Skip to main content

Notch-Signaling and Nonmelanoma Skin Cancer: An Ancient Friend, Revisited

  • Chapter
Notch Signaling in Embryology and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 727))

Abstract

In humans and other species, Notch-signaling is of critical importance for carcinogenesis in several organs, including the skin. Interestingly, Notch-signaling appears to exert opposite roles in skin carcinogenesis as compared to carcinogenesis in other tissues. While the Notch1 receptor (Notch1) acts as a proto-oncogene in most tissues, it has been shown that Notch1 deletion in epidermal keratinocytes causes skin carcinogenesis. Recent results indicate that loss of Notch1 is not involved in the initiating event of multistage skin carcinogenesis, but acts as a skin cancer-promoting event. Moreover, recent findings underline the importance of multiple other factors, including the microenvironment, for Notch signaling in skin carcinogenesis. It can be speculated that pharmacologic modulation of Notch signaling may be an interesting target for the prevention and therapy of skin cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999; 284:770–776.

    Article  PubMed  CAS  Google Scholar 

  2. Kolev V, Mandinova A, Guinea-Viniegra J et al. EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nat Cell Biol 2008; 10(8):902–911.

    Article  PubMed  CAS  Google Scholar 

  3. Moriyama M, Durham AD, Moriyama H et al. Multiple roles of Notch signaling in the regulation of epidermal development. Dev Cell 2008; 14(4):594–604.

    Article  PubMed  CAS  Google Scholar 

  4. Lefort K, Dotto GP. Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol 2004; 14:374–386.

    Article  PubMed  CAS  Google Scholar 

  5. Rangarajan A, Talora C, Okuyama R et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 2001; 20:3427–3436.

    Article  PubMed  CAS  Google Scholar 

  6. Okuyama R, Nguyen BC, Talora C et al. High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell 2004; 6:551–562.

    Article  PubMed  CAS  Google Scholar 

  7. Lai EC. Notch signaling: control of cell communication and cell fate. Development 2004; 131:965–973.

    Article  PubMed  CAS  Google Scholar 

  8. Kadesch T. Notch signaling: the demise of elegant simplicity. Curr Opin Genet Dev 2004; 14:506–512.

    Article  PubMed  CAS  Google Scholar 

  9. Nicolas M, Wolfer A, Raj K et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 2003; 33:416–421.

    Article  PubMed  CAS  Google Scholar 

  10. Kiec-Wilk B, Grzybowska-Galuszka J, Polus A et al. The MAPK-dependent regulation of the Jagged/ Notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC. J Physiol Pharmacol 2010; 61(2):217–225.

    PubMed  CAS  Google Scholar 

  11. Zhang Y, Li B, Ji ZZ et al. Notch regulates the growth of human colon cancers. Cancer 2010; 116:5207–5218.

    Article  PubMed  CAS  Google Scholar 

  12. Wang Z, Li Y, Ahmad A et al. Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J Cell Biochem 2010; 112:78–88.

    Article  Google Scholar 

  13. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med 2005; 353:2262–2269.

    Article  PubMed  CAS  Google Scholar 

  14. Bagheri MM, Safai B. Cutaneous malignancies of keratinocytic origin. Clin Dermatol 2001; 19:244–252.

    Article  PubMed  CAS  Google Scholar 

  15. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001; 344:975–983.

    Article  PubMed  CAS  Google Scholar 

  16. Reichrath J, Nürnberg B. Solar UV-radiation, vitamin D and skin cancer surveillance in organ transplant recipients (OTRs). Adv Exp Med Biol 2008; 624:203–214.

    Article  PubMed  Google Scholar 

  17. Green CL, Khavari PA. Targets for molecular therapy of skin cancer. Semin Cancer Biol 2004; 14:63–69.

    Article  PubMed  CAS  Google Scholar 

  18. Oro AE, Higgins KM, Hu Z et al. Basal cell carcinomas in mice over expressing sonic hedgehog. Science 1997; 276:817–821.

    Article  PubMed  CAS  Google Scholar 

  19. Melnikova VO, Ananthaswamy HN. Cellular and molecular events leading to the development of skin cancer. Mutat Res 2005; 571:91–106.

    Article  PubMed  CAS  Google Scholar 

  20. Tsai KY, Tsao H. The genetics of skin cancer. Am J Med Genet C Semin Med Genet 2004; 131C:82–92.

    Article  PubMed  Google Scholar 

  21. Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev 2004; 14:48–54.

