S1PR1/S1PR3-YAP signaling and S1P-ALOX15 signaling contribute to an aggressive behavior in obesity-lymphoma

J Exp Clin Cancer Res. 2023 Jan 5;42(1):3. doi: 10.1186/s13046-022-02589-7.

Abstract

Background: Excess body weight has been found to associate with an increased risk of lymphomas and some metabolic pathways are currently recognized in lymphomagenesis. Bioactive lipid metabolites such as sphingosine-1-phosphate (S1P) have been proposed to play an important role linking obesity and lymphomas. However, the underlying mechanism(s) of S1P signaling in obesity-lymphomagenesis have not been well addressed.

Methods: The gene expression of sphingosine kinase (SPHK), lymphoma prognosis, and S1P production were analyzed using Gene Expression Omnibus (GEO) and human lymphoma tissue array. Obesity-lymphoma mouse models and lymphoma cell lines were used to investigate the S1P/SPHK-YAP axis contributing to obesity-lymphomagenesis. By using the mouse models and a monocyte cell line, S1P-mediated polarization of macrophages in the tumor microenvironment were investigated.

Results: In human study, up-regulated S1P/SPHK1 was found in human lymphomas, while obesity negatively impacted progression-free survival and overall survival in lymphoma patients. In animal study, obesity-lymphoma mice showed an aggressive tumor growth pattern. Both in vivo and in vitro data suggested the existence of S1P-YAP axis in lymphoma cells, while the S1P-ALOX15 signaling mediated macrophage polarization towards TAMs exacerbated the lymphomagenesis. In addition, treatment with resveratrol in obesity-lymphoma mice showed profound effects of anti-lymphomagenesis, via down-regulating S1P-YAP axis and modulating polarization of macrophages.

Conclusion: S1P/S1PR initiated the feedback loops, whereby S1P-S1PR1/S1PR3-YAP signaling mediated lymphomagenesis contributing to tumor aggressive growth, while S1P-ALOX15 signaling mediated TAMs contributing to immunosuppressive microenvironment in obesity-lymphoma. S1P-targeted therapy could be potentially effective and immune-enhancive against obesity-lymphomagenesis.

Keywords: Free fatty acid; Lymphoma; Obesity; S1P/SPHK signaling; Tumor microenvironment.

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / metabolism
  • Arachidonate 15-Lipoxygenase
  • Disease Models, Animal
  • Humans
  • Mice
  • Neoplasms*
  • Obesity / complications
  • Obesity / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Signal Transduction*
  • Sphingosine-1-Phosphate Receptors / metabolism
  • Tumor Microenvironment

Substances

  • sphingosine 1-phosphate
  • Sphingosine-1-Phosphate Receptors
  • Phosphotransferases (Alcohol Group Acceptor)
  • S1PR1 protein, human
  • ALOX15 protein, human
  • Arachidonate 15-Lipoxygenase
  • Alox15 protein, mouse
  • Arachidonate 12-Lipoxygenase