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Epithelial stem cells, wound healing and cancer

Key Points

  • Wound healing and tumorigenesis are two processes that rely on similar molecular mechanisms. Repair of tissue injury is a self-limiting process; whereas, tumour formation is characterized by the continuous activation of the pathways involved.

  • The interplay of different cell types, such as epithelial, mesenchymal and immune cells, is of major importance in both wound repair and tumour formation. Changes in the microenvironment caused by tissue injury can permit the development of a tumour.

  • Stem cells contribute to wound healing and tumour formation. In each case, stem cells can adopt a new location that differs from their location in undamaged tissue.

  • Several crucial pathways, such as Hedgehog and WNT signalling, are deregulated in wound healing and tumorigenesis. Deregulated Hedgehog signalling is linked to the development of basal cell carcinoma; whereas, aberrant WNT signalling can result in a variety of epidermal tumours.

  • Non-dividing, differentiating and dying epithelial cells can either positively or negatively influence tumour formation.

Abstract

It is well established that tissue repair depends on stem cells and that chronic wounds predispose to tumour formation. However, the association between stem cells, wound healing and cancer is poorly understood. Lineage tracing has now shown how stem cells are mobilized to repair skin wounds and how they contribute to skin tumour development. The signalling pathways, including WNT and Hedgehog, that control stem cell behaviour during wound healing are also implicated in tumour formation. Furthermore, tumorigenesis and wound repair both depend on communication between epithelial cells, mesenchymal cells and bone marrow-derived cells. These studies suggest ways to harness stem cells for wound repair while minimizing cancer risk.

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Figure 1: Comparison of the microenvironments of a healing wound and an invading tumour margin.
Figure 2: Different stem cell compartments in adult mouse back skin.
Figure 3: WNT and Hedgehog pathways.

References

  1. Watt, F. M. & Driskell, R. R. The therapeutic potential of stem cells. Philos. Trans. R. Soc. Lond. B Biol. Sci. 365, 155–163 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gonda, T. A., Tu, S. & Wang, T. C. Chronic inflammation, the tumor microenvironment and carcinogenesis. Cell Cycle 8, 2005–2013 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Dunham, L. J. Cancer in man at site of prior benign lesion of skin or mucous membrane: a review. Cancer Res. 32, 1359–1374 (1972).

    CAS  PubMed  Google Scholar 

  4. Hartnett, L. & Egan, L. J. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis 10 Jan 2012 (doi:10.1093/carcin/bgs006).

  5. Pawlotsky, J. M. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol. 12, 96–102 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Wang, X. W. et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 181–182, 43–47 (2002).

    Article  PubMed  Google Scholar 

  7. Ruggiero, P. Helicobacter pylori and inflammation. Curr. Pharm. Des. 16, 4225–4236 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Walter, N. D. et al. Wound healing after trauma may predispose to lung cancer metastasis: review of potential mechanisms. Am. J. Respir. Cell Mol. Biol. 44, 591–596 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  10. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Shaw, T. J. & Martin, P. Wound repair at a glance. J. Cell Sci. 122, 3209–3213 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schafer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nature Rev. Mol. Cell Biol. 9, 628–638 (2008).

    Article  CAS  Google Scholar 

  13. Ortiz-Urda, S. et al. Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 307, 1773–1776 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. South, A. P. & O'Toole, E. A. Understanding the pathogenesis of recessive dystrophic epidermolysis bullosa squamous cell carcinoma. Dermatol. Clin. 28, 171–178 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Martins-Green, M., Boudreau, N. & Bissell, M. J. Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res. 54, 4334–4341 (1994).

    CAS  PubMed  Google Scholar 

  16. Dolberg, D. S., Hollingsworth, R., Hertle, M. & Bissell, M. J. Wounding and its role in RSV-mediated tumor formation. Science 230, 676–678 (1985).

