| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892
The multistage nature of cancer pathogenesis was first defined over 50 years ago by the sequential topical application of chemical agents to mouse skin. Since then, the skin model has provided remarkable insights into the biology, biochemistry, pharmacology, and genetics of carcinogenesis. Discoveries from studies of mouse skin have proved to be landmarks in cancer research including: the binding of carcinogens to DNA; the monoclonal origin of benign and malignant tumors; the powerful tumor-promoting action of phorbol esters; the antipromoting potency of retinoids and steroids; the modifying role of age, caloric intake, and specific dietary constituents on cancer induction; the variable risk for benign tumors to progress to cancer; and the requirement for multiple genetic changes in malignant conversion. Many of these concepts are now widely applied to the interpretation of specific molecular discoveries both in simple experimental systems and in human cancers, but the power of this quantitative, multistage skin carcinogenesis model has made these assessments possible. It has also provided the separation of mechanistically distinct stages in cancer pathogenesis: initiation; promotion; premalignant progression; and malignant conversion. This paper will review our current understanding of the genetic, biological, and biochemical alterations that contribute to the evolution of each of these stages in skin carcinogenesis. These new insights provide an opportunity to replace the traditional operational-based schemata defining the process of carcinogenesis with a working model designed around functional alterations in neoplastic cells.
1 Presented at the 84th Annual Meeting of the American Association for Cancer Research, May 20, 1993, Orlando, FL.
Received 1/ 5/94. Accepted 1/ 5/94.
This article has been cited by other articles:
|
|
 |
|
  A. Bhoumik, B. Fichtman, C. DeRossi, W. Breitwieser, H. M. Kluger, S. Davis, A. Subtil, P. Meltzer, S. Krajewski, N. Jones, et al. Suppressor role of activating transcription factor 2 (ATF2) in skin cancer PNAS, February 5, 2008; 105(5): 1674 - 1679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lu, O. Rho, E. Wilker, L. Beltran, and J. DiGiovanni Activation of Epidermal Akt by Diverse Mouse Skin Tumor Promoters Mol. Cancer Res., December 1, 2007; 5(12): 1342 - 1352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-J. Oh, V. Rishi, S. Pelech, and C. Vinson Histological and proteomic analysis of reversible H-RasV12G expression in transgenic mouse skin Carcinogenesis, October 1, 2007; 28(10): 2244 - 2252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Loomis, S. Zhu, K. Yoon, P. F. Johnson, and R. C. Smart Genetic Ablation of CCAAT/Enhancer Binding Protein {alpha} in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis Cancer Res., July 15, 2007; 67(14): 6768 - 6776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Trempus, R. J. Morris, M. Ehinger, A. Elmore, C. D. Bortner, M. Ito, G. Cotsarelis, J. G.W. Nijhof, J. Peckham, N. Flagler, et al. CD34 Expression by Hair Follicle Stem Cells Is Required for Skin Tumor Development in Mice Cancer Res., May 1, 2007; 67(9): 4173 - 4181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Makita, M. Mutoh, T. Maruyama, K. Yonemoto, A. Kobayashi, H. Fujitsuka, M. Toida, T. Shibata, S. Miyamoto, Y. Yasui, et al. A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis Carcinogenesis, March 1, 2007; 28(3): 677 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Cardiff, M. R. Anver, G. P. Boivin, M. W. Bosenberg, R. R. Maronpot, A. A. Molinolo, A. Y. Nikitin, J. E. Rehg, G. V. Thomas, R. G. Russell, et al. Precancer in Mice: Animal Models Used to Understand, Prevent, and Treat Human Precancers Toxicol Pathol, October 1, 2006; 34(6): 699 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. M. Sung, G. He, and S. M. Fischer Lack of Expression of the EP2 but not EP3 Receptor for Prostaglandin E2 Results in