Apoptosis: An early event in metastatic inefficiency

Whereas large numbers of cells from a primary tumor may gain access to the circulation, few of them will give rise to metastases. The mechanism of eli mination of these tumor cells, often termed "metastatic inefficiency," is p oorly understood. In this study, we show that apoptosis in the lungs within 1-2 days of introduction of the cells is an important component of metasta tic inefficiency. First, we show that death of transformed, metastatic rat embryo cells occurred via apoptosis in the lungs 24-48 h after injection in to the circulation. Second, we show that Bcl-2 overexpression in these cell s inhibited apoptosis in culture and also conferred resistance to apoptosis in vivo in the lungs 24-48 h after injection. This inhibition of apoptosis led to significantly more macroscopic metastases. Third, comparison betwee n the extent of apoptosis by a poorly metastatic cell line to that by a hig hly metastatic cell line 24 h after injection in the lungs revealed more ap optosis by the poorly metastatic cell line. These results indicate that apo ptosis, which occurs at 24-48 h after hematogenous dissemination in the lun gs is an important determinant of metastatic inefficiency. Although prior w ork has shown an association between apoptosis in culture and metastasis in vivo, this work shows that apoptosis in vivo corresponds to decreased meta stasis in vivo.