Apoptotic cell death in mammary adenocarcinoma cells is prevented by soluble factors present in the target organ of metastasis

Target organ of metastasis determines the fate of metastasis. The soluble f actors released from one or more cell types in the new stroma may influence growth and survival of metastatic cells. In the present study, we used con ditioned media from the kidney, liver and lung, the latter being the target organ of metastasis of murine mammary adenocarcinoma cell lines LM3, LMM3 and F3II, to assess whether the soluble factors released from these organs could modulate in vitro survival of these cell lines after apoptosis-induci ng treatments and to investigate the mechanisms involved in this effect. We demonstrate that conditioned medium from lung, but not from liver or kidne y, promotes survival of these cells after doxorubicin, cisplatin, agonistic anti-Fas antibody and serum withdrawal treatments. Furthermore, LMM3 cells treated with lung conditioned medium after doxorubicin exposure maintained their tumorigenic capacity and metastatic potential. Neither IGF nor EGF c ould promote survival but, surprisingly, TGF-beta could reduce sensitivity of LMM3 cells to doxorubicin in vitro. Doxorubicin treatment induced Bax ex pression and down-regulated Bcl-2 expression. In contrast, lung conditioned medium increased Bcl-2 expression and inhibited doxorubicin-mediated Bcl-2 down-regulation. Neither of those treatments alone modified Bcl-x(L) expre ssion, although co-treatment induced a 3- to 5-fold increase of its express ion. These results suggest that the lung microenvironment could promote met astasis of these adenocarcinoma cell lines by increasing survival of metast atic cells, possibly by modulation of Bcl-2 protein family expression.