Suppression of Skin Tumor Development Cancer Res., October 15, 2005; 65(20): 9304 - 9311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fuhrman, L. Shafer, S. Repertinger, T. Chan, and L. A. Hansen Mechanisms of SEPA 0009-Induced Tumorigenesis in v-rasHa Transgenic Tg.AC Mice Toxicol Pathol, October 1, 2005; 33(6): 623 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Iyer, K. Pumiglia, and C. M. DiPersio {alpha}3{beta}1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: a novel mechanism of integrin-mediated MMP gene expression J. Cell Sci., March 15, 2005; 118(6): 1185 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Bai, H. Edamatsu, S. Maeda, H. Saito, N. Suzuki, T. Satoh, and T. Kataoka Crucial Role of Phospholipase C{epsilon} in Chemical Carcinogen-Induced Skin Tumor Development Cancer Res., December 15, 2004; 64(24): 8808 - 8810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Wyde, A. P. J. M. Braen, M. Hejtmancik, J. D. Johnson, J. D. Toft, J. C. Blake, S. D. Cooper, J. Mahler, M. Vallant, J. R. Bucher, et al. Oral and Dermal Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Induces Cutaneous Papillomas and Squamous Cell Carcinomas in Female Hemizygous Tg.AC Transgenic Mice Toxicol. Sci., November 1, 2004; 82(1): 34 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Shuman, T. Sebastian, P. Kaldis, T. D. Copeland, S. Zhu, R. C. Smart, and P. F. Johnson Cell Cycle-Dependent Phosphorylation of C/EBP{beta} Mediates Oncogenic Cooperativity between C/EBP{beta} and H-RasV12 Mol. Cell. Biol., September 1, 2004; 24(17): 7380 - 7391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Woodworth, E. Michael, L. Smith, K. Vijayachandra, A. Glick, H. Hennings, and S. H. Yuspa Strain-dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte Carcinogenesis, September 1, 2004; 25(9): 1771 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Fraga, M. Herranz, J. Espada, E. Ballestar, M. F. Paz, S. Ropero, E. Erkek, O. Bozdogan, H. Peinado, A. Niveleau, et al. A Mouse Skin Multistage Carcinogenesis Model Reflects the Aberrant DNA Methylation Patterns of Human Tumors Cancer Res., August 15, 2004; 64(16): 5527 - 5534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Helfrich, M. Chen, R. Schmidt, G. Furstenberger, A. Kopp-Schneider, D. Trick, H.-J. Grone, H. zur Hausen, and F. Rosl Increased Incidence of Squamous Cell Carcinomas in Mastomys natalensis Papillomavirus E6 Transgenic Mice during Two-Stage Skin Carcinogenesis J. Virol., May 1, 2004; 78(9): 4797 - 4805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Shaham, Y Bomstein, R Gurvich, M Rashkovsky, and Z Kaufman DNA-protein crosslinks and p53 protein expression in relation to occupational exposure to formaldehyde Occup. Environ. Med., June 1, 2003; 60(6): 403 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tarutani, T. Cai, M. Dajee, and P. A. Khavari Inducible Activation of Ras and Raf in Adult Epidermis Cancer Res., January 15, 2003; 63(2): 319 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Weinberg and M. F. Denning P21WAF1 CONTROL OF EPITHELIAL CELL CYCLE AND CELL FATE Crit. Rev. Oral. Biol. Med., November 1, 2002; 13(6): 453 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sheng, S. Goich, A. Wang, M. Grachtchouk, L. Lowe, R. Mo, K. Lin, F. J. de Sauvage, H. Sasaki, C.-c. Hui, et al. Dissecting the Oncogenic Potential of Gli2: Deletion of an NH2-Terminal Fragment Alters Skin Tumor Phenotype Cancer Res., September 15, 2002; 62(18): 5308 - 5316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Cripps, A. T. Figueredo, A. M. Oza, M. J. Taylor, A. L. Fields, J. T. Holmlund, L. W. McIntosh, R. S. Geary, and E. A. Eisenhauer Phase II Randomized Study of ISIS 3521 and ISIS 5132 in Patients with Locally Advanced or Metastatic Colorectal Cancer: A National Cancer Institute of Canada Clinical Trials Group Study Clin. Cancer Res., July 1, 2002; 8(7): 2188 - 2192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. F. Tiano, C. D. Loftin, J. Akunda, C. A. Lee, J. Spalding, A. Sessoms, D. B. Dunson, E. G. Rogan, S. G. Morham, R. C. Smart, et