    Article  PubMed  CAS  Google Scholar 

  22. Lowell S, Jones P, Le Roux I et al. Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr Biol 2000; 10:491–500.

    Article  PubMed  CAS  Google Scholar 

  23. Lai EC. Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins. EMBO Rep 2002; 3:840–845.

    Article  PubMed  CAS  Google Scholar 

  24. Wu L, Maillard I, Nakamura M et al. The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development. Blood 2007; 110(10):3618–3623.

    Article  PubMed  CAS  Google Scholar 

  25. Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003; 194:237–255.

    Article  PubMed  CAS  Google Scholar 

  26. Thelu J, Rossio P, Favier B. Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol 2002; 2:7.

    Article  PubMed  Google Scholar 

  27. Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 2003; 3:756–767.

    Article  PubMed  CAS  Google Scholar 

  28. Massi D, Tarantini F, Franchi A et al. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Modern Pathology 2006; 19:246–254.

    Article  PubMed  CAS  Google Scholar 

  29. Pinnix CC, Herlyn M. The many faces of Notch signaling in skin-derived cells. Pigment Cell Res 2007; 20:458–465.

    Article  PubMed  CAS  Google Scholar 

  30. Wuest M, Dummer R, Urosevic M. Induction of the members of Notch pathway in superficial basal cell carcinomas treated with imiquimod. Arch Dermatol Res 2007; 299(10):493–498.

    Article  PubMed  CAS  Google Scholar 

  31. Carmody RJ, Chen YH. Nuclear factor-kappaB: activation and regulation during toll-like receptor signaling. Cell Mol Immunol 2007; 4:31–41.

    PubMed  CAS  Google Scholar 

  32. Urosevic M, Dummer R. Role of imiquimod in skin cancer treatment. Am J Clin Dermatol 2004; 5:453–458.

    Article  PubMed  Google Scholar 

  33. Urosevic M, Dummer R, Conrad C et al. Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment. J Natl Cancer Inst 2005; 97:1143–1153.

    Article  PubMed  CAS  Google Scholar 

  34. Osborne BA, Minter LM. Notch signalling during peripheral T-cell activation and differentiation. Nat Rev Immunol 2007; 7:64–75.

    Article  PubMed  CAS  Google Scholar 

  35. Koch U, Radtke F. Notch and cancer: a double-edged sword, Cell Mol Life Sci 2007; 64:2746–2762.

    Article  PubMed  CAS  Google Scholar 

  36. Demehri S, Turkoz A, Kopan R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 2009; 16(1):55–66.

    Article  PubMed  CAS  Google Scholar 

  37. Zoumpourlis V, Solakidi S, Papathoma A et al. Alterations in signal transduction pathways implicated in tumour progression during multistage mouse skin carcinogenesis, Carcinogenesis 2003; 24:1159–1165.

    Article  PubMed  CAS  Google Scholar 

  38. Weinberg WC, Fernandez-Salas E, Morgan DL et al. Genetic deletion of p21WAF1 enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis, Cancer Res 1999; 59:2050–2054.

    PubMed  CAS  Google Scholar 

  39. Lee J, Basak JM, Demehri S et al. Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes, Development 2007; 134:2795–2806.

    Article  PubMed  CAS  Google Scholar 

  40. Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type, Cell Cycle 2006; 5:1597–1601.

    Article  PubMed  CAS  Google Scholar 

  41. Vauclair S, Majo F, Durham AD et al. Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism, Dev Cell 2007; 13:242–253.

    Article  PubMed  CAS  Google Scholar 

  42. Watt FM, Estrach S, Ambler CA. Epidermal Notch signalling: differentiation, cancer and adhesion, Curr Opin Cell Biol 2008; 20:171–179.

    Article  PubMed  CAS  Google Scholar 

  43. Bissell MJ, Radisky D. Putting tumours in context, Nat Rev Cancer 2001; 1:46–54.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jörg Reichrath .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Reichrath, J., Reichrath, S. (2012). Notch-Signaling and Nonmelanoma Skin Cancer: An Ancient Friend, Revisited. In: Reichrath, J., Reichrath, S. (eds) Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology, vol 727. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0899-4_20

Download citation

Publish with us

Policies and ethics