Intercellular induction of apoptosis in transformed cells does not depend on p53.

Transformed fibroblast from p53 null/null mice were tested for their sensitivity to intercellular induction of apoptosis by TGF-beta-treated nontransformed cells. They were found to be as sensitive as p53-positive transformed cells. Based on morphological criteria, detection of chromatin condensation and DNA strand breaks, death of p53-negative transformed cells was due to apoptosis. p53-negative nontransformed cells were as efficient in the induction of apoptosis in transformed cells as p53-positive nontransformed cells. These data show that intercellular induction of apoptosis in transformed cells does not depend on functional p53. Therefore it may be assumed that mutations of p53 or modulation of its concentration are without relevance for this particular aspect of control of oncogenesis.

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.