Abstract
Multi-cell spheroids were grown in soft agar. When each spheroid was cultured in a large volume of medium, frequently renewed, all spheroids eventually reached a dormant phase at a diameter of approximately 3–4 mm and a population of approximately 106 cells. In the dormant spheroid, newly generated cells at the periphery balanced those lost by necrosis in the center. We propose that this dormant phase is due to a gradual reduction in the ratio of surface area to volume: a size is achieved beyond which there is insufficient surface area for the spheroid to eliminate catabolites and absorb nutrients. Thus, in the face of unlimited space and of new medium, three-dimensional cell populations become self-regulating. This phenomenon contrasts with standard tissue culture in which cell populations, living on a flat plane in two dimensions, will not stop growing in the face of unlimited space and new medium because the ratio of surface area to volume remains constant. These experiments provide a mechanism for our observations in vivo: before vascularization, solid tumors live by simple diffusion as three-dimensional spheroids or ellipsoids. They become dormant at a diameter of only a few millimeters; once vascularized, they are released from this dormant phase and begin exponential growth. Thus, tumor dormancy resulting from absence of angiogenesis in vivo, may operate by the same mechanism responsible for dormancy of spheroids in vitro.
Full Text
The Full Text of this article is available as a PDF (500.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Chu M. Y., Fischer G. A. The incorporation of 3H-cytosine arabinoside and its effect on murine leukemic cells (L5178Y). Biochem Pharmacol. 1968 May;17(5):753–767. doi: 10.1016/0006-2952(68)90012-9. [DOI] [PubMed] [Google Scholar]
- Dalen H., Burki H. J. Some observations on the three-dimensional growth of L5178Y cell colonies in soft agar culture. Exp Cell Res. 1971 Apr;65(2):433–438. doi: 10.1016/0014-4827(71)90023-1. [DOI] [PubMed] [Google Scholar]
- Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971 Nov 18;285(21):1182–1186. doi: 10.1056/NEJM197111182852108. [DOI] [PubMed] [Google Scholar]
- Gimbrone M. A., Jr, Leapman S. B., Cotran R. S., Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med. 1972 Aug 1;136(2):261–276. doi: 10.1084/jem.136.2.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hochberg M. S., Folkman J. Mechanism of size limitation of bacterial colonies. J Infect Dis. 1972 Dec;126(6):629–635. doi: 10.1093/infdis/126.6.629. [DOI] [PubMed] [Google Scholar]
- Kruse P. F., Jr, Miedema E. Production and characterization of multiple-layered populations of animal cells. J Cell Biol. 1965 Nov;27(2):273–279. doi: 10.1083/jcb.27.2.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shinoara K., Okada S. Radiosensitivities of murine lymphoma L5178Y cells in a multi-cellular colony system. J Radiat Res. 1972 Jun;13(2):109–116. doi: 10.1269/jrr.13.109. [DOI] [PubMed] [Google Scholar]
- Stoker M. Contact and short-range interactions affecting growth of animal cells in culture. Curr Top Dev Biol. 1967;2:107–128. doi: 10.1016/s0070-2153(08)60285-9. [DOI] [PubMed] [Google Scholar]
- Sutherland R. M., McCredie J. A., Inch W. R. Growth of multicell spheroids in tissue culture as a model of nodular carcinomas. J Natl Cancer Inst. 1971 Jan;46(1):113–120. [PubMed] [Google Scholar]
- THOMLINSON R. H., GRAY L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955 Dec;9(4):539–549. doi: 10.1038/bjc.1955.55. [DOI] [PMC free article] [PubMed] [Google Scholar]