Selective inhibition of partial EMT-induced tumour cell growth by cerium valence states of extracellular ceria nanoparticles for anticancer treatment

Targeting specific tumour cells and their microenvironments is essential for enhancing the efficacy of chemotherapy and reducing its side effects. A partial epithelial-to-mesenchymal transition state (pEMT, with a hybrid epithelial/mesenchymal phenotype) in tumour cells is an attractive targeting for anticancer treatment because it potentially provides maximal stemness and metastasis relevant to malignant cancer stem cell-like features. However, treatment strategies to target pEMT in tumour cells remain a challenge. This study demonstrates that extracellular cerium oxide nanoparticles (CNPs) selectively inhibit the growth of pEMT-induced tumour cells, without affecting full epithelial tumour cells. Herein, highly concentrated Ce3+ and Ce4+ ions are formed on CNP-layered poly-L-lactic acid surfaces. Cell cultures of pEMT-induced and uninduced lung cancer cell lines on the CNP-layered substrates allow the effect of extracellular CNPs on tumour cell growth to be investigated. The extracellular CNPs with dominant Ce3+ and Ce4+ ions were able to trap pEMT-induced tumour cells in a growth-arrested quiescent/dormant or cytostatic state without generating redox-related reactive oxygen species (ROS), i.e. non-redox mechanisms. The dominant Ce3+ state provided highly efficient growth inhibition of the pEMT-induced tumour cells. In contrast, the dominant Ce4+ state showed highly selective and appropriate growth regulation of normal and tumour cells, including a mesenchymal phenotype. Furthermore, Ce4+-CNPs readily adsorbed serum-derived fibronectin and laminin. Cerium valence-specific proteins adsorbed on CNPs may influence receptor-mediated cell-CNP interactions, leading to tumour cell growth inhibition. These findings provide new perspectives for pEMT-targeting anticancer treatments based on the unique biointerface of extracellular CNPs with different Ce valence states.