Abstract / Summary
Abstract In western countries, secondary lymphedema often occurs after cancer treatments. However, lymphedema appears months, sometimes years after treatment suggesting that it is not only a side effect of surgery and may be promoted in part by cancer treatments. In this study, we demonstrate that the first line chemotherapeutic agent 5-Fluorouracil (5-FU) induces lymphatic system damage, thereby increasing the risk of developing lymphedema. We found that metformin, a complex I respiration inhibitor widely used for decades in the treatment of diabetes, protects lymphatic endothelial cells and counteracts the deleterious effects of chemotherapy. Notably, metformin restores the gene expression of key molecules involved in lymphatic system maintenance, including Gata2, Foxc2, and Sox18. In vivo, the vessel collapse induced by 5-FU is not observed in the presence of metformin. In a murine model of lymphedema, metformin reduces the limb volume increased by 5-FU treatment. This is accompanied by a marked reduction in lymph reflux into tissues, a reduced dermal thickening, and disorganized lymphatic proliferation. Mechanistically, metformin prevents lymphatic endothelial cells from mitochondrial superoxide accumulation by restoring maximal respiration, ATP production, and spare respiratory capacity impaired by 5-FU, while also reducing mitochondrial mass. We found that the anti-oxidative effect of metformin is dependent on GATA2 pathway. Altogether, our study suggests that metformin could offer a pharmacological approach for the management of cancer-related secondary lymphedema.