Fibroblasts transformed by chemical carcinogens are sensitive to intercellular induction of apoptosis: implications for the control of oncogenesis

The ability of neighbouring normal cells to inhibit proliferation of transformed cells is regarded as the classical mode of intercellular control of potential tumour cells. This mechanism, however, only controls the pool size of transformed cells, but does not impair their survival. We have recently shown that cells transformed by biological agents are subject to a novel control system: transforming growth factor beta (TGF-beta) induces normal cells to release factors that mediate apoptosis specifically in transformed cells. Here we show that cells transformed by chemical carcinogens are also subject to this dominant control mechanism. The number of foci induced by methylcholanthrene, N-methyl-N'-nitro-N-nitrosoguanidine or quercetin was significantly reduced when the cultures were treated with TGF-beta. Established lines of chemically transformed cells proved to be sensitive to induction of apoptosis by neighbouring normal cells in the presence of TGF-beta. This finding demonstrates that sensitivity to induction of apoptosis is a general feature of transformed cells, irrespective of the transforming agent. It is particularly relevant for chemical carcinogenesis. As transformed cells were shown to trigger induction of their own apoptosis, the acquisition of resistance to this process may be a central regulatory step in carcinogenesis in vitro and possibly also in vivo. This study may help to elucidate mechanisms that protect transformed cells at an early stage of tumour progression that has until now not been the focus of investigation.