al. Deficiency of Either Cyclooxygenase (COX)-1 or COX-2 Alters Epidermal Differentiation and Reduces Mouse Skin Tumorigenesis Cancer Res., June 1, 2002; 62(12): 3395 - 3401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Joseloff, C. Cataisson, H. Aamodt, H. Ocheni, P. Blumberg, A. J. Kraker, and S. H. Yuspa Src Family Kinases Phosphorylate Protein Kinase C delta on Tyrosine Residues and Modify the Neoplastic Phenotype of Skin Keratinocytes J. Biol. Chem., March 29, 2002; 277(14): 12318 - 12323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yamamoto, T. Ochiya, F. Takeshita, H. Toriyama-Baba, K. Hirai, H. Sasaki, H. Sasaki, H. Sakamoto, T. Yoshida, I. Saito, et al. Enhanced Skin Carcinogenesis in Cyclin D1-conditional Transgenic Mice: Cyclin D1 Alters Keratinocyte Response to Calcium-induced Terminal Differentiation Cancer Res., March 1, 2002; 62(6): 1641 - 1647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Coleman, A. E. Pegg, L. C. Megosh, Y. Guo, J. A. Sawicki, and T. G. O'Brien Targeted expression of spermidine/spermine N1-acetyltransferase increases susceptibility to chemically induced skin carcinogenesis Carcinogenesis, February 1, 2002; 23(2): 359 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhu, K. Yoon, E. Sterneck, P. F. Johnson, and R. C. Smart CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling PNAS, December 21, 2001; (2001) 12437299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hatoum, M. E. El-Sabban, J. Khoury, S. H. Yuspa, and N. Darwiche Overexpression of retinoic acid receptors alpha and gamma into neoplastic epidermal cells causes retinoic acid-induced growth arrest and apoptosis Carcinogenesis, December 1, 2001; 22(12): 1955 - 1963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ahmad, A. C. Gilliam, S. K. Katiyar, T. G. O'Brien, and H. Mukhtar A Definitive Role of Ornithine Decarboxylase in Photocarcinogenesis Am. J. Pathol., September 1, 2001; 159(3): 885 - 892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Feith, L. M. Shantz, and A. E. Pegg Targeted Antizyme Expression in the Skin of Transgenic Mice Reduces Tumor Promoter Induction of Ornithine Decarboxylase and Decreases Sensitivity to Chemical Carcinogenesis Cancer Res., August 1, 2001; 61(16): 6073 - 6081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Owens and F. M. Watt Influence of {beta}1 Integrins on Epidermal Squamous Cell Carcinoma Formation in a Transgenic Mouse Model: {{alpha}}3{beta}1, but not {{alpha}}2{beta}1, Suppresses Malignant Conversion Cancer Res., July 1, 2001; 61(13): 5248 - 5254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Jansen, E. G. Verwiebe, N. E. Dreckschmidt, D. L. Wheeler, T. D. Oberley, and A. K. Verma Protein Kinase C-{{epsilon}} Transgenic Mice: A Unique Model for Metastatic Squamous Cell Carcinoma Cancer Res., February 1, 2001; 61(3): 808 - 812. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Shen, A. Alt, E. Wertheimer, M. Gartsbein, T. Kuroki, M. Ohba, L. Braiman, S. R. Sampson, and T. Tennenbaum PKC{delta} Activation: A Divergence Point in the Signaling of Insulin and IGF-1--Induced Proliferation of Skin Keratinocytes Diabetes, February 1, 2001; 50(2): 255 - 264. [Abstract] [Full Text]
|
|
|
|
|
|
V. K. Harris, C. M. Coticchia, B. L. Kagan, S. Ahmad, A. Wellstein, and A. T. Riegel Induction of the Angiogenic Modulator Fibroblast Growth Factor-binding Protein by Epidermal Growth Factor Is Mediated through Both MEK/ERK and p38 Signal Transduction Pathways J. Biol. Chem., April 6, 2000; 275(15): 10802 - 10811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Coghlan, I. Gimenez-Conti, H. E. Kleiner, S. M. Fischer, J. E. Rundhaug, C. J. Conti, T. J. Slaga, and J. DiGiovanni Development and initial characterization of several new inbred strains of SENCAR mice for studies of multistage skin carcinogenesis Carcinogenesis, April 1, 2000; 21(4): 641 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhao, M. Lahiri-Chatterjee, Y. Sharma, and