Epidermal stem cells: Location, potential and contribution to cancer

Journal of Pathology

Volumn 217, Issue 2, 2009, Pages 206-216

  Ambler, C A ^a   Maatta A ^a  

^a DURHAM UNIVERSITY   (United Kingdom)

Author keywords

catenin; c myc; Epidermis; Hedgehog; Neoplasia; Niche; Notch; p63; Stem cell; Wnt

Indexed keywords

BETA CATENIN; CELL MARKER; NOTCH RECEPTOR; PROTEIN P63; SONIC HEDGEHOG PROTEIN; WNT PROTEIN;

CANCER STEM CELL; CELL DIFFERENTIATION; CELL LINEAGE; CELL MEMBRANE POTENTIAL; CELLULAR DISTRIBUTION; EPIDERMIS CELL; HAIR FOLLICLE; HUMAN; KERATINOCYTE; NONHUMAN; ONCOGENE C MYC; PRIORITY JOURNAL; REVIEW; SQUAMOUS CELL CARCINOMA; STEM CELL; TUMOR CELL;

ANIMALS; BIOLOGICAL MARKERS; CELL LINEAGE; EPIDERMIS; HUMANS; NEOPLASMS, SQUAMOUS CELL; NEOPLASTIC STEM CELLS; SIGNAL TRANSDUCTION; SKIN NEOPLASMS; STEM CELL NICHE; STEM CELLS;

EID: 58449125163     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.2468     Document Type: Review

References (129)