    Article  CAS  PubMed  Google Scholar 

  17. Pedersen, T. X. et al. Laser capture microdissection-based in vivo genomic profiling of wound keratinocytes identifies similarities and differences to squamous cell carcinoma. Oncogene 22, 3964–3976 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chang, H. Y. et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2, e7 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Silva-Vargas, V. et al. β-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev. Cell 9, 121–131 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95, 605–614 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Nguyen, H. et al. Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia. Nature Genet. 41, 1068–1075 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Jensen, K. B. et al. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell 4, 427–439 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T. T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351–1354 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Jaks, V. et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nature Genet. 40, 1291–1299 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Nowak, J. A., Polak, L., Pasolli, H. A. & Fuchs, E. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell 3, 33–43 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vidal, V. P. et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr. Biol. 15, 1340–1351 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Snippert, H. J. et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 327, 1385–1389 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Nijhof, J. G. et al. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development 133, 3027–3037 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Brownell, I., Guevara, E., Bai, C. B., Loomis, C. A. & Joyner, A. L. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell 8, 552–565 (2011). This study demonstrates that SHH-responding perineural bulge cells incorporate into healing skin wounds where they can change their lineage into epidermal stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Levy, V., Lindon, C., Zheng, Y., Harfe, B. D. & Morgan, B. A. Epidermal stem cells arise from the hair follicle after wounding. FASEB J. 21, 1358–1366 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Horsley, V. et al. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell 126, 597–609 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Langton, A. K., Herrick, S. E. & Headon, D. J. An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution. J. Invest. Dermatol. 128, 1311–1318 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Rhee, H., Polak, L. & Fuchs, E. Lhx2 maintains stem cell character in hair follicles. Science 312, 1946–1949 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mardaryev, A. N. et al. Lhx2 differentially regulates Sox9, Tcf4 and Lgr5 in hair follicle stem cells to promote epidermal regeneration after injury. Development 138, 4843–4852, (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Oro, A. E. & Higgins, K. Hair cycle regulation of Hedgehog signal reception. Dev. Biol. 255, 238–248 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Chiang, C. et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Oro, A. E. et al. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276, 817–821 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Aszterbaum, M., Beech, J. & Epstein, E. H. Jr . Ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas. J. Investig. Dermatol. Symp. Proc. 4, 41–45 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Mancuso, M. et al. Hair cycle-dependent basal cell carcinoma tumorigenesis in Ptc1neo67/+ mice exposed to radiation. Cancer Res. 66, 6606–6614 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Grachtchouk, M. et al. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J. Clin. Invest. 121, 1768–1781 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genet. 24, 216–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Kasper, M. et al. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc. Natl Acad. Sci. USA 108, 4099–4104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nature Cell Biol. 12, 299–305 (2011).

    Article  CAS  Google Scholar 

  51. Wong, S. Y. & Reiter, J. F. Wounding mobilizes hair follicle stem cells to form tumors. Proc. Natl Acad. Sci. USA 108, 4093–4098 (2011). References 49 and 51 demonstrate that BCC-like tumours can originate from stem cells that normally reside in the bulge of the hair follicle, and that wounding stimulates stem cell migration and tumour promotion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, G. Y., Wang, J., Mancianti, M. L. & Epstein, E. H. Jr . Basal cell carcinomas arise from hair follicle stem cells in Ptch1+/− mice. Cancer Cell 19, 114–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Winton, D. J., Blount, M. A. & Ponder, B. A. Polyclonal origin of mouse skin papillomas. Br. J. Cancer 60, 59–63 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chan, E. F., Gat, U., McNiff, J. M. & Fuchs, E. A common human skin tumour is caused by activating mutations in β-catenin. Nature Genet. 21, 410–413 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Takeda, H. et al. Human sebaceous tumors harbor inactivating mutations in LEF1. Nature Med. 12, 395–397 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Lo Celso, C., Prowse, D. M. & Watt, F. M. Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 131, 1787–1799 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Niemann, C., Owens, D. M., Schettina, P. & Watt, F. M. Dual role of inactivating Lef1 mutations in epidermis: tumor promotion and specification of tumor type. Cancer Res. 67, 2916–2921 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Niemann, C., Owens, D. M., Hulsken, J., Birchmeier, W. & Watt, F. M. Expression of ΔNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours. Development 129, 95–109 (2002).

