Open AccessSelection of Bone Metastasis Seeds by Mesenchymal Signals in the Primary Tumor Stroma
Author(s) -
Xiang H.-F. Zhang,
Xin Jin,
Srinivas Malladi,
Yilong Zou,
Yong Hannah Wen,
Edi Brogi,
Marcel Smid,
John A. Foekens,
Joan Massagué
Publication year - 2013
Publication title -
cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 26.304
H-Index - 776
eISSN - 1097-4172
pISSN - 0092-8674
DOI - 10.1016/j.cell.2013.07.036
Subject(s) - biology , metastasis , stromal cell , cancer research , stroma , primary tumor , cancer , tumor microenvironment , bone marrow , breast cancer , cancer cell , cancer associated fibroblasts , bone metastasis , pathology , immunology , tumor cells , genetics , medicine , immunohistochemistry
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.
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