Macrophage deficiency discordantly regulated tumor growth and metastasis through increased thrombospondin-1 production.

[OBJECTIVE] Metadherin (MTDH) is a recognized oncogene involved in the progression and metastasis of various cancers. However, further studies are needed to elucidate the biological role of MTDH, which is expressed in macrophages during tumor progression.

[METHODS] Mouse colorectal cancer and melanoma cells were subcutaneously and intravenously injected into myeloid-specific knockout mice to evaluate tumor growth and lung metastases. The effects of macrophage with knockout on angiogenesis and fibrosis were examined using mass spectrometry, immunofluorescence staining, analyses of data from The Cancer Genome Atlas (TCGA) colon adenocarcinoma and melanoma cohorts, and western blotting. A thrombospondin (TSP-1) blocking peptide was used to inhibit transforming growth factor β1 (TGF-β1) activation for suppression of fibrosis in vivo and in vitro. The molecular mechanisms were investigated using RNA sequencing data from the Gene Expression Omnibus database, ELISA, immunoprecipitation, chromatin immunoprecipitation assay, quantitative real-time PCR, and western blotting.

[RESULTS] -deficient macrophages suppressed lung metastasis but, unexpectedly, promoted subcutaneous tumor growth of both cancer cell types. This discordant effect was attributed to increased production of TSP-1, an angiogenesis inhibitor that also regulates fibrosis through TGF-β1 activation. knockout in macrophages inhibited angiogenesis in both lung metastatic and subcutaneous tumors, whereas enhanced fibrosis was observed only in subcutaneous tumors. In TCGA colon adenocarcinoma data, higher TSP-1 expression correlated with advanced pathological T stage and cancer-associated fibroblasts abundance. Furthermore, loss in macrophages induced activation of latent TGF-β1 in tumor cells, promoting fibroblast-to-myofibroblast transition, fibrosis, and unexpected tumor growth through the TSP-1/TGF-β1 axis. Mechanistically, MTDH deficiency led to nuclear retention of murine double minute-2 (MDM2), disruption of the MDM2-p53 interaction, and enhanced p53-dependent TSP-1 transcription.

[CONCLUSIONS] We found that macrophage deficiency discordantly regulates tumor metastasis and growth through either TSP-1-mediated anti-angiogenic effect or a TSP-1/TGF-β1-mediated pro-fibrotic effect. This study, therefore, provides novel insights into the mechanisms underlying the discordance between tumor growth and metastasis.