Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Deciphering the cells of origin of squamous cell carcinomas

Abstract

Squamous cell carcinomas (SCCs) are among the most prevalent human cancers. SCC comprises a wide range of tumours originated from diverse anatomical locations that share common genetic mutations and expression of squamous differentiation markers. SCCs arise from squamous and non-squamous epithelial tissues. Here, we discuss the different studies in which the cell of origin of SCCs has been uncovered by expressing oncogenes and/or deleting tumour suppressor genes in the different cell lineages that compose these epithelia. We present evidence showing that the squamous differentiation phenotype of the tumour depends on the type of mutated oncogene and the cell of origin, which dictate the competence of the cells to initiate SCC formation, as well as on the aggressiveness and invasive properties of these tumours.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Lineage tracing and the cells of origin of cancer.
Fig. 2: Architecture and cellular hierarchy present in the tissues from which SCC arise.
Fig. 3: Common genetic alterations found in the different types of SCC.
Fig. 4: The cells at the origin of CSCC.
Fig. 5: The cells of origin in HNSCC and ESCC.
Fig. 6: SOX2 promotes LSCC differentiation irrespective of the cell of origin.

References

  1. 1.

    Dotto, G. P. & Rustgi, A. K. Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell 29, 622–637 (2016). This is a landmark review summarizing the aetiology and genetic determinants of SCCs arising from different body locations.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Alam, M. & Ratner, D. Cutaneous squamous-cell carcinoma. N. Engl. J. Med. 344, 975–983 (2001).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Herbst, R. S., Heymach, J. V. & Lippman, S. M. Lung cancer. N. Engl. J. Med. 359, 1367–1380 (2008).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Leemans, C. R., Braakhuis, B. J. & Brakenhoff, R. H. The molecular biology of head and neck cancer. Nat. Rev. Cancer 11, 9–22 (2011).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Rustgi, A. K. & El-Serag, H. B. Esophageal carcinoma. N. Engl. J. Med. 371, 2499–2509 (2014).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Bray, F. et al. Trends in cervical squamous cell carcinoma incidence in 13 European countries: changing risk and the effects of screening. Cancer Epidemiol. Biomarkers Prev. 14, 677–686 (2005).

    PubMed  Article  Google Scholar 

  7. 7.

    Malik, R. D. et al. Squamous cell carcinoma of the prostate. Rev. Urol. 13, 56–60 (2011).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Tunio, M. A., Al Asiri, M., Fagih, M. & Akasha, R. Primary squamous cell carcinoma of thyroid: a case report and review of literature. Head Neck Oncol. 4, 8 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Ben Kridis, W. et al. Primary squamous cell carcinoma of the pancreas: a report of two cases and review of the literature. Intern. Med. 54, 1357–1359 (2015).

    PubMed  Article  Google Scholar 

  10. 10.

    Martin, J. W. et al. Squamous cell carcinoma of the urinary bladder: systematic review of clinical characteristics and therapeutic approaches. Arab J. Urol. 14, 183–191 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Blanpain, C. Tracing the cellular origin of cancer. Nat. Cell Biol. 15, 126–134 (2013).

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Van Keymeulen, A. & Blanpain, C. Tracing epithelial stem cells during development, homeostasis, and repair. J. Cell Biol. 197, 575–584 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Blanpain, C. & Fuchs, E. Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration. Science 344, 1242281 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat. Rev. Mol. Cell Biol. 10, 207–217 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

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

    PubMed  Article  CAS  Google Scholar 

  16. 16.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nat. Biotechnol. 22, 411–417 (2004).

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Page, M. E., Lombard, P., Ng, F., Gottgens, B. & Jensen, K. B. The epidermis comprises autonomous compartments maintained by distinct stem cell populations. Cell Stem Cell 13, 471–482 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    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).

    PubMed  Article  CAS  Google Scholar 

  21. 21.

