Abstract
Recent evidence indicates that immune cells contribute to the formation of tumor metastases by regulating the pre-metastatic niche. Whether tumor-derived factors involved in primary tumor formation play a role in metastasis formation is poorly characterized. Oxysterols act as endogenous regulators of lipid metabolism through the interaction with the nuclear Liver X Receptors-(LXR)α and LXRβ. In the context of tumor development, they establish a pro-tumor environment by dampening antitumor immune responses, and by recruiting pro-angiogenic and immunosuppressive neutrophils. However, the ability of LXR/oxysterol axis to promote tumor invasion and metastasis by exploiting immune cells, is still up to debate. In this study we provide evidence that oxysterols participate in the primary growth of orthotopically implanted 4T1 breast tumors by establishing a tumor-promoting microenvironment. Furthermore, we show that oxysterols are involved in the metastatic spread of 4T1 breast tumors, since their enzymatic inactivation mediated by the sulfotransferase 2B1b, reduces the number of metastatic cells in the lungs of tumor-bearing mice. Finally, we provide evidence that oxysterols support the metastatic cascade by modifying the lung metastatic niche, particularly allowing the recruitment of tumor-promoting neutrophils. These results identify a possible new metastatic pathway to target in order to prevent metastasis formation in breast cancer patients.
Highlights
The role exerted by inflammation in promoting tumor cell formation as well as the mechanisms of immune escape favoring tumor growth have recently been considered as pillars of cancer hallmarks [1]
We have investigated the contribution of the Liver X Receptors (LXRs)/oxysterol axis to the formation of primary and metastatic breast tumors
In line with our previous results [19, 25], the injection of 4T1 breast tumor cells, genetically engineered to express SULT2B1b, resulted in tumor growth delay and prolonged overall survival (Figures 1E–G), indicating that oxysterols contribute to the establishment of primary 4T1 breast tumors by impinging on antitumor immune responses, as demonstrated by experiments carried out in immunodeficient mice (Figure 1H)
Summary
The role exerted by inflammation in promoting tumor cell formation (neoplastic transformation) as well as the mechanisms of immune escape favoring tumor growth have recently been considered as pillars of cancer hallmarks [1]. Emphasis has recently been given to metabolic pathways altered in cancer cells, which may condition tumor-infiltrating immune cells. On the other hand, defined metabolic pathways specific for immune cell subsets have been identified. Metabolites produced by cancer cells may hamper the antitumor immune response by affecting distinct tumor-infiltrating. Oxysterols and Neutrophil-Mediated Tumor Metastases immune cells [2]. Among these factors cholesterol metabolites, namely oxysterols, help tumor progression by promoting immunosuppressive networks or angiogenesis. Oxysterols were identified as ligands of the nuclear Liver X Receptors (LXRs) [7]
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