Molecular Pathogenesis of Squamous Cell Carcinoma

  • Ingo Nindl
  • Frank Rösl
Part of the Cancer Treatment and Research book series (CTAR, volume 146)

Nonmelanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC), Bowen’s disease, cutaneous squamous cell carcinoma (SCC), and its early-stage actinic keratosis (AK), is the most frequent malignancy among populations of European origin [1,2]. Cutaneous SCC accounts for 10% to 20% of all skin malignancies and is the second most common skin cancer after BCC. Epidermal keratinocytes from the suprabasal layer are the origin of this cancer. The major risk factor is ultraviolet radiation (UV), and multiple factors result in the development of this disease. SCC are invasive tumours whose cells histologically appear like differentiated suprabasal keratinocytes, and approximately 3% metastasise. It grows faster than BCC and produces a more indurated, hyperkeratotic lesion with ulceration. Cutaneous SCC frequently occurs as multiple primary tumours in the same skin area (“field”) in proximity to each other and is termed field cancerisation [3].


Squamous Cell Carcinoma Skin Cancer Basal Cell Carcinoma Actinic Keratosis Cutaneous Squamous Cell Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988; 1:795–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003; 348:1681–91.PubMedCrossRefGoogle Scholar
  3. 3.
    Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6:963–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B 2001; 63:8–18.PubMedCrossRefGoogle Scholar
  5. 5.
    Erb P, Ji J, Wernli M et al. Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunol Lett 2005; 100:68–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Ziegler A, Jonason AS, Leffell DJ et al. Sunburn and p53 in the onset of skin cancer. Nature 1994; 372:773–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Soufir N, Moles JP, Vilmer C et al. P16 UV mutations in human skin epithelial tumors. Oncogene 1999; 18:5477–81.PubMedCrossRefGoogle Scholar
  8. 8.
    Kreimer-Erlacher H, Seidl H, Bäck B et al. High frequency of ultraviolet mutations at the INK4a-ARF locus in squamous cell carcinomas from psoralen-plus-ultraviolet-A-treated psoriasis patients. J Invest Dermatol 2003; 120:676–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Saridaki Z, Liloglou T, Zafiropoulos A et al. Mutational analysis of CDKN2A genes in patients with squamous cell carcinoma of the skin. Br J Dermatol 2003; 148:638–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Brown VL, Harwood CA, Crook T et al. p16 and p14 tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma. J Invest Dermatol 2004; 122:1284–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Ananthaswamy HN, Pierceall WE. Molecular alterations in human skin tumors. Prog Clin Biol Res 1992; 376:61–84.PubMedGoogle Scholar
  12. 12.
    Popp S, Waltering S, Herbst C et al. UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas. Int J Cancer 2002; 99:352–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Boukamp P. Non-melanoma skin cancer: what drives tumor development and progression? Carcinogenesis 2005; 26:1657–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001; 344:975–83.PubMedCrossRefGoogle Scholar
  15. 15.
    Pierceall WE, Goldberg LH, Tainsky MA et al. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog 1991; 4:196–202.PubMedCrossRefGoogle Scholar
  16. 16.
    Corominas M, Kamino H, Leon J et al. Oncogene activation in human benign tumors of the skin (keratoacanthomas): is HRAS involved in differentiation as well as proliferation? Proc Natl Acad Sci U S A 1989; 86:6372–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Spencer JM, Kahn SM, Jiang W et al. Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas. Arch Dermatol 1995; 131:796–800.PubMedCrossRefGoogle Scholar
  18. 18.