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

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Aragona, M. et al. Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat. Commun. 8, 14684 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Rompolas, P. et al. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis. Science 352, 1471–1474 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Sada, A. et al. Defining the cellular lineage hierarchy in the interfollicular epidermis of adult skin. Nat. Cell Biol. 18, 619–631 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Mascre, G. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257–262 (2012).

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Gomez, C. et al. The interfollicular epidermis of adult mouse tail comprises two distinct cell lineages that are differentially regulated by Wnt, Edaradd, and Lrig1. Stem Cell Rep. 1, 19–27 (2013).

    Article  CAS  Google Scholar 

  27. 27.

    Sanchez-Danes, A. et al. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536, 298–303 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

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

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Doupe, D. P., Klein, A. M., Simons, B. D. & Jones, P. H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev. Cell 18, 317–323 (2010).

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Potten, C. S. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int. Rev. Cytol. 69, 271–318 (1981).

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat. Cell Biol. 12, 299–305 (2010).

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Hume, W. J. & Potten, C. S. The ordered columnar structure of mouse filiform papillae. J. Cell Sci. 22, 149–160 (1976).

    PubMed  CAS  Google Scholar 

  33. 33.

    Arnold, K. et al. Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9, 317–329 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Okubo, T., Clark, C. & Hogan, B. L. Cell lineage mapping of taste bud cells and keratinocytes in the mouse tongue and soft palate. Stem Cells 27, 442–450 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Marques-Pereira, J. P. & Leblond, C. P. Mitosis and differentiation in the stratified squamous epithelium of the rat esophagus. Am. J. Anat. 117, 73–87 (1965).

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Leblond, C. P., Clermont, Y. & Nadler, N. J. The pattern of stem cell renewal in three epithelia. (esophagus, intestine and testis). Proc. Can. Cancer Conf. 7, 3–30 (1967).

    PubMed  CAS  Google Scholar 

  37. 37.

    Doupe, D. P. et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091–1093 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Seery, J. P. & Watt, F. M. Asymmetric stem-cell divisions define the architecture of human oesophageal epithelium. Curr. Biol. 10, 1447–1450 (2000).

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Croagh, D., Phillips, W. A., Redvers, R., Thomas, R. J. & Kaur, P. Identification of candidate murine esophageal stem cells using a combination of cell kinetic studies and cell surface markers. Stem Cells 25, 313–318 (2007).

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    DeWard, A. D., Cramer, J. & Lagasse, E. Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep. 9, 701–711 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Giroux, V. et al. Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. J. Clin. Invest. 127, 2378–2391 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Barbera, M. et al. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut 64, 11–19 (2015).

    PubMed  Article  Google Scholar 

  43. 43.

    Rock, J. R. et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106, 12771–12775 (2009).

    PubMed  Article  Google Scholar 

  44. 44.

    Rawlins, E. L. et al. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525–534 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Rawlins, E. L. & Hogan, B. L. Ciliated epithelial cell lifespan in the mouse trachea and lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L231–L234 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Barkauskas, C. E. et al. Type 2 alveolar cells are stem cells in adult lung. J. Clin. Invest. 123, 3025–3036 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Desai, T. J., Brownfield, D. G. & Krasnow, M. A. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507, 190–194 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Tata, P. R. et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503, 218–223 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Rock, J. R. & Hogan, B. L. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu. Rev. Cell Dev. Biol. 27, 493–512 (2011).

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Pardo-Saganta, A. et al. Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations. Cell Stem Cell 16, 184–197 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51.

    Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Pickering, C. R. et al. Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin. Cancer Res. 20, 6582–6592 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    South, A. P. et al. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. J. Invest. Dermatol. 134, 2630–2638 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    Wang, N. J. et al. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc. Natl Acad. Sci. USA 108, 17761–17766 (2011).

    PubMed  Article  Google Scholar 

  55. 55.

    The Cancer Genome Atlas Research, N. et al. Integrated genomic characterization of oesophageal carcinoma. Nature 541, 169–175 (2017).

