Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor...

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Pathways

Background:

• The tumor immune microenvironment (TIME) significantly influences cancer progression.
• Macrophages differentiate into tumor-associated macrophages (TAMs) within the tumor microenvironment (TME), altering their metabolic functions.
• Sphingosine-1-phosphate (S1P) is a lipid metabolite involved in immune regulation, but its role in TAM differentiation and metabolism, and its source in the TME, remain unclear.

Purpose of the Study:

• To investigate the role of S1P in TAM differentiation and metabolic regulation.
• To identify the source of S1P within the TME.
• To elucidate the signaling pathway connecting tumor cells, hepatic stellate cells (HSCs), and macrophages.

Main Methods:

• Co-culture of hepatic stellate cells with tumor cells to observe macrophage differentiation.
• Analysis of S1P receptor 4 (S1PR4) and peroxisome proliferator-activated receptor α (PPARα) activation in macrophages.
• Investigation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and sphingosine kinase 1 (SphK1) pathway in HSCs.

Main Results:

• Co-culture of HSCs and tumor cells induced macrophage differentiation into M2-type TAMs.
• S1P activated PPARα via S1PR4 on macrophages, upregulating lipid metabolism and promoting M2 TAM differentiation.
• Tumor cells activated the Nrf2/SphK1 pathway in HSCs, increasing S1P production and secretion.

Conclusions:

• Tumor cells orchestrate a signaling cascade involving HSCs and macrophages to promote a pro-tumorigenic TIME.
• The Nrf2/SphK1 pathway in HSCs, stimulated by tumor cells, leads to S1P secretion.
• S1P acts on macrophages, activating S1PR4/PPARα, driving M2 TAM polarization and supporting tumor progression.