Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

Abstract

Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications.

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

“…Relative to differentiated tumor cells, drug-packaging T-MPs are more partial to attacking stem-like TRCs as they are softer than differentiated tumor cells and easier to deform when taking up T-MPs. 17 These TRCs were generated by the previously reported soft 3D fibrin gel method. 5 About 1,250 tumor cells were mixed with 125 mL fibrinogen solution (2 mg/mL fibrinogen, activated by 0.5 units of thrombin) and seeded on 24-well plate.…”

“…14 Such specialized subcellular vesicles with 0.1-1 mm sizes are called microparticles (MPs). Recently, we have demonstrated that tumor cell-derived MPs (T-MPs) are capable of delivering chemotherapeutic drugs or oncolytic adenoviruses to nuclei of TRCs and disrupting them through a lysosomemediated pathway, [15][16][17][18][19] suggesting that drug-packaging MPs might be a potential means to improve antitumor immunity by abrogating TRCs. However, whether such drug-packaging MP-based approach of targeting TRCs can be strengthened by other means is not clear.…”

Killing me softly: microparticles target deformable cells

“…The findings by Ma and colleagues [10] open the door to a new potential therapeutic approach that takes advantage of the mechanical changes that accompany carcinogenesis. Whether solid tumors can be targeted in this manner by intravenous injection of MPs in human patients, and which types of cancers are susceptible, are important questions for further study.…”

“…In this manner, the death of cancer cells that ingest MPs, perhaps proximal to tumor vasculature that is sufficiently leaky, could spread to others not initially reached by intravenous delivery. Like a domino, the first cell to fall could trigger a therapeutic chain reaction that eliminates cancer (Figure 1) potentially due to effects on drug transporter expression or nuclear entry [10]. Whether the cellular origin, lipid content, or otherwise specific composition of MPs is important for their cytotoxic effects will be interesting to examine in future studies.…”

“…Alternatively, it may be possible to identify therapeutic approaches that take advantage of the differences in tension between cancer and normal cells. In a recent paper in Cell Research, Ma et al [10] report a potential therapeutic strategy that does just that: it exploits the lowered tension of cancer cells and TRCs.…”