Abstract
Tumour formation relies on a complex combination of genetic and environmental factors. In particular, the contributions from inherited predisposition genes as well as carcinogens, for example from cigarettes or in the diet, are amongst the major contributors to tumorigenesis. Since the study of such processes in particularly difficult in human cancers, the availability of a well-defined model system is of obvious benefit. The mouse skin model of multistage carcinogenesis offers an excellent tool for the study of the target cells, the target genes and the biological events associated with neoplasia. In this system, tumorigenesis occurs in a series of defined stages, each of which is characterized by specific and reproducible alterations in genes such as H-ras, cyclin D1, p53 and p16INK4A. Additional changes occur in the production of, or response to, factors such as transforming growth factor beta (TGF beta). These genetic and biological alterations are mirrored in human tumours of epithelial origin. Hence, research into the general principles of tumour initiation, promotion and progression in the context of the mouse skin model is likely to prove valuable in the continual search for new methods for the diagnosis, prevention, and therapeutic treatment of human cancers.
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- Bailleul B., Surani M. A., White S., Barton S. C., Brown K., Blessing M., Jorcano J., Balmain A. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell. 1990 Aug 24;62(4):697–708. doi: 10.1016/0092-8674(90)90115-u. [DOI] [PubMed] [Google Scholar]
- Behrens J., Mareel M. M., Van Roy F. M., Birchmeier W. Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol. 1989 Jun;108(6):2435–2447. doi: 10.1083/jcb.108.6.2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bianchi A. B., Aldaz C. M., Conti C. J. Nonrandom duplication of the chromosome bearing a mutated Ha-ras-1 allele in mouse skin tumors. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6902–6906. doi: 10.1073/pnas.87.17.6902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bianchi A. B., Fischer S. M., Robles A. I., Rinchik E. M., Conti C. J. Overexpression of cyclin D1 in mouse skin carcinogenesis. Oncogene. 1993 May;8(5):1127–1133. [PubMed] [Google Scholar]
- Bremner R., Balmain A. Genetic changes in skin tumor progression: correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7. Cell. 1990 May 4;61(3):407–417. doi: 10.1016/0092-8674(90)90523-h. [DOI] [PubMed] [Google Scholar]
- Bremner R., Kemp C. J., Balmain A. Induction of different genetic changes by different classes of chemical carcinogens during progression of mouse skin tumors. Mol Carcinog. 1994 Oct;11(2):90–97. doi: 10.1002/mc.2940110206. [DOI] [PubMed] [Google Scholar]
- Brown K., Buchmann A., Balmain A. Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumor progression. Proc Natl Acad Sci U S A. 1990 Jan;87(2):538–542. doi: 10.1073/pnas.87.2.538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bubb V. J., Curtis L. J., Cunningham C., Dunlop M. G., Carothers A. D., Morris R. G., White S., Bird C. C., Wyllie A. H. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. 1996 Jun 20;12(12):2641–2649. [PubMed] [Google Scholar]
- Buchmann A., Ruggeri B., Klein-Szanto A. J., Balmain A. Progression of squamous carcinoma cells to spindle carcinomas of mouse skin is associated with an imbalance of H-ras alleles on chromosome 7. Cancer Res. 1991 Aug 1;51(15):4097–4101. [PubMed] [Google Scholar]
- Caelles C., Helmberg A., Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature. 1994 Jul 21;370(6486):220–223. doi: 10.1038/370220a0. [DOI] [PubMed] [Google Scholar]
- Cairns J. Mutation selection and the natural history of cancer. Nature. 1975 May 15;255(5505):197–200. doi: 10.1038/255197a0. [DOI] [PubMed] [Google Scholar]