    Article  CAS  Google Scholar 

  56. 56.

    Song, Y. et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509, 91–95 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  57. 57.

    Lin, D. C. et al. Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat. Genet. 46, 467–473 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Gao, Y. B. et al. Genetic landscape of esophageal squamous cell carcinoma. Nat. Genet. 46, 1097–1102 (2014).

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    The Cancer Genome Atlas, N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).

    Article  CAS  Google Scholar 

  60. 60.

    Agrawal, N. et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333, 1154–1157 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Seiwert, T. Y. et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin. Cancer Res. 21, 632–641 (2015).

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Lechner, M. et al. Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors. Genome Med. 5, 49 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Pickering, C. R. et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 3, 770–781 (2013).

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    The Cancer Genome Atlas Research, N. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

    Article  CAS  Google Scholar 

  66. 66.

    Kim, Y. et al. Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients. J. Clin. Oncol. 32, 121–128 (2014).

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Li, C. et al. Whole exome sequencing identifies frequent somatic mutations in cell-cell adhesion genes in chinese patients with lung squamous cell carcinoma. Sci. Rep. 5, 14237 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    The Cancer Genome Atlas Research, N. et al. Integrated genomic and molecular characterization of cervical cancer. Nature 543, 378–384 (2017).

    Article  CAS  Google Scholar 

  69. 69.

    Ojesina, A. I. et al. Landscape of genomic alterations in cervical carcinomas. Nature 506, 371–375 (2014).

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Chen, J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med. 6, a026104 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Baldin, V., Lukas, J., Marcote, M. J., Pagano, M. & Draetta, G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7, 812–821 (1993).

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Meyer, N. & Penn, L. Z. Reflecting on 25 years with MYC. Nat. Rev. Cancer 8, 976–990 (2008).

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3, 11–22 (2003).

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Quintanilla, M., Brown, K., Ramsden, M. & Balmain, A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322, 78–80 (1986).

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Spencer, J. M., Kahn, S. M., Jiang, W., DeLeo, V. A. & Weinstein, I. B. Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas. Arch. Dermatol. 131, 796–800 (1995).

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Koch, U., Lehal, R. & Radtke, F. Stem cells living with a Notch. Development 140, 689–704 (2013).

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Nowell, C. S. & Radtke, F. Notch as a tumour suppressor. Nat. Rev. Cancer 17, 145–159 (2017).

    PubMed  Article  CAS  Google Scholar 

  81. 81.

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

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Rangarajan, A. et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427–3436 (2001).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Watanabe, H. et al. SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas. J. Clin. Invest. 124, 1636–1645 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Crum, C. P. & McKeon, F. D. p63 in epithelial survival, germ cell surveillance, and neoplasia. Annu. Rev. Pathol. 5, 349–371 (2010).

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Melino, G., Memmi, E. M., Pelicci, P. G. & Bernassola, F. Maintaining epithelial stemness with p63. Sci. Signal. 8, re9 (2015).

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Blanpain, C. & Fuchs, E. p63: revving up epithelial stem-cell potential. Nat. Cell Biol. 9, 731–733 (2007).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Dotto, G. P. Notch tumor suppressor function. Oncogene 27, 5115–5123 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Boumahdi, S. et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature 511, 246–250 (2014).

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Siegle, J. M. et al. SOX2 is a cancer-specific regulator of tumour initiating potential in cutaneous squamous cell carcinoma. Nat. Commun. 5, 4511 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Fickie, M. R. et al. Adults with Sotos syndrome: review of 21 adults with molecularly confirmed NSD1 alterations, including a detailed case report of the oldest person. Am. J. Med. Genet. A 155A, 2105–2111 (2011).

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Papillon-Cavanagh, S. et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat. Genet. 49, 180–185 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94.

    Hoadley, K. A. et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158, 929–944 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Liu, F., Wang, L., Perna, F. & Nimer, S. D. Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape. Nat. Rev. Cancer 16, 359–372 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Lapouge, G. et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl Acad. Sci. USA 108, 7431–7436 (2011). This study demonstrates that only stem cells and not transit-amplifying cells from the epidermis are able to form CSCC.

