Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway.

BACKGROUND: Elevated lactate results in an acidic tumor microenvironment (TME), which stimulates the progression of esophageal cancer (EC). Tumor-associated macrophages (TAMs) are an essential component of the TME. However, the regulatory mechanisms of lactate secreted by EC on TAMs and the effects of EC advancement are unclear. METHODS: Proteins and mRNA expression were determined by western blot and RT-qPCR. Cell metastasis and growth were assessed by scratch assay, transwell and BrdU assays. Lactate in cells was quantified using a lactate kit. A mouse model was constructed for validation in vivo. RESULTS: First, we determined that lactate upgraded the M2-type polarization marker levels of macrophages. Cell function assays confirmed that lactate-activated M2 macrophages accelerated EC cell migration and proliferation in vitro. However, the lactate inhibitor - oxamate hampered the level of lactate in TE-1 cells. Oxamate abolished the facilitation of macrophage polarization by lactate. In addition, we discovered that phosphorylated AKT and phosphorylated ERK was obviously raised in lactate-stimulated macrophages, and oxamate addition reversed this change, implying that AKT and ERK signaling pathways were involved in macrophage polarization. Response experiments proved that attenuation of AKT/ERK signaling markedly returned the lactate-induced promotion of EC migration and proliferation by macrophages. Finally, mouse tumor models demonstrated that lactate enhanced EC growth by inducing M2 macrophage polarization. CONCLUSION: EC-secreted lactate stimulated macrophage M2 polarization via the AKT/ERK pathway thereby boosting the growth of EC.

Long-term exposure to air pollution and lung function among children in China: Association and effect modification.

Background: Children are vulnerable to the respiratory effects of air pollution, and their lung function has been associated with long-term exposure to low air pollution level in developed countries. However, the impact of contemporary air pollution level in developing countries as a result of recent efforts to improve air quality on children's lung function is less understood. Methods: We obtained a cross-sectional sample of 617 schoolchildren living in three differently polluted areas in Anhui province, China. 2-year average concentrations of air pollutants at the year of spirometry and the previous year (2017-2018) obtained from district-level air monitoring stations were used to characterize long-term exposure. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and forced expiratory flow between 25 and 75% of FVC (FEF25-75) were determined under strict quality control. Multivariable regression was employed to evaluate the associations between air pollution level and lung function parameters, overall and by demographic characteristics, lifestyle, and vitamin D that was determined by liquid chromatography tandem mass spectrometry. Results: Mean concentration of fine particulate matter was 44.7 µg/m3, which is slightly above the interim target 1 standard of the World Health Organization. After adjusting for confounders, FVC, FEV1, and FEF25-75 showed inverse trends with increasing air pollution levels, with children in high exposure group exhibiting 87.9 [95% confidence interval (CI): 9.5, 166.4] mL decrement in FEV1 and 195.3 (95% CI: 30.5, 360.1) mL/s decrement in FEF25-75 compared with those in low exposure group. Additionally, the above negative associations were more pronounced among those who were younger, girls, not exposed to secondhand smoke, non-overweight, physically inactive, or vitamin D deficient. Conclusions: Our study suggests that long-term exposure to relatively high air pollution was associated with impaired lung function in children. More stringent pollution control measures and intervention strategies accounting for effect modification are needed for vulnerable populations in China and other developing countries.