Determinants of carcinogen-induced malignant conversion in rat brain: proliferative properties of neural precursor cell subpopulations analyzed by multi-parameter flow cytometry.

The induction of neuroectodermal tumors in BDIX rats by N-ethyl-N-nitrosourea (EtNU) is a model system for the analysis of transformation risk as a function of target cell properties. The yield of neural tumors induced by EtNU varies with the developmental window chosen for the carcinogen pulse; i.e. with the relative proportions of different neural precursor cells exposed to EtNU at distinct developmental stages. Different subsets of fetal brain cells have been characterized previously with respect to their relative risk of malignant transformation using monoclonal antibodies. As DNA replication of target cells is considered to be a prerequisite for malignant conversion, we analyzed the cell cycle distributions, using flow-cytometry, of 4 subsets of neural precursor cells considered to be at high or low risk, respectively, of malignant conversion by EtNU in vivo. Cell populations associated with an elevated risk of transformation exhibited higher proportions of cells in S-phase. One of the 2 putative low-risk populations exhibited a significantly lower fraction of S-phase cells, while the value of the second one exceeded those obtained for the 2 high-risk subpopulations. Therefore, a higher than average fraction of cells in S-phase appears to be positively correlated with the cellular risk of malignant transformation by EtNU, but does not represent a dominant risk determinant per se.