Abstract
A concept of carcinogenesis was recently devised in our laboratory that suggests the development of defects in the control of cell differentiation is associated with an early phase of carcinogenesis. To test this proposal directly, the effects of an initiator of carcinogenesis (i.e., UV irradiation) on proadipocyte stem cell differentiation and proliferation was assayed. In this regard, 3T3 T proadipocytes represent a nontransformed mesenchymal stem cell line that possesses the ability to regulate its differentiation at a distinct state in the G1 phase of the cell cycle as well as the ability to regulate its proliferation at two additional G1 states that are induced by culture in growth factor-deficient or nutrient-deficient microenvironments. The results establish that a low dosage of 254 nm UV irradiation selectively and stably inhibits the differentiation of a high percentage of proadipocyte stem cells without significantly altering their ability to regulate cellular proliferation in growth factor-deficient or nutrient-deficient culture conditions. Differentiation-defective proadipocyte stem cells are demonstrated not to be completely transformed but to show an increased spontaneous transformation rate, as evidenced by the formation of type III foci in high density cell cultures. These data support the role of defects in the control of differentiation in the initiation of carcinogenesis. Other data, however, also suggest that additional cellular defects must be expressed for a cell to be completely initiated. These observations support a concept that the initiation of carcinogenesis involves multiple phases.
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- Cairns J. The origin of human cancers. Nature. 1981 Jan 29;289(5796):353–357. doi: 10.1038/289353a0. [DOI] [PubMed] [Google Scholar]
- Chan G. L., Little J. B. Induction of oncogenic transformation in vitro by ultraviolet light. Nature. 1976 Dec 2;264(5585):442–444. doi: 10.1038/264442a0. [DOI] [PubMed] [Google Scholar]
- Chen T. R. In situ detection of mycoplasma contamination in cell cultures by fluorescent Hoechst 33258 stain. Exp Cell Res. 1977 Feb;104(2):255–262. doi: 10.1016/0014-4827(77)90089-1. [DOI] [PubMed] [Google Scholar]
- Comings D. E. A general theory of carcinogenesis. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3324–3328. doi: 10.1073/pnas.70.12.3324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DiPaolo J. A. Relative difficulties in transforming human and animal cells in vitro. J Natl Cancer Inst. 1983 Jan;70(1):3–8. [PubMed] [Google Scholar]
- Diamond L., O'Brien T. G., Rovera G. Inhibition of adipose conversion of 3T3 fibroblasts by tumour promoters. Nature. 1977 Sep 15;269(5625):247–249. doi: 10.1038/269247a0. [DOI] [PubMed] [Google Scholar]
- Hennings H., Devor D., Wenk M. L., Slaga T. J., Former B., Colburn N. H., Bowden G. T., Elgjo K., Yuspa S. H. Comparison of two-stage epidermal carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene or N-methyl-N'-nitro-N-nitrosoguanidine in newborn and adult SENCAR and BALB/c mice. Cancer Res. 1981 Mar;41(3):773–779. [PubMed] [Google Scholar]
- Johnson L. D., Nickerson R. J., Easterday C. L., Stuart R. S., Hertig A. T. Epidemiologic evidence for the spectrum of change from dysplasia through carcinoma in situ to invasive cancer. Cancer. 1968 Nov;22(5):901–914. doi: 10.1002/1097-0142(196811)22:5<901::aid-cncr2820220502>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
- Kennedy A. R., Fox M., Murphy G., Little J. B. Relationship between x-ray exposure and malignant transformation in C3H 10T1/2 cells. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7262–7266. doi: 10.1073/pnas.77.12.7262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kennedy A. R., Little J. B. Protease inhibitors suppress radiation-induced malignant transformation in vitro. Nature. 1978 Dec 21;276(5690):825–826. doi: 10.1038/276825a0. [DOI] [PubMed] [Google Scholar]
- Kennedy A. R., Ritter M. A., Little J. B. Fluorescent light induces malignant transformation in mouse embryo cell cultures. Science. 1980 Mar 14;207(4436):1209–1211. doi: 10.1126/science.7355282. [DOI] [PubMed] [Google Scholar]
- Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kopelovich L., Bias N. E., Helson L. Tumour promoter alone induces neoplastic transformation of fibroblasts from humans genetically predisposed to cancer. Nature. 1979 Dec 6;282(5739):619–621. doi: 10.1038/282619a0. [DOI] [PubMed] [Google Scholar]
