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Cell. 2013 Aug 29;154(5):1060-1073. doi: 10.1016/j.cell.2013.07.036.

Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
4
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 21205, USA. Electronic address: j-massague@ski.mskcc.org.

Abstract

How organ-specific metastatic traits arise in primary tumors remains unknown. Here, we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations toward a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.

PMID:
23993096
PMCID:
PMC3974915
DOI:
10.1016/j.cell.2013.07.036
[Indexed for MEDLINE]
Free PMC Article

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