Basal cell carcinoma (BCC) is the most frequent cancer among the white population, representing 75% of all skin cancers [1]. The incidence of BCC cases is increasing, probably because of changes of leisure activities and migration to regions with higher solar radiation. BCCs rarely metastasize (<0.1%), and mortality rates are low; however, some tumors grow aggressively and may cause extensive tissue damage. Aggressive growth of BCC correlates with histological subtypes. Nodular and superficial BCC, representing 60% and 25% of all BCC, respectively, are usually considered less aggressive than morpheaform, infiltrative, micronodular, and metatypic BCC, which are associated with a higher rate of local recurrences [2, 3]. Several risk factors for the development of BCC have been described, which include physical characteristics, exposures to environmental carcinogens, immunosuppression, and genetic predisposition. Other genetic changes, acquired subsequently and affecting cell proliferation and apoptosis, may also be involved in tumorigenesis. In the following sections, some recently identified molecular mechanisms are described that are involved in BCC development and which potentially represent targets of new pharmacologic treatment modalities.
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References
Marks R (1995) An overview of skin cancers: incidence and causation. Cancer (Phila) 75:607–612.
Jacobs GH, Rippey JJ, Altini M (1982) Prediction of aggressive behaviour in basal cell carcinoma. Cancer (Phila) 49:533–537.
Batra RS, Kelly JC (2002) Predictors of extensive subclinical spread in nonmelanoma skin cancer treated with Mohs micrographic surgery. Arch Dermatol 138:1043–1051.
Gallagher RP, Hill GB, Bajdik CD et al. (1995) Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol 131:157–163.
Rubin AI, Chen EH, Ratner D (2005) Basal cell carcinoma. N Engl J Med 353:2262–2269.
Euvrard S, Kanitakis J, Claudy A (2003) Skin cancers after organ transplantation. N Engl J Med 348: 1681–1691.
Shamanin V, zur Hausen H, Lavergne D et al. (1996) Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients. J Natl Cancer Inst 88:802–811.
Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T (2004) Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg 30:604–609.
Wieland U, Ritzkowsky A, Stoltidis M et al. (2000) Papillomavirus DNA in basal cell carcinomas of immunocompetent patients: an accidental association? J Invest Dermatol 115:124–128.
Caldeira S, Zehbe I, Accardi R et al. (2003) The E6 and E7 proteins of the cutaneous human papillomavirus type 38 display transforming properties. J Virol 77:2195–2206.
Jackson S, Harwood C, Thomas M et al. (2000) Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 14:3065–3073.
Flanagan N, Healy E, Ray A et al. (2000) Pleiotropic effects of the melanocortin-1 receptor (MC1R) gene on human pigmentation. Hum Mol Genet 9:2531–2537.
Landi MT, Kanetsky PA, Tsang S et al. (2005) MC1R, ASIP, and DNA repair in sporadic and familial melanoma in a Mediterranean population. J Natl Cancer Inst 97:998–1007.
Liboutet M, Portela M, Delestaing G et al. (2006) MC1R and PTCH gene polymorphism in French patients with basal cell carcinoma. J Invest Dermatol 126:1510–1517.
Griffith HR, Mistry P, Herbert KE et al. (1998) Molecular and cellular effects of ultraviolet light-induced genotoxicity. Crit Rev Clin Lab Sci 35:189–237.
Raza H, Awashi YC, Zaim MT et al. (1991) Glutathione S-transferases in human and rodent skin. J Invest Dermatol 96:463–467.
Kerb B, Brockmöller J, Reum T, Roots I (1997) Deficiency of glutathione S-transferases T1 and M1 as heritable factors of increased cutaneous UV sensitivity. J Invest Dermatol 108:229–232.
Yengl I, Inskip A, Gilford J et al. (1996) Polymorphism at the glutathione S-transferase locus GSTM3: interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple basal cell carcinomas. Cancer Res 56:1974–1977.
Lear JT, Heagerty AHM, Smith A et al. (1996) Multiple cutaneous basal cell carcinomas: glutathione S-transferases (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) polymorphisms influence tumour numbers and accrual. Carcinogenesis (Oxf) 17:1891–1896.
Ramachandran S, Lear JT, Ramsey H et al (1999) Presentation with multiple basal cell carcinomas: association with glutathione S-transferase and cytochrome P450 genotypes with clinical phenotypes. Cancer Epidemiol Biomarkers Prev 8: 61–67.
Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum. Nature (Lond) 218:652–656.
Sarasin A (1999) The molecular pathways of ultraviolet-induced carcinogenesis. Mutat Res 428: 5–10.
Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 11:1513–1530.
Vogel U, Hedayati M, Dybdahl M, Grossmann L, Nexo BA (2001) Polymorphismsm of the DNA repair gene XPD: correlations with risk of basal cell carcinoma revisited. Carcinogenesis (Oxf) 22:899–904.
Vogel U, Olesen A, Wallin H, Overad K, Tjonneland A, Nexo BA (2005) Effect of polymorphisms in XPD, RAI, ASE-1 and ERCC1 on the risk of basal cell carcinoma among Caucasians after age of 50. Cancer Detect Prev 29:209–214.
Lovatt T, Alldersea J, Lear JT et al. (2005) Polymorphisms in the nuclear excision repair gene ERCC2/XPD: association between an exon 6-exon 10 haplotype and susceptibility to cutaneous basal cell carcinoma. Hum Mutat 25:353–359.
Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature (Lond) 411:366–374.
Kimonis VE, Goldstein AM, Pastakia B et al. (1997) Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 69:299–308.
Farndon PA, Del Mastro RG, Evans DGR et al (1992) Location of gene for gorlin syndrome. Lancet 339:581–582.
Reis A, Kuster W, Linss G et al. (1992) Location of gene for nevoid basal cell carcinoma syndrome. Lancet 339: 617.
Hahn H, Wicking C, Zaphiropoulos PG et al. (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841–851.
Johnson RL, Rothmann AL, Xie J et al. (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1771.
Wicking C, Smyth I, Bale A (1999) The hedgehog signalling pathway in tumorigenesis and development. Oncogene 18:7844–7851.
Ho KS, Scott MP (2002) Sonic hedgehog in the nervous system: functions, modifications and mechanisms. Curr Opin Neurobiol 12: 57–63.
Boukamp P (2005) Non-melanoma skin cancer: what drives tumor development and progression. Carcinogenesis (Oxf) 26:1657–1667.
Ingham PW, McMahon AP (2001) Hedgehog signalling in animal development: paradigms and principles. Genes Dev 15:3059–3087.
Ruiz I Altaba, A, Sanchez P, Dahmane N (2002) Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2:361–372.
Tilli CMLJ, van Steensel MAM, Krekels GAM et al. (2005) Molecular aetiology and pathogenesis of basal cell carcinoma. Br J Dermatol 152:1108–1124.
Jih DM, Lyle S, Elenitsas R et al (1999) Cytokeratin 15 expression in trichoepitheliomas and a subset of basal cell carcinomas suggests they originate from hair follicle stem cells. J Cutan Pathol 26:113–118.
Pasca di Magliano M, Hebrok M (2003) Hedgehog signaling in cancer formation and maintenance. Nat Rev Cancer 3:903–911.
Kasper M, Regl G, Frischauf AM, Aberger F (2006) GLI transcription factors: mediators of oncogenic hedgehog signaling. Eur J Cancer 42:437–445.
Kalderon D (2004) Hedgehog signaling: costal-2 bridges the transduction gap. Curr Biol 14:R67–R69.
Callahan CA, Ofstad T, Horng L (2004) MIM/BEG4, a sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev 18:2724–2729.
Kinzler KW, Vogelstein B (1990) The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol 10:634–642.
Sasaki H, Nishizaki Y, Hui C et al. (1999) Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of SHH signaling. Development (Camb) 126:3915–3924.
Altaba AR (1999) Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development (Camb) 126:3205–3216.
Cohen MM Jr (2003) The hedgehog signaling network. Am J Med Genet 123A: 5–23.
Regl G, Kasper M, Schnidar H et al. (2004) Activation of the BCL2 promoter in response to hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res 64:7724–7731.
Eichberger T, Regl G, Ikram MS et al. (2004) FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. J Invest Dermatol 122:1180–1187.
Regl G, Kasper M, Schnidar H et al. (2004) The zinc-finger transcription factor GLI-2 antagonizes contact inhibition and differentiation in human epidermal cells. Oncogene 23:1263–1274.
Yoon JW, Kita Y, Frank DJ et al. (2002) Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 277:5548–5555.