    CAS  PubMed  Google Scholar 

  59. Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452, 650–653 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Baker, C. M., Verstuyf, A., Jensen, K. B. & Watt, F. M. Differential sensitivity of epidermal cell subpopulations to β-catenin-induced ectopic hair follicle formation. Dev. Biol. 343, 40–50 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cheon, S. S. et al. β-catenin regulates wound size and mediates the effect of TGF-β in cutaneous healing. FASEB J. 20, 692–701 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Fathke, C. et al. Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol. 7, 4 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Okuse, T., Chiba, T., Katsuumi, I. & Imai, K. Differential expression and localization of WNTs in an animal model of skin wound healing. Wound Repair Regen. 13, 491–497 (2005).

    Article  PubMed  Google Scholar 

  64. Cheon, S. S. et al. β-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds. Proc. Natl Acad. Sci. USA 99, 6973–6978 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ridky, T. W. & Khavari, P. A. Pathways sufficient to induce epidermal carcinogenesis. Cell Cycle 3, 621–624 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Owens, D. M. & Watt, F. M. Contribution of stem cells and differentiated cells to epidermal tumours. Nature Rev. Cancer 3, 444–451 (2003).

    Article  CAS  Google Scholar 

  67. Lapouge, G. et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl Acad. Sci. USA 108, 7431–7436 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. White, A. C. et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc. Natl Acad. Sci. USA 108, 7425–7430 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Schober, M. & Fuchs, E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. Proc. Natl Acad. Sci. USA 108, 10544–10549 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sibilia, M. et al. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell 102, 211–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Bailleul, B. et al. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell 62, 697–708 (1990).

    Article  CAS  PubMed  Google Scholar 

  72. Greenhalgh, D. A. et al. Induction of epidermal hyperplasia, hyperkeratosis, and papillomas in transgenic mice by a targeted v-Ha-ras oncogene. Mol. Carcinog. 7, 99–110 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. Brown, K., Strathdee, D., Bryson, S., Lambie, W. & Balmain, A. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr. Biol. 8, 516–524 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. DiGiovanni, J., Bhatt, T. S. & Walker, S. E. C57BL/6 mice are resistant to tumor promotion by full thickness skin wounding. Carcinogenesis 14, 319–321 (1993).

    Article  CAS  PubMed  Google Scholar 

  75. Balmain, A. Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models. Cell 108, 145–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Popova, N. V., Teti, K. A., Wu, K. Q. & Morris, R. J. Identification of two keratinocyte stem cell regulatory loci implicated in skin carcinogenesis. Carcinogenesis 24, 417–425 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Perez-Losada, J. & Balmain, A. Stem-cell hierarchy in skin cancer. Nature Rev. Cancer 3, 434–443 (2003).

    Article  CAS  Google Scholar 

  78. Li, F. et al. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci. Signal 3 ra13 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. Owens, D. M. & Watt, F. M. Influence of β1 integrins on epidermal squamous cell carcinoma formation in a transgenic mouse model: α3β1, but not α2β1, suppresses malignant conversion. Cancer Res. 61, 5248–5254 (2001).