1. Fuchs E, Horsley V. More than one way to skin. Genes Dev 2008;22(8):976-985.
2. Watt FM, Lo Celso C, Silva-Vargas V. Epidermal stem cells: an update. Curr Opin Genet Dev 2006;16(5):518-524.
3. Lajtha LG. Stem cell concepts. Differentiation 1979;14(1-2):23-34.
4. Clayton E, Doupe DP, Klein AM, Winton DJ, Simons BD, Jones PH. A single type of progenitor cell maintains normal epidermis. Nature 2007;446(7132):185-189.
5. Jones PH, Simons BD, Watt FM. Sic transit gloria: farewell to the epidermal transit amplifying cell? Cell Stem Cell 2007;1(4):371- 381.
6. Ghazizadeh S, Taichman LB. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J 2001;20(6):1215-1222.
7. Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, et al.Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 2005;11(12):1351-1354.
8. Levy V, Lindon C, Harfe BD, Morgan BA. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev Cell 2005;9(6):855-861.
9. Levy V, Lindon C, Zheng Y, Harfe BD, Morgan BA. Epidermal stem cells arise from the hair follicle after wounding. FASEB J 2007;21(7): 1358-1366.
10. Owens DM, Watt FM. Contribution of stem cells and differentiated cells to epidermal tumours. Nat Rev Cancer 2003;3(6):444-451.
11. Jahoda CA, Whitehouse J, Reynolds AJ, Hole N. Hair follicle dermal cells differentiate into adipogenic and osteogenic lineages. Exp Dermatol 2003;12(6):849-859.
12. Waters JM, Richardson GD, Jahoda CA. Hair follicle stem cells. Semin Cell Dev Biol 2007;18(2):245-254.
13. Hu YF, Zhang ZJ, Sieber-Blum M. An epidermal neural crest stem cell (EPI-NCSC) molecular signature. Stem Cells 2006;24(12):2692-2702.
14. Sieber-Blum M, Grim M, Hu YF, Szeder V. Pluripotent neural crest stem cells in the adult hair follicle. Dev Dyn 2004;231(2):258-269.
15. Bickenbach JR. Identification and behavior of label-retaining cells in oral mucosa and skin. J Dent Res 1981;60((Spec No C)):1611-1620.
16. Bickenbach JR, McCutecheon J, Mackenzie IC. Rate of loss of tritiated thymidine label in basal cells in mouse epithelial tissues. Cell Tissue Kinet 1986;19(3):325-333.
17. Morris RJ, Fischer SM, Slaga TJ. Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. J Invest Dermatol 1985;84(4):277-281.
18. Potten CS. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet 1974;7(1):77-88.
19. Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, et al. Defining the epithelial stem cell niche in skin. Science 2004;303(5656):359-363.
20. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61(7):1329-1337.
21. Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 2001;104(2):233-245.
22. Rochat A, Kobayashi K, Barrandon Y. Location of stem cells of human hair follicles by clonal analysis. Cell 1994;76(6):1063-1073.
23. Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 2004;118(5):635-648.
24. Braun KM, Niemann C, Jensen UB, Sundberg JP, Silva-Vargas V, Watt FM. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 2003;130(21):5241-5255.
25. Mackenzie IC. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature 1970;226(5246):653- 655.
26. Mackenzie JC. Ordered structure of the stratum corneum of mammalian skin. Nature 1969;222(5196):881-882.
27. Allen TD, Potten CS. Fine-structural identification and organization of the epidermal proliferative unit. J Cell Sci 1974;15(2):291-319.
28. Mackenzie IC, Zimmerman K, Peterson L. The pattern of cellular organization of human epidermis. J Invest Dermatol 1981;76(6):459- 461.
29. Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 2004;22(4):411-417.
30. Ohyama M, Terunuma A, Tock CL, Radonovich MF, Pise-Masison CA, Hopping SB, et al. Characterization and isolation ofstem cell-enriched human hair follicle bulge cells. J Clin Invest 2006;116(1):249-260.
31. Kloepper JE, Tiede S, Brinckmann J, Reinhardt DP, Meyer W, Faessler R, et al. Immunophenotyping of the human bulge region: the quest to define useful in situ markers for human epithelial hair follicle stem cells and their niche. Exp Dermatol 2008;17(7):592-609.
32. Claudinot S, Nicolas M, Oshima H, Rochat A, Barrandon Y. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc Natl Acad Sci USA 2005;102(41):14677-14 682.
33. Jensen UB, Lowell S, Watt FM. The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis. Development 1999;126(11):2409-2418.
34. Jones PH, Harper S, Watt FM. Stem cell patterning and fate in human epidermis. Cell 1995;80(1):83-93.
35. Legg J, Jensen UB, Broad S, Leigh I, Watt FM. Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis. Development 2003;130(24):6049-6063.
36. Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal differentiation by δ-notch signalling at the boundaries of stem-cell clusters. Curr Biol 2000;10(9):491-500.
37. Jensen KB, Watt FM. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc Natl Acad Sci USA 2006;103(32):11 958-11 963.
