Growth advantage (“clonal dominance”) of metastatically competent tumor cell variants expressed under selective two- or three-dimensional tissue culture conditions |
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Authors: | Janusz W Rak Robert S Kerbel |
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Institution: | (1) Division of Cancer Research, Reichmann Research Building, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto;(2) the Departments of Medical Biophysics and Medical Genetics, University of Toronto, M4N 3M5, Ontario, Canada |
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Abstract: | Summary In previous experiments it was shown that injection into syngeneic CBA/J mice of cell mixtures containing an excess of non-metastatic
SP1 mouse mammary carcinoma cells with aras transfected metastatic variant of SP1 called C1, always resulted in the eventual dominance of the C1 subpopulation at the
site of inoculation. This occurred despite the growth rates of the two cell populations being identical in vivo when grown
separately. The means by which the C1 subpopulation achieved “clonal dominance” is thought to involve its responsiveness to
stimulatory paracrine growth factors liberated by the non-metastatic SP1 population. The clonal dominance process, however,
could not be recapitulated in conventional monolayer tissue culture conditions in which SP1 and C1 cells were grown together
in high concentrations of serum, i.e. under non-limiting culture conditions. We now show that clonal dominance of C1 cells
can be observed when the cell mixture is maintained in tissue culture for extended periods, or when the cells are grown under
selective, limiting conditions, some of which may mimic growth conditions in vivo more accurately. These conditions were a)
growth in low (limiting) serum concentrations; and b) growth as three-dimensional multicellular aggregates, i.e. as “tumor
spheroids”. Under all of these conditions dominance of the C1 subpopulation always took place, but with an efficiency 6- to
40-fold less than generally observed in vivo. C1 cells were also able to form more stable (compact) spheroids compared to
SP1 cells. Entrapment of the latter in mixed C1/SP1 spheroids increased the recovery of the SP1 cells suggesting some kind
of “rescue” mechanism in which cells are protected from physical forces by three-dimensional structure. The relevance of these
in vitro interactions for clonal dominance in primary tumors and metastasis in vivo are discussed. |
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Keywords: | metastasis tumor progression cell-to-cell interactions tumor spheroids |
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