Abstract
Understanding the survival mechanism of metastatic cancer cells in circulation will provide new perspectives on metastasis prevention and also shed new light on metastasis-derived drug resistance. In this study, we made it feasible to detect apoptosis of circulating tumor cells (CTCs) in real-time by integrating a fluorescence resonance energy transfer (FRET)-based caspase sensor into one in vitro microfluidic circulatory system, and two in vivo models: zebrafish circulation and mouse lung metastatic model. Our study demonstrated that fluid shear stresses triggered apoptosis of breast cancer cells in circulation by elevating the mitochondrial production of the primary free radical, superoxide anion. Cancer cells with high levels of manganese superoxide dismutase (MnSOD) exhibited stronger resistance to shear force-induced apoptosis and formed more lung metastases in mice. These metastasized cells further displayed higher resistance to chemotherapeutic agent doxorubicin, which also generates superoxide in mitochondria. Specific siRNA-mediated MnSOD knockdown reversed all three phenotypes. Our findings therefore suggest that MnSOD plays an important integrative role in supporting cancer cell survival in circulation, metastasis, and doxorubicin resistance. MnSOD can serve as a new biomarker for identifying metastatic CTCs and a novel therapeutic target for inhibiting metastasis and destroying doxorubicin-resistant breast cancer cells.
Highlights
Most cancer patients, especially breast cancer patients, die of metastasis because metastatic tumors are difficult to remove surgically and often develop resistance to conventional chemotherapy [1]
Once tumor cells enter the bloodstream, most of them are eliminated in the circulation through several mechanisms: 1) anoikis due to the detachment of cancer cells from the extracellular matrix and the disruption of cytoskeleton, which lead to cell rounding [2]; 2) immune system-mediated destruction, which is executed by natural killer cells [3]; and 3) hemodynamic shear stress (SS), which is mainly generated from the blood flow and from collisions between circulating tumor cells (CTCs), blood cells, and endothelial cells lining the vessel wall
High levels of manganese superoxide dismutase (MnSOD) increase metastatic potential of breast cancer cells we examined whether high levels of MnSOD can increase the metastatic capacity of breast cancer cells by establishing three generations of 231-C3 cells (Figure 7A). 231-M1 cells were isolated from lung micrometastases on the 45 days after 231-C3 cells were injected into the tail vein of nude mice (Figure 1E)
Summary
Especially breast cancer patients, die of metastasis because metastatic tumors are difficult to remove surgically and often develop resistance to conventional chemotherapy [1]. Once tumor cells enter the bloodstream, most of them are eliminated in the circulation through several mechanisms: 1) anoikis due to the detachment of cancer cells from the extracellular matrix and the disruption of cytoskeleton, which lead to cell rounding [2]; 2) immune system-mediated destruction, which is executed by natural killer cells [3]; and 3) hemodynamic shear stress (SS), which is mainly generated from the blood flow and from collisions between CTCs, blood cells, and endothelial cells lining the vessel wall. Understanding these issues will www.impactjournals.com/oncotarget provide new insights on how CTCs survive SS to establish distant metastatic colonies
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