38. Horsley V, O'Carroll D, Tooze R, Ohinata Y, Saitou M, Obukhanych T, et al. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell 2006;126(3):597-609.
39. Waghmare SK, Bansal R, Lee J, Zhang YV, McDermitt DJ, Tumbar T. Quantitative proliferation dynamics and random chromosome segregation of hair follicle stem cells. EMBO J 2008;27(9):1309-1320.
40. Weinberg WC, Goodman LV, George C, Morgan DL, Ledbet-ter S, Yuspa SH, et al. Reconstitution of hair follicle development in vivo: determination of follicle formation, hair growth, and hair quality by dermal cells. J Invest Dermatol 1993;100(3):229-236.
41. Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA 1987;84(8):2302-2306.
42. Trempus CS, Morris RJ, Bortner CD, Cotsarelis G, Faircloth RS, Reece JM, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol 2003;120(4):501-511.
43. Nijhof JG, Braun KM, Giangreco A, van Pelt C, Kawamoto H, Boyd RL, et al. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development 2006;133(15):3027-3037.
44. Depreter MG, Blair NF, Gaskell TL, Nowell CS, Davern K, Pagliocca A, et al. Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. Proc Natl Acad Sci USA 2008;105(3): 961-966.
45. Jensen UB, Yan X, Triel C, Woo SH, Christensen R, Owens DM. A distinct population of clonogenic and multipotent murine fol-licular keratinocytes residing in the upper isthmus. J Cell Sci 2008;121(5):609-617.
46. Yan X, Owens DM. The skin: a home to multiple classes of epithelial progenitor cells. Stem Cell Rev 2008;4(2):113-118.
47. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999;398(6729):708-713.
48. Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bron-son RT, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999;398(6729):714-718.
49. Keyes WM, Wu Y, Vogel H, Guo X, Lowe SW, Mills AA. p63 deficiency activates a program of cellular senescence and leads to accelerated aging. Genes Dev 2005;19(17):1986-1999.
50. Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 2004;18(2):126-131.
51. Senoo M, Pinto F, Crum CP, McKeon F. p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell 2007;129(3):523-536.
52. Lo Celso C, Prowse DM, Watt FM. Transient activation of ß-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 2004;131(8):1787-1799.
53. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. ß-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 2001;105(4):533-545.
54. Lowry WE, Blanpain C, Nowak JA, Guasch G, Lewis L, Fuchs E. Defining the impact of ß -catenin/Tcf transactivation on epithelial stem cells. Genes Dev 2005;19(13):1596-1611.
55. Van Mater D, Kolligs FT, Dlugosz AA, Fearon ER. Transient activation of ß-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev 2003;17(10):1219-1224.
56. Andl T, Reddy ST, Gaddapara T, Millar SE. WNT signals are required for the initiation of hair follicle development. Dev Cell 2002;2(5):643-653.
57. Niemann C, Owens DM, Hulsken J, Birchmeier W, Watt FM. Expression of δNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours. Development 2002;129(1):95-109.
58. Takeda H, Lyle S, Lazar AJ, Zouboulis CC, Smyth I, Watt FM. Human sebaceous tumors harbor inactivating mutations in LEF1. Nat Med 2006;12(4):395-397.
59. Honeycutt KA, Roop DR. c-Myc and epidermal stem cell fate determination. J Dermatol 2004;31(5):368-375.
60. Watt FM, Frye M, Benitah SA. MYC in mammalian epidermis: how can an oncogene stimulate differentiation? Nat Rev Cancer 2008;8(3):234- 242.
61. Arnold I, Watt FM. c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny. Curr Biol 2001;11(8):558-568.
62. Frye M, Gardner C, Li ER, Arnold I, Watt FM. Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment. Development 2003;130(12):2793-2808.
63. Koster MI, Huntzinger KA, Roop DR. Epidermal differentiation: transgenic/knockout mouse models reveal genes involved in stem cell fate decisions and commitment to differentiation. J Investig Dermatol Symp Proc 2002;7(1):41-45.
64. Waikel RL, Kawachi Y, Waikel PA, Wang XJ, Roop DR. Deregulated expression of c-Myc depletes epidermal stem cells. Nat Genet 2001;28(2):165- 168.
65. Silva-Vargas V, Lo Celso C, Giangreco A, Ofstad T, Prowse DM, Braun KM, et al. ß-Catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev Cell 2005;9(1):121-131.
66. Gritli-Linde A, Hallberg K, Harfe BD, Reyahi A, Kannius-Janson M, Nilsson J, et al. Abnormal hair development and apparent follicular transformation to mammary gland in the absence of hedgehog signaling. Dev Cell 2007;12(1):99-112.
67. Lee J, Basak JM, Demehri S, Kopan R. Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes. Development 2007;134(15): 2795-2806.
68. Blanpain C, Lowry WE, Pasolli HA, Fuchs E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev 2006;20(21):3022-3035.
