Sonic hedgehog signaling in basal cell carcinomas

doi:10.1016/j.canlet.2004.10.003

Cancer Letters

Volume 225, Issue 2, 28 July 2005, Pages 181-192

https://doi.org/10.1016/j.canlet.2004.10.003 Get rights and content

Abstract

The development of basal cell carcinoma, the commonest human cancer in fair skinned populations, is clearly associated with constitutive activation of sonic hedgehog signaling. Insight into the genesis of BCC came from the identification of germline mutations of the tumor suppressor gene, PATCHED, a key regulatory component of hedgehog signaling in the nevoid basal cell carcinoma syndrome. Analysis of sporadic basal cell carcinomas and those from repair deficient xeroderma pigmentosum patients has revealed mutational inactivation of PATCHED and gain of function mutations of the proto-oncogenes, SMOOTHENED and SONIC HEDGEHOG associated with solar UV exposure. The molecular mechanisms involved in alterations of the hedgehog signaling pathway that lead to the formation of basal cell carcinomas are being unraveled and has already allowed the investigation of future therapeutic strategies for treating these skin cancers.

Introduction

The Hedgehog (HH) signaling pathway, highly conserved in vertebrates and invertebrates, is critical in governing embryonic development and adult tissue homeostasis. Originally identified by genetic analysis of embryonic mutants of the fruit fly Drosophila melanogaster, the hedgehog protein (hh) is found to play an essential role in the signaling pathway involved in cell type specification, patterning and the regulation of cell proliferation and differentiation in nearly all tissue types during development [1]. HH signaling is more complex in vertebrates than in drosophila and three hedgehog homologue proteins have been identified in mammals: Sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dhh) [2]. Amongst these, Shh is the most potent [3] and most often expressed in embryonic and adult tissues [4], [5]. Mutations in the key components of the SHH signaling pathway can result in severe congenital malformation resulting in phenotypes such as holoprosencephaly and the nevoid basal cell carcinoma syndrome (NBCC) [6], [7], [8]. Modifications of SHH signaling can also lead to tumor development in tissues of different origin, predominantly basal cell carcinomas (BCCs) in skin, medulloblastomas and gliomas in brain and rhabdosarcomas in muscle [4], [5], [9], [10]. Recent reports indicate that upregulation of the SHH pathway is also involved in digestive tract, pancreatic and small-cell lung cancers [11], [12], [13]. This review highlights our knowledge of the involvement of the SHH signaling pathway in the pathogenesis of basal cell carcinoma, the most common malignancy in the white population today. Much of our understanding of the mechanisms of SHH signal transduction which are implicated both in development and disease has been clarified by the study of animal models and analysis of human tumors, including BCCs.

Section snippets

Basal cell carcinomas

Cancer of the skin is the most common cancer in Caucasians and basal cell carcinomas (BCC) account for 90% of all skin cancers. Its incidence is increasing and shows marked geographical variations as highlighted by the elevated levels of skin cancers observed in the white skinned Australian population submitted to high levels of solar UV exposure. Indeed, exposure to ultraviolet (UV) radiation has been identified as the most important environmental risk factor because unrepaired UV induced DNA

SHH signaling

The hedgehog family of secreted proteins are subjected to different autoprocessing, post-translational modifications in order to be fully activated (Fig. 1). The SHH protein is synthesized as a 45kD precursor protein which undergoes maturation by intramolecular cleavage catalyzed by the C-terminal portion of the precursor generating a 19 kD N-terminal signal peptide and a 25 kD C-terminal fragment which diffuses away as it seems to have no other function [33], [34]. The autocleavage process

Activation of the SHH signaling pathway in BCC

It is clear that constitutive activation of the sonic hedgehog signaling pathway can lead to the development of BCCs (Fig. 3). Several studies have shown consistent overexpression of PTCH in BCCs [52], [53], [54], [55], [56], [57]. This clearly indicates that deregulation of the SHH pathway by mutation or altered activity of one or more of the members must be occurring in all BCCs. It should be noted that the 34 kb human PTCH gene expresses three alternative transcripts differing at the 5′ end