- Caulín C., Scholl F. G., Frontelo P., Gamallo C., Quintanilla M. Chronic exposure of cultured transformed mouse epidermal cells to transforming growth factor-beta 1 induces an epithelial-mesenchymal transdifferentiation and a spindle tumoral phenotype. Cell Growth Differ. 1995 Aug;6(8):1027–1035. [PubMed] [Google Scholar]
- Clarke A. R., Gledhill S., Hooper M. L., Bird C. C., Wyllie A. H. p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following gamma-irradiation. Oncogene. 1994 Jun;9(6):1767–1773. [PubMed] [Google Scholar]
- Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
- Cui W., Fowlis D. J., Bryson S., Duffie E., Ireland H., Balmain A., Akhurst R. J. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell. 1996 Aug 23;86(4):531–542. doi: 10.1016/s0092-8674(00)80127-0. [DOI] [PubMed] [Google Scholar]
- Dameron K. M., Volpert O. V., Tainsky M. A., Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science. 1994 Sep 9;265(5178):1582–1584. doi: 10.1126/science.7521539. [DOI] [PubMed] [Google Scholar]
- Filmus J., Robles A. I., Shi W., Wong M. J., Colombo L. L., Conti C. J. Induction of cyclin D1 overexpression by activated ras. Oncogene. 1994 Dec;9(12):3627–3633. [PubMed] [Google Scholar]
- Graeber T. G., Osmanian C., Jacks T., Housman D. E., Koch C. J., Lowe S. W., Giaccia A. J. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996 Jan 4;379(6560):88–91. doi: 10.1038/379088a0. [DOI] [PubMed] [Google Scholar]
- Greenhalgh D. A., Wang X. J., Donehower L. A., Roop D. R. Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha. Cancer Res. 1996 Oct 1;56(19):4413–4423. [PubMed] [Google Scholar]
- Hall M., Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. 1996;68:67–108. doi: 10.1016/s0065-230x(08)60352-8. [DOI] [PubMed] [Google Scholar]
- Hall P. A., Watt F. M. Stem cells: the generation and maintenance of cellular diversity. Development. 1989 Aug;106(4):619–633. doi: 10.1242/dev.106.4.619. [DOI] [PubMed] [Google Scholar]
- Hannon G. J., Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994 Sep 15;371(6494):257–261. doi: 10.1038/371257a0. [DOI] [PubMed] [Google Scholar]
- Hirakawa T., Ruley H. E. Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1519–1523. doi: 10.1073/pnas.85.5.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jen J., Harper J. W., Bigner S. H., Bigner D. D., Papadopoulos N., Markowitz S., Willson J. K., Kinzler K. W., Vogelstein B. Deletion of p16 and p15 genes in brain tumors. Cancer Res. 1994 Dec 15;54(24):6353–6358. [PubMed] [Google Scholar]
- Jouanneau J., Tucker G. C., Boyer B., Vallés A. M., Thiery J. P. Epithelial cell plasticity in neoplasia. Cancer Cells. 1991 Dec;3(12):525–529. [PubMed] [Google Scholar]
- Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436–440. doi: 10.1126/science.8153634. [DOI] [PubMed] [Google Scholar]
- Kemp C. J., Donehower L. A., Bradley A., Balmain A. Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell. 1993 Sep 10;74(5):813–822. doi: 10.1016/0092-8674(93)90461-x. [DOI] [PubMed] [Google Scholar]
- Kemp C. J., Fee F., Balmain A. Allelotype analysis of mouse skin tumors using polymorphic microsatellites: sequential genetic alterations on chromosomes 6, 7, and 11. Cancer Res. 1993 Dec 15;53(24):6022–6027. [PubMed] [Google Scholar]
- Lammie G. A., Fantl V., Smith R., Schuuring E., Brookes S., Michalides R., Dickson C., Arnold A., Peters G. D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene. 1991 Mar;6(3):439–444. [PubMed] [Google Scholar]
- Lassus P., Ferlin M., Piette J., Hibner U. Anti-apoptotic activity of low levels of wild-type p53. EMBO J. 1996 Sep 2;15(17):4566–4573. [PMC free article] [PubMed] [Google Scholar]
- Lee E. Y., To H., Shew J. Y., Bookstein R., Scully P., Lee W. H. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science. 1988 Jul 8;241(4862):218–221. doi: 10.1126/science.3388033. [DOI] [PubMed] [Google Scholar]