    PubMed  Article  Google Scholar 

  97. 97.

    White, A. C. et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc. Natl Acad. Sci. USA 108, 7425–7430 (2011). References 96 and 97 report that only stem cells and not hair follicle transit-amplifying cells are able to give rise to CSCC.

    PubMed  Article  Google Scholar 

  98. 98.

    Karia, P. S., Han, J. & Schmults, C. D. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J. Am. Acad. Dermatol. 68, 957–966 (2013).

    PubMed  Article  Google Scholar 

  99. 99.

    Arnault, J. P. et al. Keratoacanthomas and squamous cell carcinomas in patients receiving sorafenib. J. Clin. Oncol. 27, e59–61 (2009).

    PubMed  Article  Google Scholar 

  100. 100.

    Abel, E. L., Angel, J. M., Kiguchi, K. & DiGiovanni, J. Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications. Nat. Protoc. 4, 1350–1362 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. 101.

    Van Duuren, B. L., Sivak, A., Katz, C., Seidman, I. & Melchionne, S. The effect of aging and interval between primary and secondary treatment in two-stage carcinogenesis on mouse skin. Cancer Res. 35, 502–505 (1975).

    PubMed  Google Scholar 

  102. 102.

    Morris, R. J. Keratinocyte stem cells: targets for cutaneous carcinogens. J. Clin. Invest. 106, 3–8 (2000).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Argyris, T. S. & Slaga, T. J. Promotion of carcinomas by repeated abrasion in initiated skin of mice. Cancer Res. 41, 5193–5195 (1981).

    PubMed  CAS  Google Scholar 

  104. 104.

    Li, S. et al. A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse. Mol. Carcinog. 52, 751–759 (2013).

    PubMed  CAS  Google Scholar 

  105. 105.

    Morris, R. J., Tryson, K. A. & Wu, K. Q. Evidence that the epidermal targets of carcinogen action are found in the interfollicular epidermis of infundibulum as well as in the hair follicles. Cancer Res. 60, 226–229 (2000).

    PubMed  CAS  Google Scholar 

  106. 106.

    Balmain, A., Ramsden, M., Bowden, G. T. & Smith, J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307, 658–660 (1984).

    PubMed  Article  CAS  Google Scholar 

  107. 107.

    Bizub, D., Wood, A. W. & Skalka, A. M. Mutagenesis of the Ha-ras oncogene in mouse skin tumors induced by polycyclic aromatic hydrocarbons. Proc. Natl Acad. Sci. USA 83, 6048–6052 (1986).

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    Nassar, D., Latil, M., Boeckx, B., Lambrechts, D. & Blanpain, C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat. Med. 21, 946–954 (2015).

    PubMed  Article  CAS  Google Scholar 

  109. 109.

    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).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    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).

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Latil, M. et al. Cell-Type-Specific Chromatin States Differentially Prime Squamous Cell Carcinoma Tumor-Initiating Cells for Epithelial to Mesenchymal Transition. Cell Stem Cell 20, 191–204.e5 (2017). This study demonstrates for the first time that the cancer cell of origin determines the tumour phenotype, occurrence of EMT and aggressiveness in CSCCs.

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Kamangar, F., Dores, G. M. & Anderson, W. F. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J. Clin. Oncol. 24, 2137–2150 (2006).

    PubMed  Article  Google Scholar 

  113. 113.

    Andrews, E., Seaman, W. T. & Webster-Cyriaque, J. Oropharyngeal carcinoma in non-smokers and non-drinkers: a role for HPV. Oral Oncol. 45, 486–491 (2009).

    PubMed  Article  Google Scholar 

  114. 114.

    zur Hausen, H. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev. Cancer 2, 342–350 (2002).

    PubMed  Article  CAS  Google Scholar 

  115. 115.

