Characterization of tumor progression from threshold tumor inocula: evidence for natural resistance.

An examination of the variant generation and selection hypothesis of tumor progression was undertaken using the NK-sensitive, NAb-sensitive SL2-5 lymphoma in the threshold inoculum model of tumor progression. Tumor cells obtained from the i.p. injection site expressed increased heterogeneity for sensitivity to syngeneic NAb and to NR measured in the 131IUdR-labelled tumor elimination assay. Cells retrieved from the s.c. injection site exhibited reductions in sensitivity to NR which correlated with decreases in sensitivity to syngeneic NAb and NK cells in vitro. These data confirm and extend our previous observations with the NK-resistant L5178Y-F9 lymphoma and further substantiate the evidence for the participation of NAb and NK cells in host-mediated anti-tumor resistance. Characterization of the model revealed that the selection for reduced sensitivity to NR in thymus-depleted AT x BM mice and normal animals could not be distinguished, suggesting that thymus-independent mechanisms may be major contributors to the surveillance of nascent tumors. The decreases in susceptibility to NR occurred in a stepwise and time-dependent manner in accord with the sequential multistage concept of progression. Furthermore, the selection for tumor cells which exhibited reductions in sensitivity to NR correlated with selection for increased tumorigenicity, in keeping with the idea that progression is associated with development towards an increasingly autonomous tumor.