- Leon J., Kamino H., Steinberg J. J., Pellicer A. H-ras activation in benign and self-regressing skin tumors (keratoacanthomas) in both humans and an animal model system. Mol Cell Biol. 1988 Feb;8(2):786–793. doi: 10.1128/mcb.8.2.786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Linardopoulos S., Street A. J., Quelle D. E., Parry D., Peters G., Sherr C. J., Balmain A. Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. Cancer Res. 1995 Nov 15;55(22):5168–5172. [PubMed] [Google Scholar]
- Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. doi: 10.1016/0092-8674(91)90642-c. [DOI] [PubMed] [Google Scholar]
- Loughran O., Edington K. G., Berry I. J., Clark L. J., Parkinson E. K. Loss of heterozygosity of chromosome 9p21 is associated with the immortal phenotype of neoplastic human head and neck keratinocytes. Cancer Res. 1994 Oct 1;54(19):5045–5049. [PubMed] [Google Scholar]
- Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
- MacCallum D. E., Hupp T. R., Midgley C. A., Stuart D., Campbell S. J., Harper A., Walsh F. S., Wright E. G., Balmain A., Lane D. P. The p53 response to ionising radiation in adult and developing murine tissues. Oncogene. 1996 Dec 19;13(12):2575–2587. [PubMed] [Google Scholar]
- Medema R. H., Bos J. L. The role of p21ras in receptor tyrosine kinase signaling. Crit Rev Oncog. 1993;4(6):615–661. [PubMed] [Google Scholar]
- Merlo A., Herman J. G., Mao L., Lee D. J., Gabrielson E., Burger P. C., Baylin S. B., Sidransky D. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995 Jul;1(7):686–692. doi: 10.1038/nm0795-686. [DOI] [PubMed] [Google Scholar]
- Moen C. J., van der Valk M. A., Snoek M., van Zutphen B. F., von Deimling O., Hart A. A., Demant P. The recombinant congenic strains--a novel genetic tool applied to the study of colon tumor development in the mouse. Mamm Genome. 1991;1(4):217–227. doi: 10.1007/BF00352328. [DOI] [PubMed] [Google Scholar]
- Nagase H., Bryson S., Cordell H., Kemp C. J., Fee F., Balmain A. Distinct genetic loci control development of benign and malignant skin tumours in mice. Nat Genet. 1995 Aug;10(4):424–429. doi: 10.1038/ng0895-424. [DOI] [PubMed] [Google Scholar]
- Navarro P., Gómez M., Pizarro A., Gamallo C., Quintanilla M., Cano A. A role for the E-cadherin cell-cell adhesion molecule during tumor progression of mouse epidermal carcinogenesis. J Cell Biol. 1991 Oct;115(2):517–533. doi: 10.1083/jcb.115.2.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nishikawa R., Furnari F. B., Lin H., Arap W., Berger M. S., Cavenee W. K., Su Huang H. J. Loss of P16INK4 expression is frequent in high grade gliomas. Cancer Res. 1995 May 1;55(9):1941–1945. [PubMed] [Google Scholar]
- Oda T., Kanai Y., Oyama T., Yoshiura K., Shimoyama Y., Birchmeier W., Sugimura T., Hirohashi S. E-cadherin gene mutations in human gastric carcinoma cell lines. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1858–1862. doi: 10.1073/pnas.91.5.1858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oft M., Peli J., Rudaz C., Schwarz H., Beug H., Reichmann E. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 1996 Oct 1;10(19):2462–2477. doi: 10.1101/gad.10.19.2462. [DOI] [PubMed] [Google Scholar]
- Parsons R., Myeroff L. L., Liu B., Willson J. K., Markowitz S. D., Kinzler K. W., Vogelstein B. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res. 1995 Dec 1;55(23):5548–5550. [PubMed] [Google Scholar]
- Pierceall W. E., Goldberg L. H., Tainsky M. A., Mukhopadhyay T., Ananthaswamy H. N. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog. 1991;4(3):196–202. doi: 10.1002/mc.2940040306. [DOI] [PubMed] [Google Scholar]
- Ponder B. A. Inherited predisposition to cancer. Trends Genet. 1990 Jul;6(7):213–218. doi: 10.1016/0168-9525(90)90181-5. [DOI] [PubMed] [Google Scholar]
- Potten C. S., Li Y. Q., O'Connor P. J., Winton D. J. A possible explanation for the differential cancer incidence in the intestine, based on distribution of the cytotoxic effects of carcinogens in the murine large bowel. Carcinogenesis. 1992 Dec;13(12):2305–2312. doi: 10.1093/carcin/13.12.2305. [DOI] [PubMed] [Google Scholar]
