Abstract
Using the Luria-Delbrück fluctuation analysis, we have examined the lung tumor-forming ability of a series of parallel clones derived from the KHT tumor, grown to small defined sizes. From these studies, we conclude that metastatic variants arise spontaneously in the clonal lines during their growth, at an apparent rate of approximately 10(-5) per cell per generation. This rapid rate has implications for our understanding of tumor heterogeneity and the process of tumor progression. Previous results have suggested that heterogeneity observed in cloning experiments reflects stable subpopulations of cells in the original tumor. We propose here an alternative "dynamic heterogeneity" model, in which metastatic variants arise at a high rate (as detected in the cloning experiments) but need not be stable mutations in order to effectively produce metastases.
Full text
PDF




Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Cairns J. The origin of human cancers. Nature. 1981 Jan 29;289(5796):353–357. doi: 10.1038/289353a0. [DOI] [PubMed] [Google Scholar]
- Chambers A. F., Hill R. P., Ling V. Tumor heterogeneity and stability of the metastatic phenotype of mouse KHT sarcoma cells. Cancer Res. 1981 Apr;41(4):1368–1372. [PubMed] [Google Scholar]
- Chow D. A., Greenberg A. H. The generation of tumor heterogeneity in vivo. Int J Cancer. 1980 Feb 15;25(2):261–265. doi: 10.1002/ijc.2910250214. [DOI] [PubMed] [Google Scholar]
- Cifone M. A., Kripke M. L., Fidler I. J. Growth rate and chromosome number of tumor cell lines with different metastatic potential. J Supramol Struct. 1979;11(4):467–476. doi: 10.1002/jss.400110405. [DOI] [PubMed] [Google Scholar]
- Dexter D. L., Kowalski H. M., Blazar B. A., Fligiel Z., Vogel R., Heppner G. H. Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res. 1978 Oct;38(10):3174–3181. [PubMed] [Google Scholar]
- Fidler I. J., Cifone M. A. Properties of metastatic and nonmetastatic cloned subpopulations of an ultraviolet-light-induced murine fibrosarcoma of recent origin. Am J Pathol. 1979 Dec;97(3):633–648. [PMC free article] [PubMed] [Google Scholar]
- Fidler I. J., Gersten D. M., Hart I. R. The biology of cancer invasion and metastasis. Adv Cancer Res. 1978;28:149–250. doi: 10.1016/s0065-230x(08)60648-x. [DOI] [PubMed] [Google Scholar]
- Fidler I. J., Hart I. R. The origin of metastatic heterogeneity in tumors. Eur J Cancer. 1981 May;17(5):487–494. doi: 10.1016/0014-2964(81)90049-9. [DOI] [PubMed] [Google Scholar]
- Fidler I. J., Kripke M. L. Metastasis results from preexisting variant cells within a malignant tumor. Science. 1977 Aug 26;197(4306):893–895. doi: 10.1126/science.887927. [DOI] [PubMed] [Google Scholar]
- Fidler I. J. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 1978 Sep;38(9):2651–2660. [PubMed] [Google Scholar]
- Kallman R. F., Silini G., Van Putten L. M. Factors influencing the quantitative estimation of the in vivo survival of cells from solid tumors. J Natl Cancer Inst. 1967 Sep;39(3):539–549. [PubMed] [Google Scholar]
- Kondo S. A theoretical study on spontaneous mutation rate. Mutat Res. 1972 Apr;14(4):365–374. doi: 10.1016/0027-5107(72)90133-9. [DOI] [PubMed] [Google Scholar]
- Kripke M. L., Gruys E., Fidler I. J. Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent origin. Cancer Res. 1978 Sep;38(9):2962–2967. [PubMed] [Google Scholar]
- Luria S. E., Delbrück M. Mutations of Bacteria from Virus Sensitivity to Virus Resistance. Genetics. 1943 Nov;28(6):491–511. doi: 10.1093/genetics/28.6.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Neri A., Nicolson G. L. Phenotypic drift of metastatic and cell-surface properties of mammary adenocarcinoma cell clones during growth in vitro. Int J Cancer. 1981 Dec;28(6):731–738. doi: 10.1002/ijc.2910280612. [DOI] [PubMed] [Google Scholar]
- Nicolson G. L., Brunson K. W., Fidler I. J. Specificity of arrest, survival, and growth of selected metastatic variant cell lines. Cancer Res. 1978 Nov;38(11 Pt 2):4105–4111. [PubMed] [Google Scholar]
- Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
- Poste G., Doll J., Fidler I. J. Interactions among clonal subpopulations affect stability of the metastatic phenotype in polyclonal populations of B16 melanoma cells. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6226–6230. doi: 10.1073/pnas.78.10.6226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poste G., Fidler I. J. The pathogenesis of cancer metastasis. Nature. 1980 Jan 10;283(5743):139–146. doi: 10.1038/283139a0. [DOI] [PubMed] [Google Scholar]
- Reading C. L., Brunson K. W., Torrianni M., Nicolson G. L. Malignancies of metastatic murine lymphosarcoma cell lines and clones correlate with decreased cell surface display of RNA tumor virus envelope glycoprotein gp70. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5943–5947. doi: 10.1073/pnas.77.10.5943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stanners C. P., Eliceiri G. L., Green H. Two types of ribosome in mouse-hamster hybrid cells. Nat New Biol. 1971 Mar 10;230(10):52–54. doi: 10.1038/newbio230052a0. [DOI] [PubMed] [Google Scholar]
- Suzuki N., Withers H. R., Koehler M. W. Heterogeneity and variability of artificial lung colony-forming ability among clones from mouse fibrosarcoma. Cancer Res. 1978 Oct;38(10):3349–3351. [PubMed] [Google Scholar]
- Weiss L. Dynamic aspects of cancer cell populations in metastasis. Am J Pathol. 1979 Dec;97(3):601–608. [PMC free article] [PubMed] [Google Scholar]
- Weiss L. Metastasis: differences between cancer cells in primary and secondary tumors. Pathobiol Annu. 1980;10:51–81. [PubMed] [Google Scholar]