CAPÍTULO II: MARCO TEÓRICO
2.2. PRINCIPIOS QUE SE DEBEN TENER EN CUENTA AL MOMENTO DE
1. de Vries, E., van de Poll‐Franse, L.V., Louwman, W.J., de Gruijl, F.R. & Coebergh, J.W. Predictions of skin cancer incidence in the Netherlands up to 2015. Br.J.Dermatol. 152, 481‐488 (2005).
2. Staples, M.P. et al. Non‐melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med.J.Aust. 184, 6‐10 (2006).
3. Bouwes Bavinck, J.N. et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow‐up study.
Transplantation 61, 715‐721 (1996). 4. Atillasoy, E.S., Elenitsas, R., Sauter, E.R.,
Soballe, P.W. & Herlyn, M. UVB induction of epithelial tumors in human skin using a RAG‐1 mouse xenograft model. J.Invest Dermatol.
109, 704‐709 (1997).
5. Brown, K. & Balmain, A. Transgenic mice and squamous multistage skin carcinogenesis.
Cancer Metastasis Rev. 14, 113‐124 (1995). 6. Dajee, M. et al. NF‐kappaB blockade and
oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639‐643 (2003).
7. Eicher, S.A. et al. Evaluation of topical gene therapy for head and neck squamous cell carcinoma in an organotypic model.
Clin.Cancer Res. 2, 1659‐1664 (1996). 8. Slaga, T.J., Budunova, I.V., Gimenez‐Conti, I.B.
& Aldaz, C.M. The mouse skin carcinogenesis model. J.Investig.Dermatol.Symp.Proc. 1, 151‐ 156 (1996).
9. Gupta, A., Rosenberger, S.F. & Bowden, G.T. Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed mouse keratinocyte cell lines. Carcinogenesis 20, 2063‐2073 (1999).
10. Popp, S. et al. Genetic characterization of a human skin carcinoma progression model: from primary tumor to metastasis. J.Invest
Dermatol. 115, 1095‐1103 (2000). 11. Proby, C.M. et al. Spontaneous keratinocyte
cell lines representing early and advanced stages of malignant transformation of the epidermis. Exp.Dermatol. 9, 104‐117 (2000). 12. El Ghalbzouri, A., Lamme, E. & Ponec, M.
Crucial role of fibroblasts in regulating epidermal morphogenesis. Cell Tissue Res.
310, 189‐199 (2002).
13. Ponec, M. et al. The formation of competent barrier lipids in reconstructed human epidermis requires the presence of vitamin C.
J Invest Dermatol 109, 348‐55 (1997).
14. El Ghalbzouri, A., Jonkman, M., Kempenaar, J. & Ponec, M. Recessive epidermolysis bullosa simplex phenotype reproduced in vitro: ablation of keratin 14 is partially compensated by keratin 17. Am.J.Pathol. 163, 1771‐1779 (2003).
15. Rheinwald, J.G. & Beckett, M.A. Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell 22, 629‐ 632 (1980).
16. El Ghalbzouri, A. et al. Fibroblasts facilitate re‐ epithelialization in wounded human skin equivalents. Lab Invest 84, 102‐112 (2004). 17. Smola, H., Thiekotter, G. & Fusenig, N.E.
Mutual induction of growth factor gene expression by epidermal‐dermal cell interaction. J Cell Biol 122, 417‐29 (1993). 18. Bloor, B.K., Seddon, S.V. & Morgan, P.R. Gene
expression of differentiation‐specific keratins in oral epithelial dysplasia and squamous cell carcinoma. Oral Oncol. 37, 251‐261 (2001). 19. Freedberg, I.M., Tomic‐Canic, M., Komine, M.
& Blumenberg, M. Keratins and the keratinocyte activation cycle. J.Invest
Dermatol. 116, 633‐640 (2001).
20. Moll, R., Franke, W.W., Schiller, D.L., Geiger, B. & Krepler, R. The catalog of human
cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31, 11‐24 (1982).
21. Smits, T. et al. Aneuploidy and proliferation in keratinocytic intraepidermal neoplasias.
Exp.Dermatol. 16, 81‐86 (2007). 22. Yoshikawa, K., Katagata, Y. & Kondo, S.
Relative amounts of keratin 17 are higher than those of keratin 16 in hair‐follicle‐derived tumors in comparison with nonfollicular epithelial skin tumors. J.Invest Dermatol. 104, 396‐400 (1995).
23. Richard, G., De, L.V., Didona, B., Bale, S.J. & Compton, J.G. Keratin 13 point mutation underlies the hereditary mucosal epithelial disorder white sponge nevus. Nat.Genet. 11, 453‐455 (1995).