    CAS  PubMed  Google Scholar 

  80. Janes, S. M. & Watt, F. M. New roles for integrins in squamous-cell carcinoma. Nature Rev. Cancer 6, 175–183 (2006).

    Article  CAS  Google Scholar 

  81. Hobbs, R. M., Silva-Vargas, V., Groves, R. & Watt, F. M. Expression of activated MEK1 in differentiating epidermal cells is sufficient to generate hyperproliferative and inflammatory skin lesions. J. Invest. Dermatol. 123, 503–515 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Arwert, E. N. et al. Tumor formation initiated by nondividing epidermal cells via an inflammatory infiltrate. Proc. Natl Acad. Sci. USA 107, 19903–19908 (2010). This study shows that differentiated epidermal cells can initiate tumour formation without reacquiring the ability to divide and that they do so by triggering an inflammatory infiltrate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nature Med. 17, 860–866 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Tang, D., Kang, R., Zeh, H. J. & Lotze, M. T. High-mobility group BOX 1 and cancer. Biochim. Biophys. Acta 1799, 131–140 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lowell, S., Jones, P., Le Roux, I., Dunne, J. & Watt, F. M. Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr. Biol. 10, 491–500 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Blanpain, C., Lowry, W. E., Pasolli, H. A. & Fuchs, E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev. 20, 3022–3035 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Estrach, S., Ambler, C. A., Lo Celso, C., Hozumi, K. & Watt, F. M. Jagged 1 is a β-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development 133, 4427–4438 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Demehri, S., Turkoz, A. & Kopan, R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16, 55–66 (2009). This study shows that loss of Notch1 in epidermal keratinocytes promotes tumorigenesis non-cell autonomously by impairing skin barrier integrity and creating a wound-like environment in the skin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nicolas, M. et al. Notch1 functions as a tumor suppressor in mouse skin. Nature Genet. 33, 416–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Ambler, C. A. & Watt, F. M. Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1. Development 137, 3569–3579 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Demehri, S. et al. Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. PLoS Biol. 6, e123 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Dumortier, A. et al. Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin. PLoS ONE 5, e9258 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Scholl, F. A., Dumesic, P. A. & Khavari, P. A. Mek1 alters epidermal growth and differentiation. Cancer Res. 64, 6035–6040 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Vassar, R., Hutton, M. E. & Fuchs, E. Transgenic overexpression of transforming growth factor α bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis. Mol. Cell. Biol. 12, 4643–4653 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Dominey, A. M. et al. Targeted overexpression of transforming growth factor α in the epidermis of transgenic mice elicits hyperplasia, hyperkeratosis, and spontaneous, squamous papillomas. Cell Growth Differ. 4, 1071–1082 (1993).

    CAS  PubMed  Google Scholar 

  96. Schioppa, T. et al. B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis. Proc. Natl Acad. Sci. USA 108, 10662–10667 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Andreu, P. et al. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Szabowski, A. et al. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 103, 745–755 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Arwert, E. N. et al. Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation. Oncogene 18 Jul 2011 (doi:10.1038/onc.2011.298).

  101. Wagers, A. J., Sherwood, R. I., Christensen, J. L. & Weissman, I. L. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Ishii, G. et al. In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions. Stem Cells 23, 699–706 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Fathke, C. et al. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells 22, 812–822 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Sasaki, M. et al. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J. Immunol. 180, 2581–2587 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Brittan, M. et al. Bone marrow cells engraft within the epidermis and proliferate in vivo with no evidence of cell fusion. J. Pathol. 205, 1–13 (2005).

    Article  PubMed  Google Scholar 

  106. Wagner, J. E. et al. Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N. Engl. J. Med. 363, 629–639 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tamai, K. et al. PDGFRα}-positive cells in bone marrow are mobilized by high mobility group BOX 1 (HMGB1) to regenerate injured epithelia. Proc. Natl Acad. Sci. USA 108, 6609–6614 (2011). These authors identified a specific subset of bone marrow-derived cells with epidermal differentiation potential that can contribute to skin graft re-epithelialization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. auf dem Keller, U. et al. Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing. Mol. Cell. Biol. 26, 3773–3784 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chida, K. et al. Disruption of protein kinase Ceta results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis. Cancer Res. 63, 2404–2408 (2003).

    CAS  PubMed  Google Scholar 

  110. Gonzalez-Suarez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Guasch, G. et al. Loss of TGFβ signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia. Cancer Cell 12, 313–327, (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wakabayashi, Y., Mao, J. H., Brown, K., Girardi, M. & Balmain, A. Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 445, 761–765 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Schultz, G., Rotatori, D. S. & Clark, W. EGF and TGF-α in wound healing and repair. J. Cell. Biochem. 45, 346–352 (1991).

