Metastatic behavior of human breast carcinomas overexpressing the Bcl-x(L) gene: a role in dormancy and organospecificity.
The ability of metastatic cells to survive antiapoptotic signals may contribute to the organospecific-spread patterns of clinical metastasis and dormancy. MDA-MB-435 breast cancer cells (435/Bcl-x(L)), which overexpress the Bcl-x(L) gene, were labeled with the luciferase gene and injected orthotopically into homozygous athymic Balb/c (nude) mice to study the metastatic behavior of the breast cancer cells. The overexpression of Bcl-x(L) in tumors increased the overall metastatic burden in mice (bones, liver, kidneys, brain, lungs, and lymph nodes) in comparison with control tumors (435/NEO:luc) during the same time interval (ANOVA, p = 0.005). The principal differences after 110 days were found in bones, which had 1.5 x 10(5) +/- 1.2 x 10(5) tumor cell equivalents (p = 0.03), and lymph nodes, which had 7.0 x 10(6) +/- 6.0 x 10(6) tumor cell equivalents (p = 0.08). The analyses of light production by tissues at different times showed that cells from 435/NEO:luc and 435/Bcl-x(L).luc tumors were detectable in several organs by the second day after intramammary fat pad implantation. Although initially arriving at the target organs in similar numbers, 435/Bcl-x(L) cells developed more metastases than 435/Neo cells, indicating that the Bcl-x(L) gene might have a role in breast cancer dormancy, promoting survival of cells in metastatic foci. Thus, we suggest that overexpression of Bcl-x(L) could counteract the proapoptotic signals in the microenvironment and favor the successful development of metastasis in specific organs.
Rubio
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Centre de Oncologia Molecular, Institut de Recerca Oncológica, Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge, Barcelona, Spain.
España
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Fernández
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Blanco
J
J
Sierra
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A
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D008156:Luciferases