24. Murphy, G.F., Flynn, T.C., Rice, R.H. & Pinkus, G.S. Involucrin expression in normal and neoplastic human skin: a marker for
keratinocyte differentiation. J.Invest Dermatol.
82, 453‐457 (1984).
25. Said, J.W., Sassoon, A.F., Shintaku, I.P. & Banks‐Schlegel, S. Involucrin in squamous and basal cell carcinomas of the skin: an immunohistochemical study. J.Invest
2
26. Kalinin, A.E., Kajava, A.V. & Steinert, P.M. Epithelial barrier function: assembly and structural features of the cornified cell envelope. Bioessays 24, 789‐800 (2002). 27. Gaggioli, C. et al. Fibroblast‐led collective
invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells.
Nat.Cell Biol. 9, 1392‐1400 (2007). 28. Merker, H.J. Morphology of the basement
membrane. Microsc.Res.Tech. 28, 95‐124 (1994).
29. Timpl, R. Macromolecular organization of basement membranes. Curr.Opin.Cell Biol. 8, 618‐624 (1996).
30. Oguro, K. et al. Immunohistochemical alterations in basement membrane components of squamous cell carcinoma.
J.Invest Dermatol. 96, 250‐254 (1991). 31. Tsuboi, R. et al. Comparison of proteinase
activities in squamous cell carcinoma, basal cell epithelioma, and seborrheic keratosis.
J.Invest Dermatol. 90, 869‐872 (1988). 32. Liotta, L.A. et al. Metastatic potential
correlates with enzymatic degradation of basement membrane collagen. Nature 284, 67‐68 (1980).
33. Chang, C. & Werb, Z. The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol.
11, S37‐S43 (2001).
34. Waterman, E.A. et al. A laminin‐collagen complex drives human epidermal carcinogenesis through phosphoinositol‐3‐ kinase activation. Cancer Res. 67, 4264‐4270 (2007).
35. Marinkovich, M.P. Tumour microenvironment: laminin 332 in squamous‐cell carcinoma.
Nat.Rev.Cancer 7, 370‐380 (2007).
36. Friedl, P. & Wolf, K. Tumour‐cell invasion and migration: diversity and escape mechanisms.
Nat.Rev.Cancer 3, 362‐374 (2003). 37. Janes, S.M. & Watt, F.M. New roles for
integrins in squamous‐cell carcinoma.
Nat.Rev.Cancer 6, 175‐183 (2006). 38. Ortiz‐Urda, S. et al. Type VII collagen is
required for Ras‐driven human epidermal tumorigenesis. Science 307, 1773‐1776 (2005). 39. Rodeck, U., Fertala, A. & Uitto, J. Anchorless
keratinocyte survival: an emerging pathogenic mechanism for squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.
Exp.Dermatol. 16, 465‐467 (2007). 40. Green, J. et al. Overexpression of the Axl
tyrosine kinase receptor in cutaneous SCC‐ derived cell lines and tumours. Br.J.Cancer 94, 1446‐1451 (2006).
41. Loercher, A. et al. Nuclear factor‐kappaB is an important modulator of the altered gene
expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. 64, 6511‐6523 (2004).
42. Papadakis, E., Vyas, J.J. & O'Toole, E.A. A role for the Receptor Tyrosine Kinase, Axl, in Cutaneous Squamous Cell Carcinoma Survival
J.Invest Dermatol. 127, Abstract 571 (2007).
Functional characterization of
cancer‐associated fibroblasts of
human cutaneous squamous cell
carcinoma
Suzan Commandeur, Suet Huy Ho, Frank R. de Gruijl, Rein Willemze, Cornelis P. Tensen and Abdoelwaheb El Ghalbzouri Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands Experimental Dermatology 2011;20(9):737‐742
3
Abstract
Cutaneous squamous cell carcinoma (SCC) is the second most common type of skin cancer
in the Caucasian population worldwide, having a propensity for invasion, local recurrence
and metastasis. Stromal cancer‐associated fibroblasts (CAFs) are suspected to play an
important role in SCC carcinogenesis. In this study, we characterized CAFs isolated from
primary cutaneous SCCs and compared them to normal fibroblasts (NFs) isolated from
healthy dermis. Human skin CAFs in monolayers displayed different morphology,
increased proliferation and migration compared to NFs. CAFs caused strong contraction of
collagen matrices in which they were seeded and released high levels of the extracellular
matrix component pro‐collagen I. CAFs decreased proliferation and differentiation in the
epidermis of human skin equivalents (HSEs) seeded with SCC cell lines, without affecting
basement membrane composition. Finally, CAFs significantly increased invasion and
dermal‐epidermal detachment of SCC cell lines SCC‐12B2 and SCC‐13, respectively, when
cultured in HSEs. These distinct features of CAFs point out a specific role in cutaneous SCC