    Article  CAS  PubMed  Google Scholar 

  114. Wang, D. et al. Autocrine TGFα expression in the regulation of initiation of human colon carcinoma growth. J. Cell. Physiol. 177, 387–395 (1998).

    Article  CAS  PubMed  Google Scholar 

  115. Kim, I., Mogford, J. E., Chao, J. D. & Mustoe, T. A. Wound epithelialization deficits in the transforming growth factor-α knockout mouse. Wound Repair Regen. 9, 386–390 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Ortega, S., Ittmann, M., Tsang, S. H., Ehrlich, M. & Basilico, C. Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc. Natl Acad. Sci. USA 95, 5672–5677 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yang, F., Strand, D. W. & Rowley, D. R. Fibroblast growth factor-2 mediates transforming growth factor-β action in prostate cancer reactive stroma. Oncogene 27, 450–459 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Nissen, N. N. et al. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am. J. Pathol. 152, 1445–1452 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Hebda, P. A., Klingbeil, C. K., Abraham, J. A. & Fiddes, J. C. Basic fibroblast growth factor stimulation of epidermal wound healing in pigs. J. Invest. Dermatol. 95, 626–631 (1990).

    Article  CAS  PubMed  Google Scholar 

  120. Assoian, R. K., Komoriya, A., Meyers, C. A., Miller, D. M. & Sporn, M. B. Transforming growth factor-β in human platelets. Identification of a major storage site, purification, and characterization. J. Biol. Chem. 258, 7155–7160 (1983).

    CAS  PubMed  Google Scholar 

  121. Crowe, M. J., Doetschman, T. & Greenhalgh, D. G. Delayed wound healing in immunodeficient TGF-β 1 knockout mice. J. Invest. Dermatol. 115, 3–11 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Roberts, A. B. et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ikushima, H. & Miyazono, K. TGFβ signalling: a complex web in cancer progression. Nature Rev. Cancer 10, 415–424 (2010).

    Article  CAS  Google Scholar 

  124. Honjo, Y. et al. TGF-β receptor I conditional knockout mice develop spontaneous squamous cell carcinoma. Cell Cycle 6, 1360–1366 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Giampieri, S. et al. Localized and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nature Cell Biol. 11, 1287–1296 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Cao, R. et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6, 333–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Crawford, Y. et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15, 21–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Kane, C. J., Hebda, P. A., Mansbridge, J. N. & Hanawalt, P. C. Direct evidence for spatial and temporal regulation of transforming growth factor β 1 expression during cutaneous wound healing. J. Cell. Physiol. 148, 157–173 (1991).

    Article  CAS  PubMed  Google Scholar 

  129. Li, H. et al. Research of PDGF-BB gel on the wound healing of diabetic rats and its pharmacodynamics. J. Surg. Res. 145, 41–48 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Bates, D. O. & Jones, R. O. The role of vascular endothelial growth factor in wound healing. Int. J. Low. Extrem. Wounds 2, 107–120 (2003).

    Article  PubMed  Google Scholar 

  131. Eichholz, A., Merchant, S. & Gaya, A. M. Anti-angiogenesis therapies: their potential in cancer management. Onco Targets Ther. 3, 69–82 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Lewis, A. M., Varghese, S., Xu, H. & Alexander, H. R. Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. J. Transl. Med. 4, 48 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Gallucci, R. M. et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 14, 2525–2531 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Schafer, Z. T. & Brugge, J. S. IL-6 involvement in epithelial cancers. J. Clin. Invest. 117, 3660–3663 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mocellin, S. & Nitti, D. TNF and cancer: the two sides of the coin. Front. Biosci. 13, 2774–2783 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Mori, R., Kondo, T., Ohshima, T., Ishida, Y. & Mukaida, N. Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration. FASEB J. 16, 963–974 (2002).

    Article  CAS  PubMed  Google Scholar 

  137. Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nature Rev. Immunol. 8, 533–544 (2008).