Eichberger T, Sander V, Schnidar H et al. (2006) Overlapping and distinct transcriptional regulator properties of the GLI1 and GLI2 oncogenes. Genomics 87:616–632.
Kaufmann E, Knochel W (1996) Five years on the wings of fork head. Mech Dev 57: 3–20.
Wu SC, Grindly J, Winnier GE et al. (1998) Mouse mesenchyme forkhead 2 (Mf2) expression, DNA binding and induction by sonic hedgehog during somitogenesis. Mech Dev 70: 3–13.
Mahlapuu M, Enerback S, Carlsson P (2001) Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling causes lung and foregut malformations. Development (Camb) 128:2397–2406.
Ye H, Holterman AX, Yoo KW et al. (1999) Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S-phase. Mol Cell Biol 19:8570–8580.
Wang X, Hung NJ, Costa RH (2001) Earlier expression of the transcription factor HFH-11B diminishes induction of p21 (CIP1/WAF1) levels and accelerates mouse hepatocyte entry into S-phase following carbon tetrachloride liver injury. Hepatology 33:1404–1414.
Teh MT, Wong ST, Neill GW et al. (2002) FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res 62:4773–4780.
Crawson AN (2006) Basal cell carcinoma: biology, morphology, and clinical implications. Mod Pathol 19:S127–S147.
Karhadkar SS, Bova GS, Abdallah N et al. (2004) Hedgehog signaling in prostate regeneration, neoplasia, and metastasis. Nature (Lond) 431:707–712.
Tseng H, Green H (1994) Association of basonuclin with ability of keratinocytes to multiply and with absence of terminal differentiation. J Biol Chem 126:495–506.
Chiang C, Swan RZ, Grachtchouk M et al. (1999) Essential role for sonic hedgehog during hair follicle morphogenesis. Dev Biol 205: 1–9.
Hahn H, Wojnowski L, Zimmer AM et al. (1998) Rhabdomyosarkomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med 4:619–622.
Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113.
Berman DM, Karhadkar SS, Maitra A et al. (2003) Widespread requirements for hedgehog ligand stimulation in growth of digestive tract tumors. Nature (Lond) 425:846–851.
Watkins DN, Berman DM, Burkholder SG et al. (2003) hedgehog signaling within airway epithelial progenitors and small-cell lung cancer. Nature (Lond) 422:313–317.
Thayer SP, di Magliano MP, Heiser PW et al. (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature (Lond) 425:851–856.
Wicking C, McGlin E (2001) The role of hedgehog signaling in tumorigenesis. Cancer Lett 173: 1–7.
Gailani MR, Stahle-Backdahl M, Leffell DJ et al. (1996) The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 14: 78–81.
Kim MY, Park HJ, Baek SC et al. (2002) Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias. J Dermatol Sci 29: 1–9.
Reifenberger J, Wolter M, Knobbe BC et al. (2005) Somatic mutations in the PTCH, SMOH, SUFUH, and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 152:43–51.
Xie J, Murone M, Luoh SM et al. (1998) Activating smoothened mutations in sporadic basal cell carcinoma. Nature (Lond) 391: 90–92.
Dahmane N, Lee J, Robins P et al. (1997) Activation of the transcription factor Gli1 and the sonic hedgehog signalling pathway in skin tumours. Nature (Lond) 389:876–881.
Ghali l, Wong ST, Green J et al. (1999) Gli protein is expressed in basal cell carcinomas, outer root sheath keratinocytes and a subpopulation of mesenchymal cells in normal human skin. J Invest Dermatol 113:595–599.
Green J, Leigh IM, Poulsom R, Quinn AG (1998) Basal cell carcinoma development is associated with induction of the expression of the transcription factor Gli-1. Br J Dermatol 139:911–915.
Nilsson M, Unden AB, Krause D et al. (2000) Induction of basal cell carcinoma and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci U S A 97:3438–3443.
Couve-Pirat S, Le Bret M, Traiffort E et al. (2004) Functional analysis of novel sonic hedgehog gene mutations identified in basal cell carcinomas from xeroderma pigmentosum patients. Cancer Res 64:3559–3565.
Cui C, Elsam T, Tian Q et al. (2004) Gli proteins up-regulate the expression basonuclin in basal cell carcinomas. Cancer Res 64:5651–5658.
Ruggero D, Pandolfi PP (2003) Does the ribosome translate cancer? Nat Rev Cancer 3:179–192.