69. Estrach S, Ambler CA, Lo Celso C, Hozumi K, Watt FM. Jagged 1 is a ß-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development 2006;133(22):4427-4438.
70. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 2001;20(13):3427-3436.
71. Moriyama M, Durham AD, Moriyama H, Hasegawa K, Nishikawa S, Radtke F, et al. Multiple roles of Notch signaling in the regulation of epidermal development. Dev Cell 2008;14(4):594-604.
72. Pan Y, Lin MH, Tian X, Cheng HT, Gridley T, Shen J, et al. γ-Secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004;7(5):731-743.
73. Vauclair S, Nicolas M, Barrandon Y, Radtke F. Notch1 is essential for postnatal hair follicle development and homeostasis. Dev Biol 2005;284(1):184-193.
74. Ambler CA, Watt FM. Expression of Notch pathway genes in mammalian epidermis and modulation by ß-catenin. Dev Dyn 2007;236(6): 1595-1601.
75. Kopan R, Weintraub H. Mouse notch: expression in hair follicles correlates with cell fate determination. J Cell Biol 1993;121(3): 631-641.
76. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 2003;33(3):416-421.
77. Sun J, Deng WM. Hindsight mediates the role of notch in suppressing hedgehog signaling and cell proliferation. Dev Cell 2007;12(3): 431-442.
78. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3(7):730-737.
79. Costea DE, Gammon L, Kitajima K, Harper L, Mackenzie IC. Epithelial stem cells and malignancy. J Anat 2008;213(1):45-51.
80. Sales KM, Winslet MC, Seifalian AM. Stem cells and cancer: an overview. Stem Cell Rev 2007;3(4):249-255.
81. Locke M, Heywood M, Fawell S, Mackenzie IC. Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res 2005;65(19):8944-8950.
82. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 2007;104(3):973-978.
83. Jensen KB, Jones J, Watt FM. A stem cell gene expression profile of human squamous cell carcinomas. Cancer Lett 2008(Jul;25).
84. Malanchi I, Peinado H, Kassen D, Hussenet T, Met-zger D, Chambon P, et al. Cutaneous cancer stem cell maintenance is dependent on ß-catenin signalling. Nature 2008;452(7187):650-653.
85. Trempus CS, Morris RJ, Ehinger M, Elmore A, Bortner CD, Ito M, et al. CD34 expression by hair follicle stem cells is required for skin tumor development in mice. Cancer Res 2007;67(9):4173-4181.
86. Bhatia N, Spiegelman VS. Activation of Wnt/ß-catenin/Tcf signaling in mouse skin carcinogenesis. Mol Carcinog 2005;42(4):213-221.
87. Braun KM. Cutaneous cancer stem cells: ß-catenin strikes again. Cell Stem Cell 2008;2(5):406-408.
88. Van Waes C, Surh DM, Chen Z, Kirby M, Rhim JS, Brager R, et al. Increase in suprabasilar integrin adhesion molecule expression in human epidermal neoplasms accompanies increased proliferation occurring with immortalization and tumor progression. Cancer Res 1995;55(22): 5434-5444.
89. Tennenbaum T, Weiner AK, Belanger AJ, Glick AB, Hen-nings H, Yuspa SH. The suprabasal expression of α6β4 integrin is associated with a high risk for malignant progression in mouse skin carcinogenesis. Cancer Res 1993;53(20):4803-4810.
90. Owens DM, Romero MR, Gardner C, Watt FM. Suprabasal α6β4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFß signalling. Cell Sci 2003;116(18):3783- 3791.
91. Raymond K, Kreft M, Song JY, Janssen H, Sonnenberg A. Dual role of α6β4 integrin in epidermal tumor growth: tumor-suppressive versus tumor-promoting function. Mol Biol Cell 2007;18(11):4210-4221.
92. Harper LJ, Piper K, Common J, Fortune F, Mackenzie IC. Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med 2007;36(10):594-603.
93. Mackenzie IC. Growth of malignant oral epithelial stem cells after seeding into organotypical cultures of normal mucosa. J Oral Pathol Med 2004;33(2):71-78.
94. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100(7):3983-3988.
95. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67(3):1030-1037.
96. DalerbaP, DyllaSJ, ParkIK, LiuR, WangX, ChoRW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007;104(24):10158-10 163.
97. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005;65(23):10946-10951.
98. Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 2004;117(16):3539-3545.
99. Ponta H, Wainwright D, Herrlich P. The CD44 protein family. Int J Biochem Cell Biol 1998;30(3):299-305.
100. Patel DD, Liao HX, Haynes BF. CD44 workshop panel report. In Leukocyte Typing VI: White Cell Differentiation Antigens, Kishimoto T, Kikutani H, von dem Borne AEGK (eds). Garland: New York, 1997; 373-375.
101. Hudson DL, Sleeman J, Watt FM. CD44 is the major peanut lectin-binding glycoprotein of human epidermal keratinocytes and plays a role in intercellular adhesion. J Cell Sci 1995;108(5):1959-1970.
102. Herold-Mende C, Seiter S, Born AI, Patzelt E, Schupp M, Zoller J, et al. Expression of CD44 splice variants in squamous epithelia and squamous cell carcinomas of the head and neck. J Pathol 1996;179(1):66-73.
