Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway
Abstract 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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-08-01
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| Series: | Thoracic Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/1759-7714.14998 |
| Summary: | Abstract 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. |
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| ISSN: | 1759-7706 1759-7714 |