- Potten C. S., Wilson J. W., Booth C. Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells. 1997;15(2):82–93. doi: 10.1002/stem.150082. [DOI] [PubMed] [Google Scholar]
- Quelle D. E., Zindy F., Ashmun R. A., Sherr C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995 Dec 15;83(6):993–1000. doi: 10.1016/0092-8674(95)90214-7. [DOI] [PubMed] [Google Scholar]
- Quintanilla M., Brown K., Ramsden M., Balmain A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature. 1986 Jul 3;322(6074):78–80. doi: 10.1038/322078a0. [DOI] [PubMed] [Google Scholar]
- Quintanilla M., Haddow S., Jonas D., Jaffe D., Bowden G. T., Balmain A. Comparison of ras activation during epidermal carcinogenesis in vitro and in vivo. Carcinogenesis. 1991 Oct;12(10):1875–1881. doi: 10.1093/carcin/12.10.1875. [DOI] [PubMed] [Google Scholar]
- Reed J. A., Loganzo F., Jr, Shea C. R., Walker G. J., Flores J. F., Glendening J. M., Bogdany J. K., Shiel M. J., Haluska F. G., Fountain J. W. Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. Cancer Res. 1995 Jul 1;55(13):2713–2718. [PubMed] [Google Scholar]
- Reynisdóttir I., Polyak K., Iavarone A., Massagué J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev. 1995 Aug 1;9(15):1831–1845. doi: 10.1101/gad.9.15.1831. [DOI] [PubMed] [Google Scholar]
- Ruggeri B. A., Bauer B., Zhang S. Y., Klein-Szanto A. J. Murine squamous cell carcinoma cell lines produced by a complete carcinogenesis protocol with benzo[a]pyrene exhibit characteristic p53 mutations and the absence of H-ras and cyl 1/cyclin D1 abnormalities. Carcinogenesis. 1994 Aug;15(8):1613–1619. doi: 10.1093/carcin/15.8.1613. [DOI] [PubMed] [Google Scholar]
- Savatier P., Lapillonne H., van Grunsven L. A., Rudkin B. B., Samarut J. Withdrawal of differentiation inhibitory activity/leukemia inhibitory factor up-regulates D-type cyclins and cyclin-dependent kinase inhibitors in mouse embryonic stem cells. Oncogene. 1996 Jan 18;12(2):309–322. [PubMed] [Google Scholar]
- Serrano M., Lee H., Chin L., Cordon-Cardo C., Beach D., DePinho R. A. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996 Apr 5;85(1):27–37. doi: 10.1016/s0092-8674(00)81079-x. [DOI] [PubMed] [Google Scholar]
- Serrano M., Lin A. W., McCurrach M. E., Beach D., Lowe S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997 Mar 7;88(5):593–602. doi: 10.1016/s0092-8674(00)81902-9. [DOI] [PubMed] [Google Scholar]
- Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. doi: 10.1101/gad.9.10.1149. [DOI] [PubMed] [Google Scholar]
- Stoler A. B., Stenback F., Balmain A. The conversion of mouse skin squamous cell carcinomas to spindle cell carcinomas is a recessive event. J Cell Biol. 1993 Sep;122(5):1103–1117. doi: 10.1083/jcb.122.5.1103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sun T. T., Cotsarelis G., Lavker R. M. Hair follicular stem cells: the bulge-activation hypothesis. J Invest Dermatol. 1991 May;96(5):77S–78S. doi: 10.1111/1523-1747.ep12471959. [DOI] [PubMed] [Google Scholar]
- Van Meir E. G., Polverini P. J., Chazin V. R., Su Huang H. J., de Tribolet N., Cavenee W. K. Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet. 1994 Oct;8(2):171–176. doi: 10.1038/ng1094-171. [DOI] [PubMed] [Google Scholar]
- Vleminckx K., Vakaet L., Jr, Mareel M., Fiers W., van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991 Jul 12;66(1):107–119. doi: 10.1016/0092-8674(91)90143-m. [DOI] [PubMed] [Google Scholar]
- Wakabayashi K., Nagao M., Esumi H., Sugimura T. Food-derived mutagens and carcinogens. Cancer Res. 1992 Apr 1;52(7 Suppl):2092s–2098s. [PubMed] [Google Scholar]
- Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
- Yoo G. H., Xu H. J., Brennan J. A., Westra W., Hruban R. H., Koch W., Benedict W. F., Sidransky D. Infrequent inactivation of the retinoblastoma gene despite frequent loss of chromosome 13q in head and neck squamous cell carcinoma. Cancer Res. 1994 Sep 1;54(17):4603–4606. [PubMed] [Google Scholar]