Bcl-x(L) promotes metastasis of breast cancer cells by induction of cytokines resistance

Metastasis is a highly complex process involving the survival of tumor cell s, both in the blood stream and within specific organs. Cell-death and surv ival are determined by a number of gene products from an expanding family o f the Bcl-2 gene, either promoting or preventing apoptosis, Furthermore, th e survival of tumor cells may favor the accumulation of additional genetic alterations causing further growth and invasive opportunities which may lea d to metastasis, To examine whether the prevention of cell-death influences the metastatic behavior, we transfected a human breast cancer cell line MD A-MB-435 with the Bcl-x(L) cDNA and then studied metastatic ability of the selected clones in vivo, Our results show that Bcl-x(L)-clones had a decrea sed tumor growth latency and an increased metastatic ability. Apoptosis-res istance to cytokines was induced in 435 cells by Bcl-x(L)-expression with m inor modifications in their proliferation rates. These cells also showed di minished adhesion to extracellular matrix proteins and a survival advantage in suspension over 435/Neo cells. Moreover, to determine survival in blood stream and in cells lodged in the lungs, we injected 435/Bcl-x(L) and 435/ Neo cells at 1:3 proportion i.v., and animals were killed at intervals of 1 5' to 16 h after injection. Tumor cells were recovered from the lungs and S outhern-blot analysis revealed the presence of exogenous Bcl-x(L) cDNA, The se results showed that 435/Bcl-x(L) cells had a survival advantage in circu lation over 435/Neo cells, This advantage in vivo was attributable to Bcl-x (L) expression. We conclude that Bcl-xL expression in breast cancer cells c an increase metastatic activity. This advantage could be created by inducin g resistance to apoptosis against cytokines, increasing cell survival in ci rculation, and enhancing anchorage-independent growth.