Abstract
Metastasis is a highly complex process involving the survival of tumor cells, both in the blood stream and within specific organs. Cell-death and survival are determined by a number of gene products from an expanding family of the Bcl-2 gene, either promoting or preventing apoptosis. Furthermore, the survival of tumor cells may favor the accumulation of additional genetic alterations causing further growth and invasive opportunities which may lead to metastasis. To examine whether the prevention of cell-death influences the metastatic behavior, we transfected a human breast cancer cell line MDA-MB-435 with the Bcl-xL cDNA and then studied metastatic ability of the selected clones in vivo. Our results show that Bcl-xL-clones had a decreased tumor growth latency and an increased metastatic ability. Apoptosis-resistance to cytokines was induced in 435 cells by Bcl-xL-expression with minor modifications in their proliferation rates. These cells also showed diminished 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-xL and 435/Neo cells at 1 : 3 proportion i.v., and animals were killed at intervals of 15′ to 16 h after injection. Tumor cells were recovered from the lungs and Southern-blot analysis revealed the presence of exogenous Bcl-xL cDNA. These results showed that 435/Bcl-xL cells had a survival advantage in circulation over 435/Neo cells. This advantage in vivo was attributable to Bcl-xL expression. We conclude that Bcl-xL expression in breast cancer cells can increase metastatic activity. This advantage could be created by inducing resistance to apoptosis against cytokines, increasing cell survival in circulation, and enhancing anchorage-independent growth. Cell Death and Differentiation (2000) 7, 350–359
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Abbreviations
- HG:
-
histological grade
- i.m.f.p.:
-
intra-mammary fat pad
- TNF-α:
-
tumor necrosis factor alpha
- TGF-β:
-
transforming growth factor beta
- IGF-1:
-
insulin-like growth factor-1
- FCS:
-
fetal calf serum
- LM:
-
laminin
- FN:
-
fibronectin
- CL IV:
-
collagen IV
- G418:
-
geneticin
- i.v.:
-
intravenous
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Acknowledgements
We are grateful to the ‘Fundación Científica de la Asociación Española Contra el Cáncer’ for supporting Yolanda Fernández as a Doctoral Fellow. We thank Dra. Angels Torregrosa for their skilful advice in the pathological selection of specimens. We also wish to thank Robin Rycroft of the Language Advisory Service at the University of Barcelona. This study was supported by grants MARATO de TV3 95/56, from the ‘Plan Nacional de Investigación Científica y Desarrollo Technológico’ CICYT, SAF 97/0210 and from ‘Ministerio de Sanidad y Consumo’ FIS 99/0770.
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Fernández, Y., España, L., Mañas, S. et al. Bcl-xL promotes metastasis of breast cancer cells by induction of cytokines resistance. Cell Death Differ 7, 350–359 (2000). https://doi.org/10.1038/sj.cdd.4400662
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DOI: https://doi.org/10.1038/sj.cdd.4400662
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