    Article  CAS  Google Scholar 

  138. Wu, L., Yu, Y. L., Galiano, R. D., Roth, S. I. & Mustoe, T. A. Macrophage colony-stimulating factor accelerates wound healing and upregulates TGF-β1 mRNA levels through tissue macrophages. J. Surg. Res. 72, 162–169 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004).

    Article  CAS  PubMed  Google Scholar 

  140. Low, Q. E. et al. Wound healing in MIP-1α−/− and MCP-1−/− mice. Am. J. Pathol. 159, 457–463 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Soria, G. & Ben-Baruch, A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 267, 271–285 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Kogan-Sakin, I. et al. Prostate stromal cells produce CXCL-1, CXCL-2, CXCL-3 and IL-8 in response to epithelia-secreted IL-1. Carcinogenesis 30, 698–705 (2009).

    Article  CAS  PubMed  Google Scholar 

  143. Wang, D. et al. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J. Exp. Med. 203, 941–951 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Rennekampff, H. O. et al. Role of melanoma growth stimulatory activity (MGSA/gro) on keratinocyte function in wound healing. Arch. Dermatol. Res. 289, 204–212 (1997).

    Article  CAS  PubMed  Google Scholar 

  145. Matsuo, Y. et al. CXCL8/IL-8 and CXCL12/SDF-1α co-operatively promote invasiveness and angiogenesis in pancreatic cancer. Int. J. Cancer 124, 853–861 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rennekampff, H. O. et al. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J. Surg. Res. 93, 41–54 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Pan, J. et al. Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Mol. Cancer 5, 56 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Toksoy, A., Muller, V., Gillitzer, R. & Goebeler, M. Biphasic expression of stromal cell-derived factor-1 during human wound healing. Br. J. Dermatol. 157, 1148–1154 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Yasumoto, K. et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res. 66, 2181–2187 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank I. Brownell, R. Toftgard, K. Kretzschmar and K. Jensen for advice on Figure 2. F.M.W. gratefully acknowledges financial support from the Wellcome Trust, Medical Research Council and Cancer Research UK. E.H. is supported by EUFP7 HEALING network. E.N.A. is a recipient of a Sir Henry Wellcome postdoctoral fellowship.

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Glossary

Keratinocytes

Epithelial cells in a multilayered epithelium, such as the epidermis.

Squamous cell carcinoma

Malignant tumour with elements of interfollicular epidermal differentiation.

Psoriasis

Benign skin disorder that affects 2% of the world's population; characterized by epidermal hyperproliferation and skin inflammation.

Sebaceous gland

Gland that is associated with the junction between the hair follicle and the interfollicular epidermis; releases sebum that lubricates the skin surface.

Interfollicular epidermis

(IFE). Multilayered epithelium of the epidermis that lies between the hair follicles; forms the barrier that protects the skin from the external environment.

Isthmus

The region of the hair follicle that extends between the bulge and the sebaceous gland.

Junctional zone

Junction between the hair follicle, sebaceous gland and infundibulum; the location of LRIG1+ stem cells.

Basal cell carcinoma

(BCC). Very common, slow-growing epidermal tumour that lacks differentiated cell markers and that is believed to arise from hair follicles.

Infundibulum

The part of the hair follicle that lies above the sebaceous gland and that is continuous with the interfollicular epidermis.

Pilomatricomas

Benign skin tumours with elements of hair follicle matrix differentiation.

Trichofolliculomas

Benign skin tumours with multiple elements of hair follicle differentiation.

Papillomas

Benign tumours with elements of interfollicular epidermal differentiation that can convert into squamous cell carcinomas.

Full-thickness wounding

Wounding that extends through all the layers of the skin (epidermis, dermis and subdermal fat layer).

Keratoacanthomas

Low-grade squamous cell carcinomas in skin.

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Arwert, E., Hoste, E. & Watt, F. Epithelial stem cells, wound healing and cancer. Nat Rev Cancer 12, 170–180 (2012). https://doi.org/10.1038/nrc3217

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