1. International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan;
2. International Center for Young Scientist (ICYS), National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan;
3. Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan;
4. Graduate School of Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan.
Objective: We propose here material-induced senescence (MIS) as a new therapeutic concept that limits cancer progression by stable cell cycle arrest. This study examined for the first time the effect of material fluidity on cellular senescence in lung carcinoma using poly(ε-caprolactone-co-D, L-lactide) (P(CL-co-DLLA)) with tunable elasticity and fluidity.
Methods: The fluidity was varied by chemically crosslinking the polymer networks: the crosslinked P(CL-co-DLLA) shows solid-like properties with a stiffness of 260 kPa, while the non-crosslinked polymer exists in a quasi-liquid state with loss and storage moduli of 33 kPa and 11 kPa, respectively.
Results: We found that cancer cells growing on the non-crosslinked, fluidic substrate undergo a non-apoptotic form of cell death and the cell cycle was accumulated in a G0/G1 phase. Next, we investigated the expression of biomarkers that are associated with cancer pathways. The cancer cells on the fluidic substrate expressed several biomarkers associated with senescence such as insulin-like growth factor binding protein 5 (IGFBP5). This result indicates that when cancer cells sense fluidity in their surroundings, the cells express IGFBP5, which in turn triggers the expression of tumor suppressor protein 53 and initiates cell cycle arrest at the G1 phase followed by cellular senescence. Furthermore, the cancer cells on the fluidic substrate maintained their epithelial phenotype, suggesting that the cancer cells do not undergo epithelial to mesenchymal transition.
Conclusion: By considering these results as the fundamental information for MIS, our system could be applied to induce senescence in treatment-resistant cancers such as metastatic cancer or cancer stem cells.
Keywords: fluidity, p(ε-caprolactone), senescence, insulin-like growth factor binding protein 5, tumor suppressor protein 53.