MMP-9 secreted by tumor associated macrophages promoted gastric cancer metastasis through a PI3K/AKT/Snail pathway

Purpose: The distant metastasis in gastric has become an obstacle for treatment in clinic. However, the underlying mechanism is not well illustrated. Here, our aim is to reveal the mechanism and try to explore the potential strategy to overcome the distant metastasis.

Materials and methods: IHC was used to detect the expressions of target proteins. H&E staining was used to evaluate the lung metastasis. Using qRT-PCR and ELISA, we detected the expression of target genes and secreted proteins. Western bolt was used to examine the target proteins expression. Wound healing and transwell assay were used to examine the ability of cell to invasion and migration. Using IF, PI3K/Akt/Snail was examined. Animal models were applied to evaluate the killing efficiency in vivo.

Results: Here, we observed accumulated CD68 (a marker of TAMs) in samples from gastric Cancer patients with metastasis compared with that in samples from non-metastasis patients. And the expression of CD68 was negatively correlated with patients' survival time. Then, we found that TAMs enhanced the ability of Cancer cells to migration and invasion in vitro and in vivo. Further, we revealed that the distant metastasis was induced by TAMs through secreting MMP-9, which induced epithelial to mesenchymal transition (EMT) process through the transcription factor Snail. Further, applying proenzyme inhibitor of MMP-9 significantly enhanced the killing efficiency of chemotherapeutic drugs and reduced the lung metastasis.

Conclusion: Our data showed that TAMs facilitate the EMT process via an MMP-9/PI3K/Akt/Snail dependent pathway, while blocking this signaling pathway with MMP-9 proenzyme inhibitor could suppress distant metastasis in gastric Cancer.