Sonic hedgehog

Alterations of SHH, a postulated proto-oncogene are extremely rare in sporadic BCCs and only one potential gain of function mutation (H133Y) has been reported among 74 sporadic BCCs analyzed to date (Fig. 3) [55], [69]. A later study, looking only for codon 133 alterations, found no modifications in 36 sporadic BCCs analyzed [70]. It is only from the recent study of XP BCCs that a role for SHH in human skin tumorigenesis has been firmly established by the finding of six novel SHH gene mutations

SHH signaling and BCC in mouse models

Genetically engineered mice have served as dynamic models and essential tools for investigating the role of the different partners involved in the SHH pathway in the development of BCCs. The analysis of mice with targeted inactivation or haploinsufficiency of the Shh, Ptch, Smo and Gli genes has enabled important insights on their impact on proliferation, development and oncogenesis. Thus, over expression of SHH in the skin of transgenic mice revealed skeletal and skin anomalies with the

Towards a therapy for BCC

The discovery of small molecules antagonists of SHH signaling, such as cyclopamine, has opened up exciting new prospects for BCC therapy [90], [91], [92], [93]. Cyclopamine, a plant derived SHH pathway inhibitor, was first discovered when sheep fetuses were found to have malformations comparable to those found in HPE because pregnant ewes had ingested cyclopamine containing plants [90], [94], [95]. This lead to the search for synthetic small molecules inhibitors of hedgehog signaling and

Conclusions

The last decade has seen the accumulation of a large body of evidence that has linked SHH deregulation to the genesis of basal cell carcinomas. The transgenic mouse models have provided striking crucial data indicating that aberrant SHH activity is an early event in BCC formation. Benign skin lesions in humans associated with BCCs, also present PTCH mutations indicating SHH pathway disruption to be an early event. The numerous studies of human BCCs has revealed that the constitutive activation

Acknowledgements

We would like to thank the Association de Recherche sur le Cancer (Villejuif), the Ligue Nationale Contre le Cancer (Creteil), the Groupement des Entreprises Françaises dans la Lutte Contre Cancer (Charenton) and l'Eléctricité de France (Paris) for their support in providing research grants for our own work on hedghog signaling in skin cancer.

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Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms.
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Ultraviolet light (UV) is one of the most common DNA damaging agents in the human environment. This paper examined the influence of DNA methylation on the level of UVB- and UVC-induced DNA damage. A purified DNA sequence containing CpG dinucleotides was methylated with a CpG methylase. We employed the linear amplification technique and the end-labelling approach followed by capillary electrophoresis with laser-induced fluorescence to investigate the sequence specificity of UV-induced DNA damage. The linear amplification technique mainly detects cyclobutane pyrimidine dimer (CPD) adducts, while the end-labelling approach mainly detects 6–4 photoproduct (6–4PP) lesions. The levels of CPD and 6–4PP adducts detected in methylated/unmethylated labelled sequences were analysed. The comparison showed that 5-methyl-cytosine significantly reduced the level of both CPD and 6–4PP adducts after UVB (308 nm) and UVC (254 nm) irradiation compared with the non-methylated counterpart.
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Recent studies have demonstrated the critical role of the sonic hedgehog in the sensory perception of taste. Salivary sonic hedgehog stimulates taste bud stem cells, also acts as a taste bud growth factor, and contributes to the receptors' development and longevity in the taste buds. This study's objective was to investigate the possible relationship between taste sensitivity and sonic hedgehog expression in saliva in normal-weight and pre-obese/obese participants (totally 46 male (47.8%) and female (52.2%) aged 19–44 were recruited). Thresholds for the six tastes (sweet, salty, bitter, sour, umami and fat) were investigated using 3-Alternate Forced Choice Methodology. Saliva was collected with the draining method for sonic hedgehog expression analysis. The results indicated significantly higher thresholds for sweet, bitter and fat in pre-obese /obese adults than normal-weight adults (p<0.05). The sonic hedgehog expression was also lower in pre-obese /obese participants than normal-weight participants (p<0.05). Furthermore, sonic hedgehog expression was higher in hypersensitive participants than hyposensitive participants (p<0.05) only among normal-weight individuals, with no significant difference in sonic hedgehog expression level by taste sensitivity in pre-obese/obese individuals (p>0.05). Sonic hedgehog expression level was negatively correlated with body mass index, sweet, salty, bitter and fat taste threshold. The study results indicated that sonic hedgehog expression level acted on taste sensitivity in normal-weight participants, with greater expression in hypersensitive individuals than hyposensitive individuals.
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Surgery is the primary treatment for basal cell carcinoma (BCC). In locally advanced basal cell carcinoma (laBCC), surgery may cause functional or aesthetic damage. In laBCC, neoadjuvant administration of vismodegib, an inhibitor of the Hedgehog signaling pathway, may reduce tumor size, facilitate resection, and reduce functional and aesthetic consequences of surgery. The VISMONEO study assessed efficacy and safety of vismodegib in neoadjuvant treatment of laBCC.
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Citation Excerpt :
The majority of these mutations are UVB-induced, with 1 study showing 75.7% of mutations in coding DNA with a “UV signature mutation”—cyclobutane dimer formation attributed to UVB radiation.76-78 Nearly all BCCs show constitutive activation of Hedgehog signaling pathway (Hh), and several animal models have shown that amplified Hh is alone sufficient for tumorigenesis (Fig 7).79,80 Via its effector protein sonic hedgehog (SHH), the Hh pathway is critical for neural, musculoskeletal, hematopoietic, and skin development by governing embryonic development and adult tissue homeostasis, as well as regulating cell type differentiation, patterning, and proliferation.79
As the most common human cancer worldwide and continuing to increase in incidence, basal cell carcinoma is associated with significant morbidity and cost. Continued advances in research have refined both our insight and approach to this seemingly ubiquitous disease. This 2-part continuing medical education article will provide a comprehensive and contemporary review of basal cell carcinoma. The first article in this series describes our current understanding of this disease regarding epidemiology, cost, clinical and histopathologic presentations, carcinogenesis, natural history, and disease associations.

