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In Vivo Enhancement of Genomic Instability in Minisatellite Sequences of Mouse C3H/10T Cells Transformed in Vitro by X-Rays¹

Harvard School of Public Health, Laboratory of Radiobiology, Boston, Massachusetts 02115

The level of genomic instability was determined during tumor development in vivo. Genomic rearrangements, a marker of genomic instability, was measured in mouse C3H/10T cells transformed in vitro by X-rays with a DNA fingerprinting assay. Three transformed clones isolated from type III foci were divided into two groups. Cells from the first group were injected s.c. into syngeneic and nonimmunosuppressed C3H mice. After 3 to 5 months, the tumors were excised, and the neoplastic cells were isolated and subcloned. Cells from the second group were incubated in vitro for 25 passages (about 6 months) to approximate the number of cell divisions occurring in the tumor, and then they were subcloned. DNA was extracted from subclones grown in vitro and in vivo and analyzed with the DNA fingerprinting assay. A high frequency of genomic rearrangements (50–100%) was found in subclones derived from tumors that arose in vivo, whereas the frequency was very low (<10%) among subclones passaged in vitro, suggesting that genetic instability may be enhanced by factors present in the C3H mouse. In one clone (F-17) genomic instability appeared to be activated and down regulated. The high frequency of instability found in tumor cell subclones did not appear to result from an in vivo selection of a more tumorigenic subpopulation of cells present in the original clone prior to injection in the animal. This enhancement of genomic instability occurring in vivo could be required to complete the process of transformation to tumorigenicity and allow the neoplastic cells to adapt to a new environment.

¹ This research was supported by Grants CA-47542 and ES-00002 from the NIH and a fellowship to B. P. from "Les Fonds de la Recherche en Santé du Québec."

² To whom requests for reprints should be addressed, at Havard School of Public Health, Laboratory of Radiobiology, 665 Huntington Avenue, Boston, MA 02115.

Received 2/ 3/94. Accepted 4/20/94.

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