Dynamic heterogeneity: experimental metastasis studies with RIF-1 fibrosarcoma

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Abstract
We have examined the metastatic behaviour of cells from a series of clones of RIF-1 fibrosarcoma, a recently derived murine tumour. The clones were grown to different sizes (small: 105−106 cells and large ∼2×107 cells) and their metastatic potential was quantified using an experimental metastasis assay. There was significant variability between the metastatic potential of clones derived from the same population. Furthermore large clones had higher metastatic efficiency (metastases/cell injected) than the small clones derived from the same population. The results from these experiments indicate that metastatic variants are generated during the growth of the clones. The mean effective rate of generation of metastatic variants was estimated using Luria-Delbruck fluctuation analysis to be 1·7×10−5/cell/generation. The data described are consistent with a dynamic heterogeneity model of metastasis, in which the variant phenotypes are postulated to arise in growing tumour cell populations at a high rate but need not be stable in order to produce metastases. The results thus indicate that the model is applicable to a recently derived tumour as well as the extensively transplanted KHT sarcoma, B16 melanoma and OTF9 embryonal cell carcinoma.