Selection of Bone Metastasis Seeds by Mesenchymal Signals in the Primary Tumor Stroma
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, dans le micro-environnement d'une tumeur primitive du sein triplement négative, des fibroblastes associés au cancer favorisent le développement de métastases osseuses
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.
"The primary tumor stroma can determine organ-specific metastatic tropism
"CAFs in breast tumors select for bone metastatic cells
"CAF-rich tumors mimic the CXCL12-rich microenvironment of the bone marrow
"CAF-derived CXCL12 and IGF1 select for high Src activity, a bone metastatic trait
Noncancerous mesenchymal cells in certain breast tumors can influence the direction of metastasis. The cells secrete growth factors that also abound in bone marrow, favoring accumulation of cancer cells that thrive on these factors both in the primary tumor microenvironment and in the bone marrow.
Cell , résumé, 2012