Tumor-initiating cells (
TICs) existing in
breast cancer are thought to be involved in initiation, progression, and relapse of
tumors. In these processes, the epithelial-to-mesenchymal transition (EMT) and
proteases are crucial factors that also dependent on the
tumor milieu, including hypoxic nutrient-deprived, as well as normoxic nutrient-rich, environments. Therefore, we investigated EMT and
proteases in
TICs and their response to different environments by means of a newly generated immortalized
TIC (iTIC) line. With the use of primary CD24+CD90+CD45-
TICs from the mouse mammary tumor virus-polyoma middle T mouse
breast cancer model, iTICs were generated by single cell-initiated sphere and subsequent 2-dimensional monolayer culture. Our data demonstrate the possibility to generate iTICs that are highly tumorigenic in culture and in mouse mammary fat pad. Contrasting environmental conditions provide these cells with a phenotypic and molecular plasticity that has a growth-promoting character in nutrient-rich normoxia and a motile character in nutrient-deprived
hypoxia. Expression profiling revealed partial and dynamically changing EMT states, as well as a significantly up-regulated proteolytic signature, including many
metalloproteinases, such as
matrix metalloproteinase 14 ( Mmp14). Inhibitor treatment of
metalloproteinases, as well as
short hairpin RNA-mediated knockdown of Mmp14 strongly impacted
TIC characteristics, including
tumor initiation, cell growth, migration, and invasion, especially in starved environments. We conclude that
metalloproteinases empower
TICs to adapt to changing environments.-Hillebrand, L. E., Wickberg, S. M., Gomez-Auli, A., Follo, M., Maurer, J., Busch, H., Boerries, M., Reinheckel, T. MMP14 empowers
tumor-initiating
breast cancer cells under hypoxic nutrient-depleted conditions.