    Dooley TP, Reddy SP, Wilborn TW et al. Biomarkers of human cutaneous squamous cell carcinoma from tissues and cell lines identified by DNA microarrays and qRT-PCR. Biochem Biophys Res Commun 2003; 306:1026–36.PubMedCrossRefGoogle Scholar
  19. 19.
    Tilli CM, Ramaekers FC, Broers JL et al. Lamin expression in normal human skin, actinic keratosis, squamous cell carcinoma and basal cell carcinoma. Br J Dermatol 2003; 148:102–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Nindl I, Dang C, Forschner T et al. Identification of differentially expressed genes in cutaneous squamous cell carcinoma by microarray expression profiling. Mol Cancer 2006; 5:30.PubMedCrossRefGoogle Scholar
  21. 21.
    Dang C, Gottschling M, Roewert J et al. Tenascin-C patterns and splice variants in actinic keratosis and cutaneous squamous cell carcinoma. Br J Dermatol 2006; 155:763–70.PubMedCrossRefGoogle Scholar
  22. 22.
    Going JJ. Epithelial carcinogenesis: challenging monoclonality. J Pathol 2003; 200:1–3.PubMedCrossRefGoogle Scholar
  23. 23.
    Glick A, Ryscavage A, Perez-Lorenzo R et al. The high-risk benign tumor: evidence from the two-stage skin cancer model and relevance for human cancer. Mol Carcinog 2007; 46:605–10.PubMedCrossRefGoogle Scholar
  24. 24.
    Balmain A, Harris CC. Carcinogenesis in mouse and human cells: parallels and paradoxes. Carcinogenesis 2000; 21:371–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Wu X, Pandolfi PP. Mouse models for multistep tumorigenesis. Trends Cell Biol 2001; 11:S2–S9.PubMedGoogle Scholar
  26. 26.
    Kemp CJ. Multistep skin cancer in mice as a model to study the evolution of cancer cells. Semin Cancer Biol 2005; 15:460–73.PubMedCrossRefGoogle Scholar
  27. 27.
    DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther 1992; 54:63–128.PubMedCrossRefGoogle Scholar
  28. 28.
    Brown K, Quintanilla M, Ramsden M et al. v-ras genes from Harvey and BALB murine sarcoma viruses can act as initiators of two-stage mouse skin carcinogenesis. Cell 1986; 46:447–56.PubMedCrossRefGoogle Scholar
  29. 29.
    Zoumpourlis V, Solakidi S, Papathoma A et al. Alterations in signal transduction pathways implicated in tumour progression during multistage mouse skin carcinogenesis. Carcinogenesis 2003; 24:1159–65.PubMedCrossRefGoogle Scholar
  30. 30.
    Darwiche N, Ryscavage A, Perez-Lorenzo R et al. Expression profile of skin papillomas with high cancer risk displays a unique genetic signature that clusters with squamous cell carcinomas and predicts risk for malignant conversion. Oncogene 2007; 26:6885–95.PubMedCrossRefGoogle Scholar
  31. 31.
    Schaeffer HJ, Weber MJ. Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 1999; 19:2435–44.PubMedGoogle Scholar
  32. 32.
    Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991; 1072:129–57.PubMedGoogle Scholar
  33. 33.
    Rutberg SE, Saez E, Lo S et al. Opposing activities of c-Fos and Fra-2 on AP-1 regulated transcriptional activity in mouse keratinocytes induced to differentiate by calcium and phorbol esters. Oncogene 1997; 15:1337–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Rutberg SE, Adams TL, Glick A et al. Activator protein 1 transcription factors are fundamental to v-ras-Ha-induced changes in gene expression in neoplastic keratinocytes. Cancer Res 2000; 60:6332–8.PubMedGoogle Scholar
  35. 35.
    Young MR, Li JJ, Rincon M et al. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA 1999; 96:9827–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Gerdes MJ, Myakishev M, Frost NA et al. Activator protein-1 activity regulates epithelial tumor cell identity. Cancer Res 2006; 66:7578–88.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Ingo Nindl
    • 1
  • Frank Rösl
    • 2
  1. 1.Charité Cooperation, Viral Skin Carcinogenesis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 24269120 HeidelbergGermany
  2. 2.Division Viral Transformation MechanismGerman Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 HeidelbergGermany

Personalised recommendations