of the body, such as the back and chest; (b) other cells may possess redundant hedgehog-restraining mechanisms lacking in keratinocytes, and hence they may achieve hedgehog dysregulation less easily; and (c) the behavior of adult cells other than keratinocytes may be less sensitive to the effects of hedgehog dysregulation. Studies of forced up-regulation of hedgehog target genes in extracutaneous tissues should help differentiate between these latter two possibilities.


   ACKNOWLEDGMENTS
 
We thank Bob Grant and Jerry Kropp, Gladstone Institute, San Francisco General Hospital, for assistance with TaqMan analysis.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by NIH Grants CA 81888-01 (to E. H. E.) and CA44968 (Cooperative Human Tissue Network), as well as generous gifts from the Michael Rainen Family Foundation and Patricia Hughes. Tissue samples were provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute (CA44968), and the University of California at San Francisco Brain Tumor Research Institute. Other investigators may have received specimens from the same subjects. Back

2 To whom requests for reprints should be addressed, at San Francisco General Hospital, Room 269, Building 100, 1001 Potrero Avenue, San Francisco, CA 94110. Phone: (415) 647-3992; Fax: (415) 647-3996; E-mail: ehepstein{at}orca.ucsf.edu Back

3 The abbreviations used are: BCC, basal cell carcinoma; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; BCNS, basal cell nevus syndrome. Back

Received 3/27/02. Accepted 1/16/03.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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