Louro ID, Bailey EC, Li X et al (2002) Comparative gene expression profile analysis of GLI and c-myc in an epithelial model of malignant transformation. Cancer Res 62:5867–5873.
Grachtchouk M, Mo R, Yu S et al. (2000) Basal cell carcinoma in mice overexpressing Gli-2 in skin. Nat Genet 24:216–217.
Ziegler A, Leffell DJ, Kunala S et al. (1993) Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancer. Proc Natl Acad Sci USA 90:4216–4220.
Giglia-Mari G, Sarasin A (2003) TP 53 mutations in human skin cancers. Hum Mutat 21:217–228.
Chan TA, Hermeking A, Lengauer C et al. (1999) 14-3-3sigma is required to prevent mitotic catastrophe after DNA damage. Nature (Lond) 401:616–620.
Lodygin D, Yazdi AS, Sander CA et al. (2003) Analysis of 14-3-3sigma expression in hyperproliferative skin diseases reveals selective loss associated with CpG-methylation in basal cell carcinoma. Oncogene 22:5519–5524.
Campbell C, Quinn AG, Rees JL (1993) Codon 12 Harvey-ras mutations are rare events in non-melanoma human skin cancer. Br J Dermatol 128:111–114.
Soufir N, Moles JP, Vilmer C et al. (1999) p16 UV mutations in human skin epithelial tumors. Oncogene 18:5477–5481.
Saridaki Z, Koumantaki E, Liloglou T et al. (2000) High frequency of loss of heterozygosity on chromosome region 9p21-p22 but lack of p16INK4a/p19ARF mutations in Greek patients with basal cell carcinoma of the skin. J Invest Dermatol 115:719–725.
Svensson S, Nilsson K, Ringberg A, Landberg G (2003) Invade or proliferate? Two contrasting events in malignant behaviour governed by p16INK4a and an intact pRB pathway illustrated by a model system of basal cell carcinoma. Cancer Res 63:1737–1742.
Brown VL, Harwood CA, Crook T et al. (2004) p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma. J Invest Dermatol 122:1284–1292.
Hodges A, Smoller BR (2002) Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin. Mod Pathol 15:1121–1125.
Hollstein M, Sidransky D, Vogelstein B et al. (1991) p53 mutations in human cancers. Science 253: 49–53.
Caspari T (2000) How to activate p53. Curr Biol 10:315–317.
Vogt Sionov RV, Haupt Y (1999) The cellular response to p53: the decision between life and death. Oncogene 18:6145–6157.
Auepemkiate S, Boonyaphiphat P, Thongsuksai P (2002) p53 expression related to the aggressive infiltrative histopathological feature of basal cell carcinoma. Histopathology (Oxf) 40:568–573.
De Rosa G, Saibano S, Barra E et al. (1993) p53 protein in aggressive and non-aggressive basal cell carcinoma. J Cutan Pathol 20:429–434.
Crawson AN, Margo CM, Kadin M et al. (1996) Differential expression of BCL-2 oncogene in human basal cell carcinoma. Hum Pathol 27:355–359.
Abdelsayed RA, Guijarro-Rojas M, Ibrahim NA et al. (2000) Immunohistochemical evaluation of basal cell carcinoma and trichoepithelioma using Bcl-2, Ki67, PCNA, and p53. J Cutan Pathol 28:538–541.
Baum HP, Meurer I, Unteregger G (1993) Ki-67 antigen expression and growth pattern of basal cell carcinoma. Arch Dermatol Res 285:291–295.
Mooney EE, Ruis Peris JM, O’Neill A, Sweeney EC (1995) Apoptotic and mitotic indices in malignant melanoma and basal cell carcinoma. J Clin Pathol 48:242–244.
Tabs S, Avci O (2004) Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur J Dermatol 14:96–102.
Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of hedgehog signalling by direct binding of cyclopamine to smoothened. Genes Dev 16:2743–2748.
Hutchin ME, Kariapper MS, Grachtchouk M et al. (2005) Sustained hedgehog signalling is required for basal cell carcinoma proliferation and survival: conditional skin tumourigensis recapitulates the hair growth cycle. Genes Dev 19:214–223.
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Meyer, T. (2009). Molecular Pathogenesis of Basal Cell Carcinoma. In: Stockfleth, E., Ulrich, C. (eds) Skin Cancer after Organ Transplantation. Cancer Treatment and Research, vol 146. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-78574-5_17
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