Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cell. 2013 Aug 29;154(5):1060-1073. doi: 10.1016/j.cell.2013.07.036.
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.
原发肿瘤中器官特异性转移特性是如何产生的仍然未知。在这里，我们展示了乳腺肿瘤基质在选择已经为骨骼转移做好准备的癌症细胞方面的作用。三阴性（TN）乳腺癌中的肿瘤相关成纤维细胞（CAF）使异质性的癌细胞群体向依赖 CAF 衍生的因子 CXCL12 和 IGF1 生长的克隆优势倾斜。这些因子的限制浓度选择了具有高Src 活性的癌细胞，Src 活性是骨复发的已知临床预测因子，并且增强了 CXCL12 和 IGF1 对 PI3K-Akt 途径的激活。以这种方式选择的癌克隆在富含 CXCL12 的骨髓微环境中为转移做好了准备。该证据表明，类似于远处器官的基质信号选择了已经为该器官转移做好准备的癌细胞，从而阐明了原发肿瘤及其远处转移中转移特性的演变。
