The Uptake of Metallic Nanoparticles in Breast Cancer Cell Lines is Modulated by the Hyaluronan-CD44 Axis

Radiation enhancement is a promising anticancer approach
based
on a local radiation dose increase due to the presence of metallic
nanoparticles (NPs) within cancer cells. Depending on their composition,
size, and cellular properties, NPs can follow multiple cellular pathways
and entry routes. We observed that gold, platinum, and TiO2 NPs are internalized at higher levels in mesenchymal cells compared
to epithelial cells in breast cancer models. A global survey of gene
expression between epithelial and mesenchymal cells exposed to 4 different
NP types revealed an involvement of membrane structure, and further
experiments confirmed that hyaluronic acid (HA) and its receptor CD44
are mediators of metallic NP uptake into cells. We extended our results
to a larger panel of breast cancer cell lines and again showed a preferential
uptake of all NPs tested in mesenchymal cells and relied on the HA/CD44
axis. These data provide considerations for the design of NP-based
therapies targeting mesenchymal cancer cells, which are often resistant
to treatment and correlate with poor prognosis and tumor recurrence.