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Sequential Appearance of Anchorage Independence, Uncontrolled Nuclear Division, and Tumorigenicity in 7,12-Dimethylbenz(a)anthracene-exposed Rat Tracheal Epithelial Cells¹

Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831

Epithelial cell lines derived from rat tracheal implants 2 and 9 months after a 4-week exposure to 200 µg dimethylbenz(a)anthracene-beeswax pellets, and previously assayed for growth in soft agarose and tumorigenicity, were tested at the same time of subculture for cytochalasin B-induced multinucleation to determine the relationships between anchorage-independent growth, uncontrolled nuclear division, and tumorigenicity. The relationships among the three phenotypic markers could be separated into five distinct groups. Group I cell lines showed no growth in agarose, showed no cytochalasin-induced multinucleation, and formed no tumors in nude mice. Group II cell lines exhibited anchorage independence but were negative for the other markers. Group III cell lines were anchorage independent and exhibited a positive response to cytochalasin B (more than 10% of the cells had three or more nuclei), but were tumor negative. Group IV cell lines were positive for all three markers. Group V cell lines grew in soft agarose, were cytochalasin B negative, but formed tumors only 4 months after the cell inoculations. The 20 cell lines generated 2 months after carcinogen exposure distributed in the groups as follows: Group I, 20%; Group 2, 20%; Group III, 50%; Group IV, 15%; and Group 5, 10%. The 27 cell lines generated 9 months after carcinogen exposure distributed among the groups as: Group I, 4%; Group II, 18%; Group III, 26%; Group IV, 52% and Group V, 0%. The results indicate that: (a) anchorage independence precedes the two other markers of growth autonomy (b) uncontrolled nuclear division appears as a separate property after anchorage independence and before tumorigenicity; (c) tumorigenicity appears preferably in the cell populations that exhibit anchorage independence and uncontrolled nuclear division; and (d) progression in growth autonomy occurs in the tracheal implants in vivo which can be detected in vitro as an increase in cell lines positive for the three phenotypic markers.

¹ Research supported by USPHS Grant CA43857 awarded by the National Cancer Institute and by the Office of Health and Environmental Research, United States Department of Energy under Contract DE-AC05840R21400 with Martin Marietta Energy Systems, Inc.

² To whom requests for reprints should be addressed.

Received 11/20/86. Revised 3/ 3/87. Accepted 4/ 7/87.