R. Agarwal Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin Carcinogenesis, April 1, 2000; 21(4): 811 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Balmain and C. C.Harris Carcinogenesis in mouse and human cells: parallels and paradoxes Carcinogenesis, March 1, 2000; 21(3): 371 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Z. Qin, V. Chaturvedi, M. F. Denning, D. Choubey, M. O. Diaz, and B. J. Nickoloff Role of NF-kappa B in the Apoptotic-resistant Phenotype of Keratinocytes J. Biol. Chem., December 31, 1999; 274(53): 37957 - 37964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Li, P. S. Lorenzo, K. Bogi, P. M. Blumberg, and S. H. Yuspa Protein Kinase Cdelta Targets Mitochondria, Alters Mitochondrial Membrane Potential, and Induces Apoptosis in Normal and Neoplastic Keratinocytes When Overexpressed by an Adenoviral Vector Mol. Cell. Biol., December 1, 1999; 19(12): 8547 - 8558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nemunaitis, J. T. Holmlund, M. Kraynak, D. Richards, J. Bruce, N. Ognoskie, T. J. Kwoh, R. Geary, A. Dorr, D. Von Hoff, et al. Phase I Evaluation of ISIS 3521, an Antisense Oligodeoxynucleotide to Protein Kinase C-Alpha, in Patients With Advanced Cancer J. Clin. Oncol., November 1, 1999; 17(11): 3586 - 3595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Kemp, K. Vo, and K. E. Gurley Resistance to skin tumorigenesis in DNAPK-deficient SCID mice is not due to immunodeficiency but results from hypersensitivity to TPA-induced apoptosis Carcinogenesis, November 1, 1999; 20(11): 2051 - 2056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kumar and A. Holmgren Induction of thioredoxin, thioredoxin reductase and glutaredoxin activity in mouse skin by TPA, a calcium ionophore and other tumor promoters Carcinogenesis, September 1, 1999; 20(9): 1761 - 1767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Duffey, Z. Chen, G. Dong, F. G. Ondrey, J. S. Wolf, K. Brown, U. Siebenlist, and C. Van Waes Expression of a Dominant-Negative Mutant Inhibitor-{{kappa}}B{{alpha}} of Nuclear Factor-{{kappa}}B in Human Head and Neck Squamous Cell Carcinoma Inhibits Survival, Proinflammatory Cytokine Expression, and Tumor Growth in Vivo Cancer Res., July 1, 1999; 59(14): 3468 - 3474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. T. Siegel, K. Schreiber, S. C. Meredith, G. B. Beck-Engeser, D. W. Lancki, C. A. Lazarski, Y.-X. Fu, D. A. Rowley, and H. Schreiber Enhanced Growth of Primary Tumors in Cancer-prone Mice after Immunization against the Mutant Region of an Inherited Oncoprotein J. Exp. Med., June 6, 1999; 191(11): 1945 - 1956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Kemp Comparative Hepatocellular Cancer Genetics Am. J. Pathol., April 1, 1999; 154(4): 975 - 977. [Full Text] [PDF]
|
|
|
|
|
|
M. Lahiri-Chatterjee, S. K. Katiyar, R. R. Mohan, and R. Agarwal A Flavonoid Antioxidant, Silymarin, Affords Exceptionally High Protection against Tumor Promotion in the SENCAR Mouse Skin Tumorigenesis Model Cancer Res., February 1, 1999; 59(3): 622 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Todd and N. J. Reynolds Up-Regulation of p21WAF1 by Phorbol Ester and Calcium in Human Keratinocytes through a Protein Kinase C-Dependent Pathway Am. J. Pathol., July 1, 1998; 153(1): 39 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Calautti, C Missero, P L Stein, R M Ezzell, and G P Dotto fyn tyrosine kinase is involved in keratinocyte differentiation control. Genes & Dev., September 15, 1995; 9(18): 2279 - 2291. [Abstract] [PDF]
|
|
|
|
|
|
A B Glick, M M Lee, N Darwiche, A B Kulkarni, S Karlsson, and S H Yuspa Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma. Genes & Dev., October 15, 1994; 8(20): 2429 - 2440. [Abstract] [PDF]
|
|
|
|
|
|
S. Zhu, K. Yoon, E. Sterneck, P. F. Johnson, and R. C. Smart CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling PNAS, January 8, 2002; 99(1): 207 - 212. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