103. Hudson DL, Speight PM, Watt FM. Altered expression of CD44 isoforms in squamous-cell carcinomas and cell lines derived from them. Int J Cancer 1996;66(4):457-463.
104. Ue T, Yokozaki H, Kagai K, Higashikawa K, Yasui W, Sugiyama M, et al. Reduced expression of the CD44 variant exons in oral squamous cell carcinoma and its relationship to metastasis. J Oral Pathol Med 1998;27(5):197-201.
105. Atsumi N, Ishii G, Kojima M, Sanada M, Fujii S, Ochiai A. Podoplanin, a novel marker of tumor-initiating cells in human squamous cell carcinoma A431. Biochem Biophys Res Commun 2008;373(1):36-41.
106. Martin-Villar E, Megias D, Castel S, Yurrita MM, Vilaro S, Quintanilla M. Podoplanin binds ERM proteins to activate RhoA and promote epithelial- mesenchymal transition. J Cell Sci 2006;119(21):4541-4553.
107. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoi-etic stem cells that are replicating in vivo. J Exp Med 1996;183(4):1797-1806.
108. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, et al. A distinct 'side population' of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 2004;101(39):14228- 14233.
109. Terunuma A, Jackson KL, Kapoor V, Telford WG, Vogel JC. Side population keratinocytes resembling bone marrow side population stem cells are distinct from label-retaining keratinocyte stem cells. J Invest Dermatol 2003;121(5):1095-1103.
110. Triel C, Vestergaard ME, Bolund L, Jensen TG, Jensen UB. Side population cells in human and mouse epidermis lack stem cell characteristics. Exp Cell Res 2004;295(1):79-90.
111. Larderet G, Fortunel NO, Vaigot P, Cegalerba M, Maltere P, Zobiri O, et al. Human side population keratinocytes exhibit long-term proliferative potential and a specific gene expression profile and can form a pluristratified epidermis. Stem Cells 2006;24(4):965-974.
112. Terunuma A, Kapoor V, Yee C, Telford WG, Udey MC, Vogel JC. Stem cell activity of human side population and α6 integrin-bright keratinocytes defined by a quantitative in vivo assay. Stem Cells 2007;25(3):664-669.
113. Yano S, Ito Y, Fujimoto M, Hamazaki TS, Tamaki K, Okochi H. Characterization and localization of side population cells in mouse skin. Stem Cells 2005;23(6):834-841.
114. Redvers RP, Li A, Kaur P. Side population in adult murine epidermis exhibits phenotypic and functional characteristics of keratinocyte stem cells. Proc Natl Acad Sci USA 2006;103(35):13168-13173.
115. Loebinger MR, Giangreco A, Groot KR, Prichard L, Allen K, Simpson C, et al. Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade. Br J Cancer 2008;98(2):380-387.
116. Adolphe C, Hetherington R, Ellis T, Wainwright B. Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res 2006;66(4):2081-2088.
117. Daya-Grosjean L, Couve-Privat S. Sonic hedgehog signaling in basal cell carcinomas. Cancer Lett 2005;225(2):181-192.
118. Athar M, Tang X, Lee JL, Kopelovich L, Kim AL. Hedgehog signalling in skin development and cancer. Exp Dermatol 2006;15(9):667-677.
119. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shan-ley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85(6):841- 851.
120. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH Jr, Scott MP. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 1997;276(5313):817-821.
121. Hutchin ME, Kariapper MS, Grachtchouk M, Wang A, Wei L, Cummings D, et al. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev 2005;19(2):214-223.
122. Hoseong Yang S, Andl T, Grachtchouk V, Wang A, Liu J, Syu LJ, et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/ß-catenin signaling. Nat Genet 2008(Aug;1).
123. Keyes WM, Vogel H, Koster MI, Guo X, Qi Y, Pether-bridge KM, et al. p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors. Proc Natl Acad Sci USA 2006;103(22):8435-8440.
124. Oskarsson T, Essers MA, Dubois N, Offner S, Dubey C, Roger C, et al. Skin epidermis lacking the c-Myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene. Genes Dev 2006;20(15):2024-2029.
125. Rounbehler RJ, Schneider-Broussard R, Conti CJ, Johnson DG. Myc lacks E2F1's ability to suppress skin carcinogenesis. Oncogene 2001;20(38):5341-5349.
126. Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, et al. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci USA 2001 Sep 11;98:10863-8.
127. Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J, et al. Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 2006;66(15):7438-7444.
128. Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolf-schoten I, et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKα kinases. Genes Dev 2007;21(5):562-577.
129. Estrach S, Cordes R, Hozumi K, Gossler A, Watt FM. Role of the Notch ligand δ1 in embryonic and adult mouse epidermis. J Invest Dermatol 2008;128(4):825-832.