- Krawisz B. R., Scott R. E. Coupling of proadipocyte growth arrest and differentiation. I. Induction by heparinized medium containing human plasma. J Cell Biol. 1982 Aug;94(2):394–399. doi: 10.1083/jcb.94.2.394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lotem J., Sachs L. Mechanisms that uncouple growth and differentiation in myeloid leukemia cells: restoration of requirement for normal growth-inducing protein without restoring induction of differentiation-inducing protein. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4347–4351. doi: 10.1073/pnas.79.14.4347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mondal S., Heidelberger C. Transformation of C3H/10T1/2CL8 mouse embryo fibroblasts by ultraviolet irradiation and a phorbol ester. Nature. 1976 Apr 22;260(5553):710–711. doi: 10.1038/260710a0. [DOI] [PubMed] [Google Scholar]
- Murphree A. L., Benedict W. F. Retinoblastoma: clues to human oncogenesis. Science. 1984 Mar 9;223(4640):1028–1033. doi: 10.1126/science.6320372. [DOI] [PubMed] [Google Scholar]
- Newbold R. F., Overell R. W., Connell J. R. Induction of immortality is an early event in malignant transformation of mammalian cells by carcinogens. Nature. 1982 Oct 14;299(5884):633–635. doi: 10.1038/299633a0. [DOI] [PubMed] [Google Scholar]
- Pardee A. B., Dubrow R., Hamlin J. L., Kletzien R. F. Animal cell cycle. Annu Rev Biochem. 1978;47:715–750. doi: 10.1146/annurev.bi.47.070178.003435. [DOI] [PubMed] [Google Scholar]
- Pound A. W. Induced cell proliferation and the initiation of skin tumour formation in mice by ultraviolet light. Pathology. 1970 Oct;2(4):269–275. doi: 10.3109/00313027009077141. [DOI] [PubMed] [Google Scholar]
- Sachs L. Constitutive uncoupling of pathways of gene expression that control growth and differentiation in myeloid leukemia: a model for the origin and progression of malignancy. Proc Natl Acad Sci U S A. 1980 Oct;77(10):6152–6156. doi: 10.1073/pnas.77.10.6152. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott R. E., Boone C. W. PRomotion of smooth surface tumorigenicity by phorbol myristate acetate in Balb/3T3 cells and Balb/3T3 T proadipocytes. J Natl Cancer Inst. 1981 Apr;66(4):733–736. [PubMed] [Google Scholar]
- Scott R. E., Florine D. L., Wille J. J., Jr, Yun K. Coupling of growth arrest and differentiation at a distinct state in the G1 phase of the cell cycle: GD. Proc Natl Acad Sci U S A. 1982 Feb;79(3):845–849. doi: 10.1073/pnas.79.3.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott R. E., Hoerl B. J., Wille J. J., Jr, Florine D. L., Krawisz B. R., Yun K. Coupling of proadipocyte growth arrest and differentiation. II. A cell cycle model for the physiological control of cell proliferation. J Cell Biol. 1982 Aug;94(2):400–405. doi: 10.1083/jcb.94.2.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott R. E., Wille J. J., Jr, Wier M. L. Mechanisms for the initiation and promotion of carcinogenesis: a review and a new concept. Mayo Clin Proc. 1984 Feb;59(2):107–117. doi: 10.1016/s0025-6196(12)60244-4. [DOI] [PubMed] [Google Scholar]
- Scott R. E., Yun K., Florine D. L. Differential mitogenic effects of methyl isobutyl xanthine and a tumor growth factor on G1-arrested 3T3 T proadipocytes at the predifferentiation GD state and the growth-factor deficiency GS state. Exp Cell Res. 1983 Feb;143(2):405–414. doi: 10.1016/0014-4827(83)90067-8. [DOI] [PubMed] [Google Scholar]
- Stanbridge E. J., Der C. J., Doersen C. J., Nishimi R. Y., Peehl D. M., Weissman B. E., Wilkinson J. E. Human cell hybrids: analysis of transformation and tumorigenicity. Science. 1982 Jan 15;215(4530):252–259. doi: 10.1126/science.7053574. [DOI] [PubMed] [Google Scholar]
- Tobey R. A., Ley K. D. Isoleucine-mediated regulation of genome repliction in various mammalian cell lines. Cancer Res. 1971 Jan;31(1):46–51. [PubMed] [Google Scholar]
- Wille J. J., Jr, Maercklein P. B., Scott R. E. Neoplastic transformation and defective control of cell proliferation and differentiation. Cancer Res. 1982 Dec;42(12):5139–5146. [PubMed] [Google Scholar]
- Wille J. J., Jr, Scott R. E. Topography of the predifferentiation GD growth arrest state relative to other growth arrest states in the G1 phase of the cell cycle. J Cell Physiol. 1982 Jul;112(1):115–122. doi: 10.1002/jcp.1041120117. [DOI] [PubMed] [Google Scholar]
- Yun K., Scott R. E. Biological mechanisms of phorbol myristate acetate-induced inhibition of proadipocyte differentiation. Cancer Res. 1983 Jan;43(1):88–96. [PubMed] [Google Scholar]
- Yunis J. J. The chromosomal basis of human neoplasia. Science. 1983 Jul 15;221(4607):227–236. doi: 10.1126/science.6336310. [DOI] [PubMed] [Google Scholar]