c-Myb Inhibits Opening of Lung Endothelium by Breast Tumor Cells Thereby Dictates Metastasis Pattern

Metastasis is a multistep process that involves dissemination of tumor cells to distant sites in body and adaptation to foreign tissue microenvironments. Following transport within the vasculature, tumor cells arrest to the endothelium and then assisted by blood cells transmigrate into the surrounding tissue. The escape from circulation (extravasation) is one of the rate-limiting steps in metastasis cascade and its probability is determined both by intrinsic characteristics of tumor cell and by specific features of endothelium in secondary tissue. We identified transcription factor c-Myb as a critical player controlling the extravasation capacity of breast tumor cells. By means of Ccl2 suppression c-Myb prevents monocyte-assisted transmigration of tumor cells across lung endothelium without compromising the passage across liver endothelial cells. c-Myb-induced block in transendothelial migration is dependent on endothelial Ccl2-Ccr2 signaling that has tissue-specific features. This unique extravasation guiding force of c-Myb is projected in the absence of lung foci in orthotopic mouse model and in the site-specific relapse free survival of breast carcinoma patients. In conclusion, c-Myb is a clinically relevant regulator of the metastatic spread of breast carcinomas.

This work was funded by grant NT 13441-4/2012 of the Internal Grant Agency of Ministry of Health of the Czech Republic, by the European Regional Development Fund Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123), and by grant SCOPES/SNF (IZ73Z0-152361).