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Mini-reviewSonic hedgehog signaling in basal cell carcinomas

Abstract

Introduction

Section snippets

Basal cell carcinomas

SHH signaling

Activation of the SHH signaling pathway in BCC

Sonic hedgehog

SHH signaling and BCC in mouse models

Towards a therapy for BCC

Conclusions

Acknowledgements

Curr. Top. Dev. Biol.

Cell

Mech. Dev.

Dermatol. Clin.

Trends Cell. Biol.

Curr. Opin. Genet. Dev.

Biochimie

Biochimie

Int. J. Oral Maxillofac. Surg.

Lancet

Cell

Cell

Eur. J. Cancer

Cell

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

Dev. Biol.

J. Invest. Dermatol.

Mutat. Res.

Gli and hedgehog in cancer: tumours, embryos and stem cells

Nat. Rev. Cancer

Hedgehog–Gli signalling and the growth of the brain

Nat. Rev. Neurosci.

Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly

Nat. Genet.

Mutations in the human Sonic Hedgehog gene cause holoprosencephaly

Nat. Genet.

Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours

Nature

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Nature

Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer

Nature

Basal cell carcinoma

Br Med J

How nucleotide excision repair protects against cancer

Nat. Rev. Cancer

High mutation frequency in ras genes of skin tumors isolated from DNA repair deficient xeroderma pigmentosum patients

Cancer Res.

Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients

Cancer Res.

Functional analysis of novel sonic hedgehog gene mutations identified in basal cell carcinomas from xeroderma pigmentosum patients

Cancer Res.

Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients

Proc. Natl Acad. Sci. USA

High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum

Proc. Natl Acad. Sci. USA

Association between INK4a-ARF and p53 mutations in skin carcinomas of xeroderma pigmentosum patients

J. Natl Cancer Inst.

Human homolog of patched, a candidate gene for the basal cell nevus syndrome

Science

Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis

Cancer Res.

Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours

Oncogene

The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas

Nat. Genet.

The product of hedgehog autoproteolytic cleavage active in local and long-range signalling

Nature

Cholesterol modification of hedgehog signaling proteins in animal development

Science

Novel lipid modifications of secreted protein signals

Annu. Rev. Biochem.

A freely diffusible form of Sonic hedgehog mediates long-range signalling

Nature

Cerebellar proteoglycans regulate sonic hedgehog responses during development

Development

Mini-review
Sonic hedgehog signaling in basal cell carcinomas