    Kutler, D. I. et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch. Otolaryngol. Head Neck Surg. 129, 106–112 (2003).

    PubMed  Article  Google Scholar 

  116. 116.

    Califano, J. et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 56, 2488–2492 (1996).

    PubMed  CAS  Google Scholar 

  117. 117.

    Hawkins, B. L. et al. 4NQO carcinogenesis: a mouse model of oral cavity squamous cell carcinoma. Head Neck 16, 424–432 (1994).

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Tang, X. H., Scognamiglio, T. & Gudas, L. J. Basal stem cells contribute to squamous cell carcinomas in the oral cavity. Carcinogenesis 34, 1158–1164 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119.

    Caulin, C. et al. Inducible activation of oncogenic K-ras results in tumor formation in the oral cavity. Cancer Res. 64, 5054–5058 (2004).

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Raimondi, A. R., Vitale-Cross, L., Amornphimoltham, P., Gutkind, J. S. & Molinolo, A. Rapid development of salivary gland carcinomas upon conditional expression of K-ras driven by the cytokeratin 5 promoter. Am. J. Pathol. 168, 1654–1665 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  121. 121.

    Raimondi, A. R., Molinolo, A. & Gutkind, J. S. Rapamycin prevents early onset of tumorigenesis in an oral-specific K-ras and p53 two-hit carcinogenesis model. Cancer Res. 69, 4159–4166 (2009).

    PubMed  Article  CAS  Google Scholar 

  122. 122.

    Bornstein, S. et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J. Clin. Invest. 119, 3408–3419 (2009).

    PubMed  PubMed Central  CAS  Google Scholar 

  123. 123.

    Bian, Y. et al. Loss of TGF-beta signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene 31, 3322–3332 (2012).

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Nakagawa, H. et al. The targeting of the cyclin D1 oncogene by an Epstein-Barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach. Oncogene 14, 1185–1190 (1997).

    PubMed  Article  CAS  Google Scholar 

  125. 125.

    Opitz, O. G. et al. A mouse model of human oral-esophageal cancer. J. Clin. Invest. 110, 761–769 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. 126.

    Tetreault, M. P. et al. Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice. Gastroenterology 139, 2124–2134.e9 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Stairs, D. B. et al. Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene. Cancer Cell 19, 470–483 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. 128.

    Frede, J., Greulich, P., Nagy, T., Simons, B. D. & Jones, P. H. A single dividing cell population with imbalanced fate drives oesophageal tumour growth. Nat. Cell Biol. 18, 967–978 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. 129.

    Alcolea, M. P. et al. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nat. Cell Biol. 16, 615–622 (2014). This study reports that equipotent oesophageal progenitors are the cells of origin of ESCC by cell fate imbalance.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Bass, A. J. et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat. Genet. 41, 1238–1242 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  131. 131.

    Liu, K. et al. Sox2 cooperates with inflammation-mediated Stat3 activation in the malignant transformation of foregut basal progenitor cells. Cell Stem Cell 12, 304–315 (2013). This study reports that oesophageal basal cells but not differentiated cells lead to ESCC upon activation of STAT3 and overexpression of SOX2.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132.

    Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).

    PubMed  Article  Google Scholar 

  133. 133.

    The Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    Article  CAS  Google Scholar 

  134. 134.

    Campbell, J. D. et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet. 48, 607–616 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. 135.

    Chen, Z., Fillmore, C. M., Hammerman, P. S., Kim, C. F. & Wong, K. K. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat. Rev. Cancer 14, 535–546 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136.

    Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).

    PubMed  Article  CAS  Google Scholar 

  137. 137.

    Xu, C. et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25, 590–604 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. 138.

    Que, J., Luo, X., Schwartz, R. J. & Hogan, B. L. Multiple roles for Sox2 in the developing and adult mouse trachea. Development 136, 1899–1907 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139.

    Mukhopadhyay, A. et al. Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Rep. 8, 40–49 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    PubMed  Article  CAS  Google Scholar 

  141. 141.

    Lu, Y. et al. Evidence that SOX2 overexpression is oncogenic in the lung. PLoS ONE 5, e11022 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  142. 142.

    Xu, X. et al. The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2. Genes Dev. 28, 1929–1939 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143.

    Ferone, G. et al. SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell 30, 519–532 (2016). This study demonstrates that three different lung lineages (basal, secretory and AT2 cells) represent the cell of origin of LSCC and that SOX2 restricts tumour lineage to SCC.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

    Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

    Rodriguez-Paredes, M. et al. Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin. Nat. Commun. 9, 577 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. 146.

    Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    PubMed  Article  CAS  Google Scholar 

  147. 147.

    Tomasetti, C., Li, L. & Vogelstein, B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330–1334 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. 148.

    Tomasetti, C. & Vogelstein, B. Cancer risk: role of environment-response. Science 347, 729–731 (2015).

    PubMed  Article  CAS  Google Scholar 

  149. 149.

    Zhu, L. et al. Multi-organ Mapping of Cancer Risk. Cell 166, 1132–1146.e7 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

C.B. is an investigator of WELBIO. A.S.-D. is supported by a fellowship of the Belgian Fund for Scientific Research (FNRS). CB is supported by the FNRS, the Fondation contre le Cancer, the Université Libre de Bruxelles Fondation, the Fondation Baillet Latour, Worldwide Cancer Research and a consolidator grant from the European Research Council.

Author information

Affiliations

Authors

Contributions

Both authors read the literature, discussed the contents of the Review and wrote the article.

Corresponding author

Correspondence to Cédric Blanpain.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Squamous cell carcinomas

(SCCs). Cancers that present squamous differentiation, which is visible by the presence of keratin materials.

Lineage tracing

A method involving experiments that enable the labelling of a cell or a group of cells and assess the fate of these labelled cells and their progeny over time.

Stem cells

Cells that are at the top of the cellular hierarchy and are characterized by long-term self-renewing capacity and give rise to progenitors, transit-amplifying cells and differentiated cells.

Progenitors

Cells that can self-renew and give rise to terminally differentiated cells. Depending on the proportion of asymmetric and symmetric divisions, progenitors can live long term or short term.

Stratified squamous epithelium

Epithelium composed of a layer of basal proliferative cells and several suprabasal layers of differentiated cells that express keratins and progressively flatten near the surface, eventually presenting as enucleated cells that are shed from the surface. These amorphous keratinized ghost cells are known as squames. The inner surface of the body is lined with non-keratinized stratified squamous epithelium, which is characterized by superficial cells that are flattened and nucleated.

Keratin pearls

Keratin-derived amorphous materials arising from the differentiation of tumour cells.

Transit-amplifying cells

Cells that divide a finite number of times and then terminally differentiate.

Clonal analysis

The study of the fate, renewal and long-term maintenance of single isolated cells over time.

Dedifferentiation

A process that occurs when committed or differentiated cells revert to a less committed state.

Secretory cells

Cells of the airway system (also known as Clara cells) that produce mucins and antimicrobial peptides.

Ciliated cells

Cells that contain tiny hair-like structures on their surface called cilia. Ciliated cells of the airway system propel debris and dirty mucus out of the respiratory tract through the movement of their cilia.

Type 1 cells

(AT1 cells). Cells of the alveolar epithelium that enable gas exchange.

Type 2 cells

(AT2 cells). Cells of the alveolar epithelium that produce surfactant, which helps the alveolar structure to stay open and thus enables gas exchange.

Lineage ablation

The selective killing of a cell lineage, which is usually performed by inducing expression of a toxin or a toxin receptor in a cell of interest and then administering that toxin.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sánchez-Danés, A., Blanpain, C. Deciphering the cells of origin of squamous cell carcinomas. Nat Rev Cancer 18, 549–561 (2018). https://doi.org/10.1038/s41568-018-0024-5

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing